Need brain rejuvenation? Time to take a skin cell sample and use it to make brain stem cells The brain stem cells have both research and therapeutic potential.
SAN FRANCISCO, CA—June 7, 2012—Scientists at the Gladstone Institutes have for the first time transformed skin cells—with a single genetic factor—into cells that develop on their own into an interconnected, functional network of brain cells. The research offers new hope in the fight against many neurological conditions because scientists expect that such a transformation—or reprogramming—of cells may lead to better models for testing drugs for devastating neurodegenerative conditions such as Alzheimer's disease.
These scientists see an advantage in their technique because they do not convert the skin cells all the way into general purpose pluripotent stem cells. The fear with pluripotent stem cells is that they might go rogue in the body and act like cancer. Pluripotent stem cells simply have too much potential and can convert into too many other cell types.
In findings appearing online today in Cell Stem Cell, researchers in the laboratory of Gladstone Investigator Yadong Huang, MD, PhD, describe how they transferred a single gene called Sox2 into both mouse and human skin cells. Within days the skin cells transformed into early-stage brain stem cells, also called induced neural stem cells (iNSCs). These iNSCs began to self-renew, soon maturing into neurons capable of transmitting electrical signals. Within a month, the neurons had developed into neural networks.
The transformation of cells into assorted specialized stem cell types will become less risky once scientists develop technology to cheaply screen out cells that have too many dangerous mutations in them. We need stem cells with good genetic state (no risky mutations or mutations that reduce functionality), good epigenetic state (they should be solidly in a desired state rather than a mix of states), and youthful (long telomere chromosome caps).
Some MIT Whitehead researchers have found thru subtle changes in methods for creating stem cells from adult cells that embryonic-like stem cells can be produced much more reliably.
FINDINGS: Tweaking the levels of factors used during the reprogramming of adult cells into induced pluriopotent stem (iPS) cells can greatly affect the quality of the resulting iPS cells, according to Whitehead Institute researchers. This finding explains at least in part the wide variation in quality and fidelity of iPS cells created through different reprogramming methods.
RELEVANCE: Like embryonic stem cells, iPS cells can become any cell type in the body, a characteristic that could make them well-suited for therapeutic cell transplantation or for creating cell lines to study such diseases as Parkinson's and Alzheimer's. Inconsistencies in iPS cell quality reported in a number of recent studies have tarnished their promise, dampened enthusiasm, and fueled speculation that they may never be used therapeutically.
Mixed results in producing iPS cells led to disappointment and doubt. But small changes resulted in much higher quality outcomes.
To Bryce Carey, first author of the Cell Stem Cell paper and a graduate student in Jaenisch's lab at the time, this death knell seemed premature. He repeated the experiment, changing a few details, including the order in which the reprogramming factors were placed on the inserted piece of DNA. Surprisingly, such small alterations had a profound effect—more adult cells were converted to high-quality iPS cells than in the earlier, nearly identical study.
"We are trying to show that the reprogramming process is not as flawed as some have thought, and that you can isolate these fully pluripotent iPS cells that have all of the developmental potential as embryonic stem cells at a pretty high frequency," says Carey, who is now a postdoctoral associate at Rockefeller University. "A lot of times these parameters are very difficult to control, so while the approach first described by [Shinya] Yamanaka back in 2006 is still the most reliable method for research purposes, we should be cautious in concluding there are inherent limitations. We show recovery of high-quality cells doesn't have to be the exception."
I think this points to a larger problem for scientists attempting to coax cells into states where they will do repairs and to grow into replacement organs. The problem is that cells are extremely sensitive to small differences. My worry here is that the use of stem cells to do repairs on the body may progress very slowly due to the size of the solution space that must be searched to find good solutions. Researchers need to search over wide ranges of variations in sequences of conditions along multiple dimensions in order to find just the right sequence if biochemical manipulations to get cells to do some desired repair.
How hard will it turn out to be to coax cells to, for example, coax cells to become kidney podocytes and then to very precisely fix the glomerulus filtering area in sick kidneys? It is difficult to know at this point how hard it will be to orchestra tissue repair with stem cells or how hard it will be to do tissue engineering to grow replacements for most organs. Do we have another decade to wait for a big surge in usable stem cell therapies? Or even two decades? Hard to tell from where I sit.
Myelin is insulation around nerves and is essential for the conduction of impulses along nerves. The ability to grow pure populations of cells that make myelin brings us closer to effective treatments for multiple sclerosis and other diseases characterized by the loss of myelin.
Scientists at Case Western Reserve University School of Medicine found a way to rapidly produce pure populations of cells that grow into the protective myelin coating on nerves in mice. Their process opens a door to research and potential treatments for multiple sclerosis, cerebral palsy and other demyelinating diseases afflicting millions of people worldwide.
The findings will be published in the online issue of Nature Methods, Sunday, Sept. 25, at 1 p.m. EST.
"The mouse cells that we utilized, which are pluripotent epiblast stem cells, can make any cell type in body," Paul Tesar, an assistant professor of genetics at Case Western Reserve and senior author of the study, explained. "So our goal was to devise precise methods to specifically turn them into pure populations of myelinating cells, called oligodendrocyte progenitor cells, or OPCs."
These results matter to us all. Why? We all suffer from a demyelinating disease called aging. One of the reason older folks have harder times with memory recall, coordination, and other mental tasks is that myelin deteriorates with age. The ability to restore myelin is an essential rejuvenation therapy. Therefore the pursuit of effective treatments for MS and other demyelinating diseases will yield useful therapies for brain rejuvenation.
Just about any therapy aimed at repairing damage caused by a specific disease will also be useful for rejuvenation. Aging causes very diffuse damage to all the tissues in the body. When enough of that damage accumulates in a single organ or structural element disease emanating from a specific location emerges. But the localized disease is really just part of a bigger pattern of damage accumulation. So therapies aimed at repair of specific locations in the body will have a great deal of overlap with therapies aimed at full body rejuvenation.
Prof. Oron, who has long used low level lasers to stimulate stem cells to encourage cell survival and the formation of blood vessels after a heart attack, was inspired to test how laser treatments could also work to heal the heart. He and his fellow researchers tried different methods, including treating the heart directly with low level lasers during surgery, and "shining" harvested stem cells before injecting them back into the body.
But he was determined to find a simpler method. After a low-level laser was "shined" into a person's bone marrow — an area rich in stem cells — the stem cells took to the blood stream, moving through the body and responding to the heart's signals of distress and harm, Prof. Oron discovered. Once in the heart, the stem cells used their healing qualities to reduce scarring and stimulate the growth of new arteries, leading to a healthier blood flow.
To determine the success of this method, Prof. Oron performed the therapy on an animal model. Following the flow of bone marrow stem cells through the use of a fluorescent marker, the researchers saw an increase in stem cell population within the heart, specifically in the injured regions of the heart. The test group that received the shining treatment showed a vastly higher concentration of cells in the injured organ than those who had not been treated with the lasers.
This leads to the important question: What mythology maps well to the summoning of stem cells using lasers? I don't see a fit for Lord Of The Rings. Do you? Which mythology summons legions of good soldiers using a light wand?
Professor Oron says his technique is ready for clinical trials...
CHICAGO -- New research published online today in Circulation Research found that injections of adult patients' own CD34+ stem cells reduced reports of angina episodes and improved exercise tolerance time in patients with chronic, severe refractory angina (severe chest discomfort that did not respond to other therapeutic options).
The phase II prospective, double-blind, randomized, controlled clinical trial was conducted at 26 centers in the United States, and is part of a long-term collaboration between researchers at Northwestern University Feinberg School of Medicine and Baxter International Inc. The objective of the trial was to determine whether delivery of autologous (meaning one's own) CD34+ stem cells directly into multiple targeted sites in the heart might reduce the frequency of angina episodes in patients suffering from chronic severe refractory angina, under the hypothesis that CD34+ stem cells may be involved in the creation of new blood vessels and increase tissue perfusion.
CD34+ cells are thought to be involved in capillary formation. Angina is caused by poor circulation of oxygen and nutrients to the heart.
By a few measures the treated groups did better.
At six months after treatment, patients in the low-dose treatment group reported significantly fewer episodes of angina than patients in the control group (6.8 vs. 10.9 episodes per week), and maintained lower episodes at one year after treatment (6.3 vs. 11 episodes per week). Additionally, the low-dose treatment group was able to exercise (on a treadmill) significantly longer at six months after treatment, as compared with those in the control group (139 seconds vs. 69 seconds, on average). Angina episodes and exercise tolerance rates were also improved in the high-dose treated group at six months and at one year post treatment compared to the control group.
Just growing up one's own stem cells outside of the body to be injected into disease sites can stimulate body repair. This seems like a rather blunt instrument approach even though it works. Treatments that involve creating local chemical signals to bring stem cells and other cells to a site to do repair will also some day accomplish the same outcome without the need for growing cells outside the body. But if stem cell therapies are easy to get going now then it makes sense to work on them first.
Some U Penn researchers injected RNA from heart cells into astrocytes and fibroblasts and in each case the cells converted into the cell type that the RNA came from.
PHILADELPHIA - For the past decade, researchers have tried to reprogram the identity of all kinds of cell types. Heart cells are one of the most sought-after cells in regenerative medicine because researchers anticipate that they may help to repair injured hearts by replacing lost tissue. Now, researchers at the Perelman School of Medicine at the University of Pennsylvania are the first to demonstrate the direct conversion of a non-heart cell type into a heart cell by RNA transfer. Working on the idea that the signature of a cell is defined by molecules called messenger RNAs (mRNAs), which contain the chemical blueprint for how to make a protein, the investigators changed two different cell types, an astrocyte (a star-shaped brain cell) and a fibroblast (a skin cell), into a heart cell, using mRNAs.
James Eberwine, PhD, the Elmer Holmes Bobst Professor of Pharmacology, Tae Kyung Kim, PhD, post-doctoral fellow, and colleagues report their findings online this week in the Proceedings of the National Academy of Sciences. This approach offers the possibility for cell-based therapy for cardiovascular diseases.
Note that the starting cell types were not stem cells. Neither adult or embryonic stem cells were needed as a starting point. This opens up a much longer list of sources of cells to make cell therapies. Continued refinements of techniques to convert cells into other cell types will lead to cell therapies for a great many diseases. Got a bad joint or muscle? Cell therapies are the ticket.
This opens up the possibility of converting just about any cell type to any other cell type.
"What's new about this approach for heart-cell generation is that we directly converted one cell type to another using RNA, without an intermediate step," explains Eberwine. The scientists put an excess of heart cell mRNAs into either astrocytes or fibroblasts using lipid-mediated transfection, and the host cell does the rest. These RNA populations (through translation or by modulation of the expression of other RNAs) direct DNA in the host nucleus to change the cell's RNA populations to that of the destination cell type (heart cell, or tCardiomyocyte), which in turn changes the phenotype of the host cell into the destination cell.
I see potential downsides: If the RNA is from the same person who needs, say, a heart cell therapy it is possible that an undesirable expression pattern of RNA in that person's diseased heart could be replicated in the converted cells. So can one use RNA from a different person's cells to cause the conversion?
Transcriptome Induced Phenotype Remodeling, or TIPeR:
The method the group used, called Transcriptome Induced Phenotype Remodeling, or TIPeR, is distinct from the induced pluripotent stem cell (iPS) approach used by many labs in that host cells do not have to be dedifferentiated to a pluripotent state and then redifferentiated with growth factors to the destination cell type. TIPeR is more similar to prior nuclear transfer work in which the nucleus of one cell is transferred into another cell where upon the transferred nucleus then directs the cell to change its phenotype based upon the RNAs that are made. The tCardiomyocyte work follows directly from earlier work from the Eberwine lab, where neurons were converted into tAstrocytes using the TIPeR process.
There are still more hurdles to making a useful cell therapy. How thorough and complete is the change in cell type? Is there a need to carefully select starting cells to screen out mutations? Does old age of the starter cells make the new cells less able to replicate and function in a heart or other organ?
My guess is that the need to screen the starter cells to identify cells that are not aged is going to be a key problem to solve to make the most effective therapies for older people.
Cutting weeks off the process Scripps scientists have found a faster way to convert adult skin cells into heart cells.
LA JOLLA, CA – Scripps Research Institute scientists have converted adult skin cells directly into beating heart cells efficiently without having to first go through the laborious process of generating embryonic-like stem cells. The powerful general technology platform could lead to new treatments for a range of diseases and injuries involving cell loss or damage, such as heart disease, Parkinson's, and Alzheimer's disease.
The work was published January 30, 2011, in an advance, online issue of Nature Cell Biology.
"This work represents a new paradigm in stem cell reprogramming," said Scripps Research Associate Professor Sheng Ding, Ph.D., who led the study. "We hope it helps overcome major safety and other technical hurdles currently associated with some types of stem cell therapies."
Think of a cell as a really complex state machine that is hard to manipulate. A large fraction of the challenge of producing cell therapies for our bodies amounts to finding ways to easily shift cells into desired states. Need heart muscle cells? That means you need a way to tell other cells to become heart muscle cells. You'll also need ways to get these cells to arrange themselves 3 dimensionally at the right locations to augment diseased failing heart cells. Tissue engineering techniques are needed to create those 3 dimensional arrangements are needed both in the body (to guide cells to repair existing organs) and outside of the body (to grow up new organs for transplant).
These researchers pulsed the cells with implanted genes for a much shorter period of time than previous techniques have used.
The team introduced the same four genes initially used to make iPS cells into adult skin fibroblast cells, but instead of letting the genes be continuously active in cells for several weeks, they switched off their activities just after a few days, long before the cells had turned into iPS cells. Once the four genes were switched off, the scientists gave a signal to the cells to make them turn into heart cells.
"In 11 days, we went from skin cells to beating heart cells in a dish," said Ding. "It was phenomenal to see."
I wonder about the effects of the short time scale. One problem with quickly turning an adult cell type into another adult cell type is that the some of the state information of the original cell type might linger. Methylation patterns that govern gene expression probably haven't all gotten updated into the new cell type (their epigenetic state has memory of the previous cell type) in such a short period of time. I suspect we need many more and better techniques for changing cell state that do so more thoroughly.
The science (or biotechnology) for creating induced pluripotent stem cells (iPS cells above) is moving along with better techniques every year. Back in August 2006 Shinya Yamanaka at Kyoto University in Japan first showed that the 4 genes Oct3/4, Sox2, c-Myc, and Klf4 could be used to induce pluripotency in adult cells. Basically, these genes caused cells to turn back into a more embryonic-like state. There is risk of producing cancerous cells from these attempts. But safer and safer ways to induce pluripotency keep getting published.
There's an overlap between cancer research and stem cell research because they both involve cell state and control of cell growth. Stem cell researchers need to avoid producing cancerous cells. Cancer researchers need to either kill cancer cells or tell them to shift into states which where they will stop growing or even kill themselves.
PHILADELPHIA – Men with type 1 diabetes may be able to grow their own insulin-producing cells from their testicular tissue, say Georgetown University Medical Center (GUMC) researchers who presented their findings today at the American Society of Cell Biology 50th annual meeting in Philadelphia.
Their laboratory and animal study is a proof of principle that human spermatogonial stem cells (SSCs) extracted from testicular tissue can morph into insulin-secreting beta islet cells normally found in the pancreas. And the researchers say they accomplished this feat without use of any of the extra genes now employed in most labs to turn adult stem cells into a tissue of choice.
Extract these stem cells and grow them outside their normal environment and they become stem cells capable of forming all cell types. So in theory these cells could be used to many different types of organs and stem cell therapies.
Because SSCs already have the genes necessary to become embryonic stem cells, it is not necessary to add any new genes to coax them to morph into these progenitor cells, Gallicano says. "These are male germ cells as well as adult stem cells."
"We found that once you take these cells out of the testes niche, they get confused, and will form all three germ layers within several weeks," he says. "These are true, pluripotent stem cells."
Okay guys, so we got that going for us. Be careful with the future source of cells for your replacement organs. The cool part of this approach to creating pluripotent stem cells is it avoids immune incompatibility that could come with embryonic stem cell lines. When we get older we are going to need replacement parts grown to replace the old failing parts. This report might be the ticket for how to get the starter cells for growing replacement parts.
LOS ANGELES –Researchers at the Cedars-Sinai Heart Institute have found in animals that infusing cardiac-derived stem cells with micro-size particles of iron and then using a magnet to guide those stem cells to the area of the heart damaged in a heart attack boosts the heart's retention of those cells and could increase the therapeutic benefit of stem cell therapy for heart disease.
The study is published today online by Circulation Research, a scientific journal of the American Heart Association. The study also will appear in the journal's May 28th printed edition.
"Stem cell therapies show great promise as a treatment for heart injuries, but 24 hours after infusion, we found that less than 10 percent of the stem cells remain in the injured area," said Eduardo Marbán, M.D., director of the Cedars-Sinai Heart Institute. "Once injected into a patient's artery, many stem cells are lost due to the combination of tissue blood flow, which can wash out stem cells, and cardiac contraction, which can squeeze out stem cells. We needed to find a way to guide more of the cells directly to the area of the heart that we want to heal."
It isn't enough to be able to grow up the desired type of stem cells in sufficient quantity. The stem cells still need to go to wherever they are most needed. Once the cells are where tissue needs replacement the stem cells still must integrate themselves into existing tissue properly in 3 dimensions and then divide to produce the needed local cell types. Not an easy proposition.
One can imagine other strategies for guiding stem cells to desired destinations. For example, for areas without the heavy blood flow of the heart just injection of the cells into the desired area might be enough in some cases. Or possibly implant something that secretes a hormone or other compound that guides stem cells to that locatio.
The rate of progress in stem cell research objectively matters more to most of us in the long run than debates about health insurance coverage. We are all going to get some disease that would be fatal if it befalls us now. But each of those disease will become curable at some point in the future. If we are lucky we will not get each of these diseases until after they become curable. Many of those diseases will become curable with stem cells.
In a leap toward making stem cell therapy widely available, researchers at the Ansary Stem Cell Institute at Weill Cornell Medical College have discovered that endothelial cells, the most basic building blocks of the vascular system, produce growth factors that can grow copious amounts of adult stem cells and their progeny over the course of weeks. Until now, adult stem cell cultures would die within four or five days despite best efforts to grow them.
I wonder how easily the stem cells can be made into useful therapies. For example, if stem cells are removed from joints, grown into much larger quantities, and then injected into damaged joints will they repair the joints? Just how many steps are there between the step where lots of stem cells can be grown to the step where the stem cells can fix damaged and aged tissue?
Blood vessels probably normally maintain stem cells.
This new finding sets forth the innovative concept that blood vessels are not just passive conduits for delivery of oxygen and nutrients, but are also programmed to maintain and proliferate stem cells and their mature forms in adult organs. Using a novel approach to harness the potential of endothelial cells by "co-culturing" them with stem cells, the researchers discovered the means to manufacture an unlimited supply of blood-related stem cells that may eventually ensure that anyone who needs a bone marrow transplant can get one.
The scientists expect this approach to work for other types of stem cells for other parts of the body.
DURHAM, N.C. -- Scientists at Duke University Medical Center have identified a new growth factor that stimulates the expansion and regeneration of hematopoietic (blood-forming) stem cells in culture and in laboratory animals. The discovery, appearing in the journal Nature Medicine, may help researchers overcome one of the most frustrating barriers to cellular therapy: the fact that stem cells are so few in number and so stubbornly resistant to expansion.
Researchers believe that umbilical cord blood could serve as a universal source of stem cells for all patients who need a stem cell transplant, but the numbers of stem cells in cord blood units are limited, so there is a clinical need to develop a method to expand cord blood stem cells for transplantation purposes. "Unfortunately, there are no soluble growth factors identified to date that have been proven to expand human stem cells for therapeutic purposes," said John Chute, M.D., a stem cell transplant physician and cell biologist at Duke and senior author of the paper.
Chute, working with Heather Himburg, a post-doctoral fellow in his laboratory, discovered that adding pleiotrophin, a naturally-occurring growth factor, stimulated a ten-fold expansion of stem cells taken from the bone marrow of a mouse.
They also found that pleiotrophin increased the numbers of human cord blood stem cells in culture that were capable of engraftment in immune-deficient mice. When they injected pleiotrophin into mice that had received bone marrow-suppressive radiation, they observed a 10-fold increase in bone marrow stem cells compared to untreated mice. "These results confirmed that pleiotrophin induces stem cell regeneration following injury," said Chute.
20 years from now this will seem like the dark ages of stem cell treatment. The scientists are making useful and promising advances. But the point of really fast uptake of stem cell therapies still lies some years in the future. The stem cell therapies that exist today are for fairly small fractions of the population.
I expect stem cell therapies to really take off once some exist that improve appearances. Rather than wait for illness people will go for treatment in much larger numbers when plastic surgeons can sell stem cells that make gray hair brown or black or blond again. People will also flock in to get skin stem cell therapies that turn back the clock on appearances.
Since plastic surgeons seem more inclined to try new treatments I expect any discovery of a hormone for boosting, say, hair follicle melanocyte pigment producing cells will get a very rapid roll-out. Or a hormone that boosts collagen-producing cell growth will find a market quickly.
A group of scientists has systematically mapped state changes in embryonic cells as they turn into the various types of cells needed to form organs and a complete organism. This information is needed, for example, to figure out how to coax stem cells into forming replacement organs.
LA JOLLA, CA – February 2, 2010 –– Scientists at The Scripps Research Institute and The Genome Institute of Singapore (GIS) led an international effort to build a map that shows in detail how the human genome is modified during embryonic development. This detailed mapping is a significant move towards the success of targeted differentiation of stem cells into specific organs, which is a crucial consideration for stem cell therapy.
The study was published in the genomics journal Genome Research on February 4, 2010.
"The cells in our bodies have the same DNA sequence," said Scripps Research Professor Jeanne Loring, who is a senior author of the paper with Chia-Lin Wei of the Genome Institute of Singapore and the National University of Singapore and Isidore Rigoutsos of IBM Thomas J. Watson Research Center. "Epigenetics is the process that determines what parts of the genome are active in different cell types, making a nerve cell, for example, different from a muscle cell."
Making stem cells into useful therapy amounts in large part to getting control of methylation patterns on the DNA and manipulating other aspects of epigenetic state. To put it another way: Scientists need to the ability to measure and manipulate the regulatory state of cells.
The genome is a few billion base pairs. Lots of methyl groups and proteins are basically parked at precise locations all over the DNA preventing some parts of the DNA from getting activated while allowing other parts to get read and used to operate the cell. How hard will it turn out to be to get all that regulatory state just right for cell therapies? If things do not go just right the risks include cancer, creation of the wrong cell types in the wrong places, and incomplete repair.
Some U Wisc Madison researchers compared induced pluripotent stem cells (iPS cells - made from reprogrammed adult cells reprogrammed) to embryonic stem cells and find embryonic stem cells become other cell types more efficiently. Techniques to make iPS cells still need additional improvement.
MADISON — The great promise of induced pluripotent stem cells is that the all-purpose cells seem capable of performing all the same tricks as embryonic stem cells, but without the controversy.
However, a new study published this week (Feb. 15) in the Proceedings of the National Academy of Sciences comparing the ability of induced cells and embryonic cells to morph into the cells of the brain has found that induced cells — even those free of the genetic factors used to program their all-purpose qualities — differentiate less efficiently and faithfully than their embryonic counterparts.
The finding that induced cells are less predictable means there are more kinks to work out before they can be used reliably in a clinical setting, says Su-Chun Zhang, the senior author of the new study and a professor in the University of Wisconsin-Madison School of Medicine and Public Health.
"Embryonic stem cells can pretty much be predicted," says Zhang. "Induced cells cannot. That means that at this point there is still some work to be done to generate ideal induced pluripotent stem cells for application."
The biggest advantage of iPS cells is that they can be made from each person's adult cells. So they avoid immuno-rejection problems. Plus, they just feel less alien. They are your own cells. I also think there's another practical benefit I've yet to see mentioned: iPS cells made into neural stem cells are less likely to change your personality by producing neurons that'll behave differently for genetic reasons.
Dr. Zhang does not expect this advantage of embryonic stem cells to last for long.
Despite their unpredictability, Zhang notes that induced stem cells can still be used to make pure populations of specific types of cells, making them useful for some applications such as testing potential new drugs for efficacy and toxicity. He also noted that the limitations identified by his group are technical issues likely to be resolved relatively quickly.
"It appears to be a technical issue," he says. "Technical things can usually be overcome."
Many researchers are quite busy working on improved techniques for making iPS cells. For example, some Stanford researchers have just developed a safer and easier way to make induced pluripotent stem cells.
STANFORD, Calif. - Tiny circles of DNA are the key to a new and easier way to transform stem cells from human fat into induced pluripotent stem cells for use in regenerative medicine, say scientists at the Stanford University School of Medicine. Unlike other commonly used techniques, the method, which is based on standard molecular biology practices, does not use viruses to introduce genes into the cells or permanently alter a cell's genome.
It is the first example of reprogramming adult cells to pluripotency in this manner, and is hailed by the researchers as a major step toward the use of such cells in humans. They hope that the ease of the technique and its relative safety will smooth its way through the necessary FDA approval process.
"This technique is not only safer, it's relatively simple," said Stanford surgery professor Michael Longaker, MD, and co-author of the paper. "It will be a relatively straightforward process for labs around the world to begin using this technique. We are moving toward clinically applicable regenerative medicine."
Lowly fat cells harnessed to a higher purpose.
The Stanford researchers used the so-called minicircles - rings of DNA about one-half the size of those usually used to reprogram cell - to induce pluripotency in stem cells from human fat.
NEW YORK (Jan. 20, 2010) -- In a significant step toward restoring healthy blood circulation to treat a variety of diseases, a team of scientists at Weill Cornell Medical College has developed a new technique and described a novel mechanism for turning human embryonic and pluripotent stem cells into plentiful, functional endothelial cells, which are critical to the formation of blood vessels. Endothelial cells form the interior "lining" of all blood vessels and are the main component of capillaries, the smallest and most abundant vessels. In the near future, the researchers believe, it will be possible to inject these cells into humans to heal damaged organs and tissues.
The new approach allows scientists to generate virtually unlimited quantities of durable endothelial cells -- more than 40-fold the quantity possible with previous approaches. Based on insights into the genetic mechanisms that regulate how embryonic stem cells form vascular endothelial cells, the approach may also yield new ways to study genetically inherited vascular diseases. The study appears in the advance online issue of Nature Biotechnology.
We are getting closer to the point where use of stem cells against degenerative diseases enters into large scale clinical practice. We aren't there yet. But in the next 10 years we will very likely see this happen.
The ability to repair the cardiovascular system will certainly be used to treat diseases. But if blood vessels can be repaired then stroke and most heart attacks could be avoidable in the first place.
"This technique is the first of its kind with serious potential as a treatment for a diverse array of diseases, especially cardiovascular disease, stroke and vascular complications of diabetes," says Dr. Shahin Rafii, the study's senior author. Dr. Rafii is the Arthur B. Belfer Professor in Genetic Medicine and co-director of the Ansary Stem Cell Institute at Weill Cornell Medical College, and an investigator of the Howard Hughes Medical Institute.
Dr. Shinya Yamanaka, a scientist who did key scientific experiments to turn adult cells into pluripotent stem cells is the subject of a New York Times story on the bright prospects for stem cell research. Yamanaka sees both embryonic and induced pluripotent stem cells as still risky for therapies. But he's optimistic about solving these problems.
As for the cells with which he now works, iPS cells, many hurdles remain before they are truly as versatile as the embryonic stem cells they mimic. “Embryonic stem cells are not safe,” he said. “But at the moment, iPS cells are more dangerous.”
For instance, many skin cells only partly complete the transition to stem cells, and there are no reliable markers yet to flag those that are incomplete. Embryonic stem cells also tend to form benign tumors made of a mix of muscle, bone and other cell types. For unknown reasons, Dr. Yamanaka’s stem cells are more prone to produce them. One of the trigger genes can cause cancer, and the viruses that ferry the transforming genes into a target skin cell may not deliver them where they are needed.
To turn stem cells into other cell types requires many changes in the regulatory state of the cells. DNA has many sites on it where proteins bind, methyl groups get placed, and other changes are made to regulate the behavior of tens of thousands of genes. Each type of cell in the body has a different pattern of regulation. To develop control over cell state is a very difficult undertaking.
The iPS (induced pluripotent stem) cells made by transforming adult cells (e.g a piece of skin tissue) hold much promise for two reasons. First, since creation of the cells avoids use of an embryo the iPS cells do not elicit big ethical objections. Second, iPS cells can be made using a person's own starter cells. So they are much more likely to be immunologically compatible. Dr. Yamanaka’s work in figuring out how to create iPS cells will eventually result in therapies that many of us will get. If you are still alive 30 years from now expect to get in line for stem cell therapies for all that ails you.
What I first want from stem cell therapy: the quality of eyesight I had as a teenager.
DALLAS, Dec. 8, 2009 — Cells from heart attack survivors’ own bone marrow reduced the risk of death or another heart attack when they were infused into the affected artery after successful stent placement, according to research reported in the American Heart Association journal Circulation: Heart Failure.
Benefits found early in the Reinfusion of Enriched Progenitor Cells And Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial could last for at least two years, researchers said.
“More research is needed, but this gives us a hint of what might be possible with this new treatment — prevention of another heart attack and of rehospitalization for heart failure, both life-threatening complications,” said Birgit Assmus, M.D., first author of the study and assistant professor of cardiology at J.W. Goethe University in Frankfurt, Germany.
We are still in the year 2009 and stem cell experiments for modest heart repair are yielding promising results. When will heart repair with stem cells after a heart attack become standard practice? 2020? 2025?
Blood vessel blockage, a common condition in old age or diabetes, leads to low blood flow and results in low oxygen, which can kill cells and tissues. Such blockages can require amputation resulting in loss of limbs. Now, using mice as their model, researchers at Johns Hopkins have developed therapies that increase blood flow, improve movement and decrease tissue death and the need for amputation. The findings, published online last week in the early edition of the Proceedings of the National Academy of Sciences, hold promise for developing clinical therapies.
"In a young, healthy individual, hypoxia — low oxygen levels — triggers the body to make factors that help coordinate the growth of new blood vessels but this process doesn't work as well as we age," says Gregg Semenza, M.D., Ph.D., professor of pediatrics and genetic medicine and director of the vascular biology program at the Johns Hopkins Institute for Cell Engineering. "Now, with the help of gene therapy and stem cells we can help reactivate the body's response to hypoxia and save limbs."
Injected stem cells and gene therapy partially restored blood flow in mice whose blood flow had been reduced.
Previously, Semenza's team generated a virus that carries the gene encoding an active form of the HIF-1 protein, which turns on genes necessary for building new blood vessels. When injected into the hind legs of otherwise healthy mice and rabbits that had been treated to reduce blood flow, the HIF-1 virus treatment partially restored blood flow.
We are starting to live in the science fiction future.
(Santa Barbara, Calif.) –– An international team of scientists has rescued visual function in laboratory rats with eye disease by using cells similar to stem cells. The research shows the potential for stem cell-based therapies to treat age-related macular degeneration in humans.
A team led by Dennis Clegg, of UC Santa Barbara, and Pete Coffey, of University College London (UCL), published their work in two papers, including one published this week in the journal PloS One. The first paper was published in the October 27 issue of the journal Stem Cells.
The scientists worked with rats that have a mutation which causes a defect in retinal pigmented epithelial (RPE) cells and leads to photoreceptor death and subsequent blindness. Human RPE cells were derived from induced pluripotent stem cells –– embryonic stem cell-like cells that can be made from virtually any cell in the body, thus avoiding the controversy involved in using stem cells derived from embryos. Pluripotent means that the cells can become almost any cell in the body.
In experiments spearheaded by UCL's Amanda Carr, the team found that by surgically inserting stem cell-derived RPE into the retinas of the rats before photoreceptor degeneration, vision was retained. They found that the rats receiving the transplant tracked their visual focus in the direction of moving patterns more efficiently than control groups that did not receive a transplant.
Stem cell therapies are, for the most part, rejuvenation therapies. I say "for the most part" because stem cells will also repair damage due to trauma and malfunction due to congenital defects. But most uses of stem cells will be for repairing damage that accumulates with age.
While the idea of full body rejuvenation as a goal is still not mainstream the on-going development of stem cell therapies for aging-related diseases means that medical researchers are already developing many of the therapies we will need in order to be able to reverse the aging process.
We keep getting closer to being able to make needed replacement parts.Researchers converted human skin cells into induced pluripotent stem cells and then converted the stem cells into liver cells that were able to function in the livers of mice.
Scientists at The Medical College of Wisconsin in Milwaukee have successfully produced liver cells from patients' skin cells opening the possibility of treating a wide range of diseases that affect liver function. The study was led by Stephen A. Duncan, D. Phil., Marcus Professor in Human and Molecular Genetics, and professor of cell biology, neurobiology and anatomy, along with postdoctoral fellow Karim Si-Tayeb, Ph.D., and graduate student Ms. Fallon Noto.
This result shows that induced pluripotent stem cells can be converted into useful functioning cells. Still a lot of work to do to prove these cells are safe and effective in the long term. But this is a good step.
The Medical College research team generated patient–specific liver cells by first repeating the work of James Thomson and colleagues at University of Wisconsin-Madison who showed that skin cells can be reprogrammed to become cells that resemble embryonic stem cells. They then tricked the skin–derived pluripotent stem cells into forming liver cells by mimicking the normal processes through which liver cells are made during embryonic development. Pluripotent stem cells are so named because of their capacity to develop into any one of the more than 200 cell types in the human body.
At the end of this process, the researchers found that they were able to very easily produce large numbers of relatively pure liver cells in laboratory culture dishes. "We were excited to discover that the liver cells produced from human skin cells were able to perform many of the activities associated with healthy adult liver function and that the cells could be injected into mouse livers where they integrated and were capable of making human liver proteins," says Dr. Duncan.
They refer to work done by Jamie Thomson which they built upon to produce these latest results. See my previous post on Thomson's work in developing the ability to convert adult cells into pluripotent stem cells.
Results: MIT engineers have boosted stem cells' ability to regenerate vascular tissue (such as blood vessels) by equipping them with genes that produce extra growth factors (naturally occurring compounds that stimulate tissue growth). In a study in mice, the researchers found that the stem cells successfully generated blood vessels near the site of an injury, allowing damaged tissue to survive.
The researchers used nanoparticles to deliver genes for an angiogenesis (stimulates blood vessel growth) compound to grow blood vessels using stem cells.
Methods: After removing stem cells from mouse bone marrow, the researchers used specially developed nanoparticles to deliver the gene for the growth factor VEGF (vascular endothelial growth factor). The stem cells were then implanted into damaged tissue areas. These nanoparticles, which the MIT team has also tested to deliver cancer treatments, are believed to be safer than the viruses often used for gene delivery.
Note that angiogenesis genes are problematic for therapies because mutations in angiogenesis genes are necessary steps for the development of killer cancers. Ideally to carry out safe the added genes need to break down after the repairs are completed.
As we age changes in factors excreted by muscle cells suppress stem cells to make them do less repair. So our muscles decay. A change in biochemical signaling can activate stem cells to do more muscle repair.
Berkeley -- A study led by researchers at the University of California, Berkeley, has identified critical biochemical pathways linked to the aging of human muscle. By manipulating these pathways, the researchers were able to turn back the clock on old human muscle, restoring its ability to repair and rebuild itself.
The findings will be reported in the Sept. 30 issue of the journal EMBO Molecular Medicine, a peer-reviewed, scientific publication of the European Molecular Biology Organization.
"Our study shows that the ability of old human muscle to be maintained and repaired by muscle stem cells can be restored to youthful vigor given the right mix of biochemical signals," said Professor Irina Conboy, a faculty member in the graduate bioengineering program that is run jointly by UC Berkeley and UC San Francisco, and head of the research team conducting the study. "This provides promising new targets for forestalling the debilitating muscle atrophy that accompanies aging, and perhaps other tissue degenerative disorders as well."
This builds on work stretching back to when Irina Conboy was at Thomas Rando's lab at Stanford about 6 years ago. This report shows how she and her collaborators are really rolling along progressively putting together more pieces of the puzzle needed to rejuvenate aging muscle. Conboy says she wants to eventually get into human trials with techniques to turn up muscle repair. I fear that getting to human trials will not be easy because the pathways that suppress stem cells in aged bodies do that in order to reduce cancer risk or perhaps other disease risks.
The problem is that aged muscle cells send the wrong mix of signals to neighboring stem cells. This turns down stem cell activity and reduces the amount of repairs that get done.
Previous research in animal models led by Conboy, who is also an investigator at the Berkeley Stem Cell Center and at the California Institute for Quantitative Biosciences (QB3), revealed that the ability of adult stem cells to do their job of repairing and replacing damaged tissue is governed by the molecular signals they get from surrounding muscle tissue, and that those signals change with age in ways that preclude productive tissue repair.
Those studies have also shown that the regenerative function in old stem cells can be revived given the appropriate biochemical signals. What was not clear until this new study was whether similar rules applied for humans. Unlike humans, laboratory animals are bred to have identical genes and are raised in similar environments, noted Conboy, who received a New Faculty Award from the California Institute of Regenerative Medicine (CIRM) that helped fund this research. Moreover, the typical human lifespan lasts seven to eight decades, while lab mice are reaching the end of their lives by age 2.
An enzyme called MAP kinase (and kinases generally hook phosphates onto other proteins - often to regulate them) declines with age and this decline in MAP kinase (MAPK) appears to be key in turning down stem cell activity. The lowered stem cell activity means that muscle damage doesn't get repaired and therefore we accumulate more damage and muscle shrinkage as we age.
The researchers further examined the response of the human muscle to biochemical signals. They learned from previous studies that adult muscle stem cells have a receptor called Notch, which triggers growth when activated. Those stem cells also have a receptor for the protein TGF-beta that, when excessively activated, sets off a chain reaction that ultimately inhibits a cell's ability to divide.
The researchers said that aging in mice is associated in part with the progressive decline of Notch and increased levels of TGF-beta, ultimately blocking the stem cells' capacity to effectively rebuild the body.
This study revealed that the same pathways are at play in human muscle, but also showed for the first time that mitogen-activated protein (MAP) kinase was an important positive regulator of Notch activity essential for human muscle repair, and that it was rendered inactive in old tissue. MAP kinase (MAPK) is familiar to developmental biologists since it is an important enzyme for organ formation in such diverse species as nematodes, fruit flies and mice.
For old human muscle, MAPK levels are low, so the Notch pathway is not activated and the stem cells no longer perform their muscle regeneration jobs properly, the researchers said.
In February 2005 Thomas Rando's group at Stanford showed that blood from young mice helped stimulate regeneration in muscle of old mice. I found that report to be really bad news because it suggests that even if we develop ways to make youthful stem cells programmed to become assorted cell types that by itself won't increase repair by all that much. Our problem is that cells throughout an aging body are either excreting factors into the bloodstream that dampen repairs or the cells are failing to excrete factors that stimulate repairs.
In 2008 Conboy and collaborators found that they could turn up repair capability of mouse stem cells. Now in this latest report they are working with human stem cells.
If the body is turning down MAPK and suppressing stem cells as we age there's probably a constructive reason for this. The most obvious possibility: the repair stem cells are turned down because as they age they become higher risks for turning cancerous. If that is the case (and I think it likely) then efforts to turn up stem cells to do more repair will put us at greater risk of cancer. Therefore we really need effective ways to kill pre-cancerous and cancerous cells as essential capabilities in order to do rejuvenation therapies.
One way to reduce the risk of cancer that likely would come from upregulating aged stem cells would be to replace the aged stem cells with young stem cells. Youthful stem cell lines selected for few mutations would pose less of a cancer risk. But even if suitable stem cell lines could be created for all the types of stem cells in the body getting the replacement stem cells to all the places where they are found is a daunting task. Also, getting existing stem cells to basically all die off to make room for their youthful replacements is similarly daunting.
In spite of the cancer risk for some people the benefits of therapy will outweigh the risks. If, for example, you have a failing heart that is going to kill you in a couple of years then, hey, a stem cell therapy combined with a drug therapy that upregulates stem cells will offer a very favorable ratio of benefits to risks. Stem cell therapies and other therapies to stimulate repair will make the most sense for the most unhealthy first.
A continuing series of improvements in how to make cells revert to pluripotent (highly flexible) state open up the possibility of stem cell therapies for a large assortment of disorders and diseaess. But a group that has developed a new safer method for reverting cells to the pluripotent state finds that the converted cells still show signs of their original differentiated state.
A team of researchers from the University of California, San Diego School of Medicine and the Salk Institute for Biological Studies in La Jolla have developed a safe strategy for reprogramming cells to a pluripotent state without use of viral vectors or genomic insertions. Their studies reveal that these induced pluripotent stem cells (iPSCs) are very similar to human embryonic stem cells, yet maintain a "transcriptional signature." In essence, these cells retain some memory of the donor cells they once were.
This "transcriptional signature" they speak of is the pattern of gene expression into messenger RNAs and other RNA pieces that DNA sections get used to generate. Basically, DNA gets read to create matching RNA and then the RNA gets used to guide the creation of proteins.
That a cell can be induced to become more like embryonic cells and yet still retain characteristics of, say, skin or fat cells is problematic for the desire to create stem cell therapies. Ideally one wants to convert cells back to an embryonic-like state and get them to turn off all genes that are specific to being, for example, a liver or fat or kidney cell. This report suggests that inducing cells to become pluripotent does not, by itself, make them into the ideal starting point for stem cell therapies. The job of resetting cells back to a truly embryonic state is trickier than that and scientists haven't get figured out how to fully manage that trick.
On the bright side, the scientists did identify a single gene that is enough to convert a cell into the pluripotent state.
The study, led by UCSD Stem Cell Program researcher Alysson R. Muotri, assistant professor in the Departments of Pediatrics at UCSD and Rady Children's Hospital and UCSD's Department of Cellular and Molecular Medicine, will be published online in PLoS ONE on September 17.
"Working with neural stem cells, we discovered that a single factor can be used to re-program a human cell into a pluripotent state, one with the ability to differentiate into any type of cell in the body" said Muotri. Traditionally, a combination of four factors was used to create iPSCs, in a technology using viral vectors – viruses with the potential to affect the transcriptional profile of cells, sometimes inducing cell death or tumors.
The researchers were using familiar genes for inducing pluripotency: Oct4 and Nanog. (and this link is to the full paper)
Genetic reprogramming of somatic cells to a pluripotent state (induced pluripotent stem cells or iPSCs) by over-expression of specific genes has been accomplished using mouse and human cells. However, it is still unclear how similar human iPSCs are to human Embryonic Stem Cells (hESCs). Here, we describe the transcriptional profile of human iPSCs generated without viral vectors or genomic insertions, revealing that these cells are in general similar to hESCs but with significant differences. For the generation of human iPSCs without viral vectors or genomic insertions, pluripotent factors Oct4 and Nanog were cloned in episomal vectors and transfected into human fetal neural progenitor cells. The transient expression of these two factors, or from Oct4 alone, resulted in efficient generation of human iPSCs. The reprogramming strategy described here revealed a potential transcriptional signature for human iPSCs yet retaining the gene expression of donor cells in human reprogrammed cells free of viral and transgene interference. Moreover, the episomal reprogramming strategy represents a safe way to generate human iPSCs for clinical purposes and basic research.
My guess: We need a far more detailed understanding of genetic regulation in order to create at least some types of cell therapies and for the growth of replacement organs. But for a lot of fatal diseases a cell therapy that is less than perfect might still extend life.
Some people ask me why I think we have a chance of living until rejuvenation therapies become available. I get the sense they feel that making the body young again sounds too much like science fiction. Well, stem cell therapies are no longer only in our distant science fiction future. Geron is running a spinal cord repair clinical trial with embryonic stem cells while ACT has applied for permission to try embryonic stem cells against age-related macular degeneration.
Geron, a biotech company based in Menlo Park, CA, received FDA approval in January for a trial to treat patients with acute spinal-cord injuries with cells derived from embryonic stem cells.
This latest treatment for eye disease, developed by Advanced Cell Technology (ACT), based in Worcester, MA, uses human embryonic stem cells to re-create a type of cell in the retina that supports the photoreceptors needed for vision. These cells, called retinal pigment epithelium (RPE), are often the first to die off in age-related macular degeneration and other eye diseases, which in turn leads to loss of vision. Several years ago, scientists found that human embryonic stem cells could be a source of RPE cells, and subsequent studies found that these cells could restore vision in mouse models of macular degeneration.
THe article mentions that the targeted tissue types in these therapies are being chosen due to expected lower risk of immune rejection. The use of embryonic stem cells means that the cells contain DNA from someone other than the intended therapy recipients. It is not practical to create embryonic stem cell lines for each person to be treated from that person's DNA. So immune rejection is a real concern.
I see embryonic stem cells as a transitional technology. Other approaches show signs of promise. Induced pluripotent stem cells made from a person's own adult cells will allow avoidance of the immune rejection problem by using cell lines created from one's own cells and DNA.
While the use of SENS (Strategies for Engineered Negligible Senescence) in order to do full body rejuvenation is still not an idea accepted by the mainstraem the advances needed to do rejuvenation will come as a result of attempts to repair the body for a very long list of diseases. Each type of tissue repair (e.g. stem cells and gene therapies to repair arthritic joints or to repair a heart) done to treat individual diseases will basically serve as another building block toward the goal of full body rejuvenation. We could get there faster with a big explicit SENS push. But we will get there anyway with lots of smaller steps aimed at less ambitious goals.
Scientists at the Ottawa Hospital Research Institute (OHRI) and the University of Ottawa have discovered a powerful new way to stimulate muscle regeneration, paving the way for new treatments for debilitating conditions such as muscular dystrophy.
The research, to be published in the June 5 issue of Cell Stem Cell, shows for the first time that a protein called Wnt7a increases the number of stem cells in muscle tissue, leading to accelerated growth and repair of skeletal muscle.
"This discovery shows us that by targeting stem cells to boost their numbers, we can improve the body's ability to repair muscle tissue," said senior author Dr. Michael Rudnicki. Dr. Rudnicki is the Scientific Director of Canada's Stem Cell Network and a Senior Scientist at OHRI and Director of OHRI's Sprott Centre for Stem Cell Research, as well as a Professor of Medicine at the University of Ottawa.
Research into how to stimulate stem cells to repair damage from muscular dystrophy also ends up being research into how to use stem cells to rejuvenate aged muscles. More generally, the pursuit of treatment of diseases using stem cells, gene therapy, and other treatments which aim at tissue repair inevitably leads to treatments useful for rejuvenation. Even without a big push to develop rejuvenation therapies we will end up with them anyway. But if we actively pursued rejuvenation therapies we'd get them sooner.
Salk researchers did genetic repair on cells from patients with Fanconi anemia and then turned the cells into pluripotent stem cells and then turned the cells into the type of cells that make red blood cells.
LA JOLLA, CA—A study led by researchers at the Salk Institute for Biological Studies, has catapulted the field of regenerative medicine significantly forward, proving in principle that a human genetic disease can be cured using a combination of gene therapy and induced pluripotent stem (iPS) cell technology. The study, published in the May 31, 2009 early online edition of Nature, is a major milestone on the path from the laboratory to the clinic.
The probably have safety concerns that hold back their injecting the resulting cells back into patients.
After taking hair or skin cells from patients with Fanconi anemia, the investigators corrected the defective gene in the patients' cells using gene therapy techniques pioneered in Verma's laboratory. They then successfully reprogrammed the repaired cells into induced pluripotent stem (iPS) cells using a combination of transcription factors, OCT4, SOX2, KLF4 and cMYC. The resulting FA-iPS cells were indistinguishable from human embryonic stem cells and iPS cells generated from healthy donors.
Since bone marrow failure as a result of the progressive decline in the numbers of functional hematopoietic stem cells is the most prominent feature of Fanconi anemia, the researchers then tested whether patient-specific iPS cells could be used as a source for transplantable hematopoietic stem cells. They found that FA-iPS cells readily differentiated into hematopoietic progenitor cells primed to differentiate into healthy blood cells.
"We haven't cured a human being, but we have cured a cell," Belmonte explains. "In theory we could transplant it into a human and cure the disease."
The development of therapies to repair genetic diseases involves developing capabilities needed for rejuvenation of old bodies. Cells malfunction due to aging just as they malfunction due to harmful genetic mutations inherited at birth. Every gene therapy and cell therapy developed to treat genetic diseases puts us closer to treatments to reverse damage of an aged body.
Rejuvenation therapies will first get developed as a side benefit to the development of therapies to treat genetic diseases and other diseases that are not the result of aging. Therefore the development of rejuvenation therapies is inevitable.
We need the ability to turn our own adult cells into pluripotent (i.e. capable of becoming all cell types) stem cells. Stem cells made from our own tissue will be immunologically compatible and not rejected. Such stem cells will serve as a useful starting point to grow replacement organs and to create cell therapies. The first methods developed for converting adult cells into stem cells used gene therapy that runs the risk of converting cells into cancers. But a number of labs have developed successively safer ways to make pluripotent stem cells from adult cellls. Finally a team at Scripps has found a way to totally avoid the need for gene therapy. In their very promising approach the scientists used proteins made from the genes that cause cells to become pluripotent.
In a paper publishing online April 23rd in Cell Stem Cell, a Cell Press journal, Dr. Sheng Ding and colleagues from the Scripps Research Institute in La Jolla, California, report an important step forward in the race to make reprogrammed stem cells that may be better suited for use in clinical settings.
Ding and his colleagues show that mouse cells can be reprogrammed to form stem cells with a combination of purified proteins and a chemical additive, thus avoiding the use of genetic material.
The discovery three years ago that adult cells could be reprogrammed to form induced pluripotent stem cells, or iPS cells, with similar properties to embryonic stem cells was a major scientific breakthrough. These cells hold enormous potential for drug development and even cell therapy processes, and this promise has garnered significant attention from scientists and the media worldwide. However, a major caveat to the eventual application of iPS cells is that until now all the methods used to generate them have required the introduction of genetic material to make the transcription factors needed for reprogramming. Although some research groups have recently generated iPS cells that lack genetic modifications, even the most advanced methods used genes in the form of plasmids, and thus the risk of genetic mutations caused by the introduced sequences remained.
In their new paper, Ding and co-authors avoid this risk entirely by adding specially modified versions of reprogramming proteins directly to the growing fibroblasts. The proteins are broken down by the cells after they are added to the culture, so to sustain protein activity long enough to induce reprogramming the authors used repeated cycles of protein addition. Ding and colleagues named the reprogrammed cells that arise from this process "protein-induced pluripotent stem cells," or piPS cells.
Although the technique was much less efficient than virus-based approaches -- 0.006% compared to 0.067% using Yamanaka's original method -- these reprogrammed cells, dubbed "protein-induced pluripotent stem cells," or piPS cells, passed all the benchmarks of pluripotency both in vitro and in vivo. Ding's team also showed that they could do away with one of the proteins, c-Myc, although this further reduced the already poor reprogramming efficiency by about a third.
Lots of labs will jump on this and work on ways to boost the conversion efficiency. One key to being able to do it at all came from Douglas Melton's lab at Harvard just last year. The Scientist reports a histone deacetylase inhibitor was needed in addition to the proteins. No doubt other compounds will be found that further boost the conversion process.
Being able to create pluripotent stem cells at will provides multiple benefits. The older approach of cloning with eggs doesn't just stir ethical objections from some Christians. That approach also requires availability of human eggs. Well, harvesting eggs from women entails risks and costs and not all women are willing to donate their eggs. The ability to avoid the generation of an embryo using eggs really helps make it a lot easier to create pluripotent stem cells from every person's own adult cells.
While a lot has been said about the importance of pluripotent stem cells they are, in a sense, just the starting point. Lots more work is needed to figure out how to turn them into all the other cell types that make up a human body. Each type of cell has a bunch of molecular switches (e.g. methyl groups attached to the DNA) that hold them in their state. We need to find ways to turn cells into each of the cell types. We also need to find ways to deliver the cells to where they are needed and to get them to attach and assume appropriate positions in the aged and damaged tissue. Our lives and eventual rejuvenation depend on rapid progress in solving this next set of problems.
The ability to convert adult cells from our own bodies into pluripotent (capable of becoming all cell types) cells that resemble embryonic stem cells would allow the development of cell therapies that are immunologically compatible with each person's immune system. Efforts to make cell type conversion safer keep getting better and better. The problem is how to convert the cells without DNA damage that can lead to cancer. Some UCSF researchers just took another step in this direction by reducing the number of genes that need to be inserted into adult cells to convert them into pluripotent stem cells.
A team of UCSF researchers has for the first time used tiny molecules called microRNAs to help turn adult mouse cells back to their embryonic state. These reprogrammed cells are pluripotent, meaning that, like embryonic stem cells, they have the capacity to become any cell type in the body.
The findings suggest that scientists will soon be able to replace retroviruses and even genes currently used in laboratory experiments to induce pluripotency in adult cells. This would make potential stem cell-based therapies safer by eliminating the risks posed to humans by these DNA-based methods, including alteration of the genome and risk of cancer.
"Using small molecules such as microRNAs to manipulate cells will play a major role in the future of stem cell biology," says senior author Robert Blelloch, MD, PhD, of the Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research at UCSF.
It says something (not good) about the state of gene therapy that scientists find it necessary to develop techniques that avoid the need to put genes into cells in order to achieve therapeutic results.
These scientists still need to rely on genes introduced using viruses. But they were able to reduce the number of genes from 4 to 3. They intend to do more work to develop more microRNA molecules that will substitute for the remaining 3 genes.
Previous methods for creating embryonic stem cell-like cells have relied on the introduction of DNA that encodes four transcription factors, proteins that play a role in the production of genes. The limitation of this method is that three of the four genes that code for these transcription factors -- oct4, klf4 and c-myc – are oncogenes, meaning they promote the uncontrolled cell growth characteristic of cancer.
In the current study, led by Robert Judson, a graduate student in the Blelloch lab, the scientists induced pluripotency using a combination of infection and transfection. The infection involved introducing three viruses, each containing a transcription factor known to induce pluripotency. The transcription factor for c-myc was not included. The transfection involved a simple process in which the tiny microRNA molecules were mixed with a lipid, allowing them to pass through the cell membrane. By labeling the fibroblast cells, they showed that the treated cells could be incorporated into a mouse embryo and become every cell type in the adult animal -- including germline cells that would produce the next generation of mice.
Once they've eliminated the need for genes carried by viruses These scientists also want to go even farther and use microRNAs to turn cells into whatever cell types are needed in therapy.
Currently, Blelloch and his colleagues are working to replace all four transcription factors with microRNAs and conducting experiments that will reveal the mechanism by which these small molecules are able to induce pluripotency. The team will also be looking to determine which microRNAs might be able to turn adult cells directly into particular adult cell types, by-passing the embryonic stem cell-like stage altogether.
These folks and researchers in other labs will surely succeed in finding ways to convert cells into large numbers of different cell types. Just being able to create certain desired cell types and inject them into some locations in the body will be enough to treat some problems. But other problems will require additional tissue engineering technology in order to create complex 3 dimensional structures. For example, the ability to create a nerve cell isn't enough to bridge across a severed spinal cord. The axons and dendrites of the nerves and supporting cells must form complex relationships in order to carry signals up and down the spinal cord.
Lots of organs are made up of multiple types of cells arranged to work together to perform organ functions. To grow individual organs requires the creation of 3 dimensional biochemical and physical micro-environments which growing organs encounter during embryonic development. Tissue engineering for organ growth requires not just the ability to convert cells into different cell types but also to orchestrate the arrangement of cells of multiple types. When this becomes a solvable problem human bodies will become as fixable as cars with one exception - the brain. The brain is the long pole in the tent for full body rejuvenation. To rejuvenate the brain will require solving an even larger and harder set of problems.
Doctors may soon be able to patch up damaged bones and joints anywhere in the body with a simple shot in the arm.
A team at Keele University is testing injectible stem cells that they say they can control with a magnet.
Once injected these immature cells can be guided to precisely where their help is needed and encouraged to grow new cartilage and bone, work on mice shows.
Think of all the people with knee problems, elbow problems, pains in finger joints, back pains, or other skeletal problems. They will finally become repairable when this biotechnology reaches the market. We should become repairable. We can fix our cars. We should be able to fix ourselves.
One of the problems for rejuvenation therapy development is how to replace the bad old cells with good young cells. Chemotherapy used to remove stem cells successfully made room for therapeutic stem cells. Note that the use of chemotherapy for this purpose in humans would cause damage elsewhere in the body. We need far better ways to wipe out specific classes of cells without damaging other cell types.
An experimental procedure that dramatically strengthens stem cells' ability to regenerate damaged tissue could offer new hope to sufferers of muscle-wasting diseases such as myopathy and muscular dystrophy, according to researchers from the University of New South Wales (UNSW).
The world-first procedure has been successfully used to regrow muscles in a mouse model, but it could be applied to all tissue-based illnesses in humans such as in the liver, pancreas or brain, the researchers say.
The research team, which is based at UNSW and formerly from Sydney's Westmead Children's Hospital, adapted a technique currently being trialled in bone marrow transplantation. Adult stem cells are given a gene that makes them resistant to chemotherapy, which is used to clean out damaged cells and allow the new stem cells to take hold.
A paper detailing the breakthrough appears in the prestigious journal Stem Cells this week.
The ability of adult stem cells to regenerate whole tissues opens up a world of new possibilities for many human diseases, according to the lead authors of the paper, Professor Peter Gunning, Professor Edna Hardeman and Dr Antonio Lee, from UNSW's School of Medical Sciences.
The problem is that existing aged or diseased stem cells won't get out of the way. They outcompete the youthful new stem cells just by taking up space.
"The beauty of this technique is that chemotherapy makes space for stem cells coming into muscle and also gives the stem cells an advantage over the locals. It's the first strategy that gives the good guys the edge in the battle to cure sick tissues," Professor Gunning said.
The better parts of science fiction should become reality as soon as possible.
"What has been the realm of science fiction is looking more and more like the medicine of the future," he said.
Previous attempts have run up against a limit caused by the presence of existing stem cells. This means we really do need a method to kill off the old stem cells to make room for the new youthful and healthier stem cells.
The procedure solves one of the major hurdles involving stem cell therapy – getting the cells to survive for more than an hour or so after inserting them into damaged tissue.
"In muscle, most stem cells die in the first hour or are present in such low numbers that they are not much help," Professor Gunning said. "Until now, the new healthy cells had no advantage over the existing damaged tissue and were getting out-competed.
There's an obvious parallel here with cancer. We need to solve a very similar problem to kill cancer cells as we do to kill old stem cells. They are both cells our of bodies. They are hard to differentiate from cells we do not want to kill. This makes cancer such an incredibly hard disease to treat. My guess is we are going to need the biotechnology that gets developed to kill cancer cells to use to kill aged non-cancer cells to make room for youthful replacements.
Scientists have tricked bone marrow into releasing extra adult stem cells into the bloodstream, a technique that they hope could one day be used to repair heart damage or mend a broken bone, in a new study published today in the journal Cell Stem Cell.
When a person has a disease or an injury, the bone marrow mobilises different types of stem cells to help repair and regenerate tissue. The new research, by researchers from Imperial College London, shows that it may be possible to boost the body's ability to repair itself and speed up repair, by using different new drug combinations to put the bone marrow into a state of 'red alert' and send specific kinds of stem cells into action.
In the new study, researchers tricked the bone marrow of healthy mice into releasing two types of adult stem cells – mesenchymal stem cells, which can turn into bone and cartilage and that can also suppress the immune system, and endothelial progenitor cells, which can make blood vessels and therefore have the potential to repair damage in the heart.
While the scientists haven't shown that pushing more stem cells into the bloodstream leads to more healing they have shown they can boost stem cell release by a factor of 100.
"We hope that by releasing extra stem cells, as we were able to do in mice in our new study, we could potentially call up extra numbers of whichever stem cells the body needs, in order to boost its ability to mend itself and accelerate the repair process. Further down the line, our work could lead to new treatments to fight various diseases and injuries which work by mobilising a person's own stem cells from within," added Dr Rankin.
The scientists reached their conclusions after treating healthy mice with one of two different 'growth factors' – proteins that occur naturally in the bone marrow – called VEGF and G-CSF. Following this treatment, the mice were given a new drug called Mozobil.
The researchers found that the bone marrow released around 100 times as many endothelial and mesenchymal stem cells into the bloodstream when the mice were treated with VEGF and Mozobil, compared with mice that received no treatment. Treating the mice with G-CSF and Mozobil mobilised the haematopoietic stem cells – this treatment is already used in bone marrow transplantation.
It isn't always going to be the case that just putting a large number of stem cells onto the scene of injury will lead to some or all needed repairs. Additional work might be necessary to implant signaling chemicals to direct stem cells to the right places and further to instruct them on which types of cells to convert into.
We are going to see stem cells become useful therapeutic tools for at least some problems in the next 10 years and for a lot more problems in the following 10 years.
The study, which appears in the December 18 online version of Cell Stem Cell and the January 2009 print edition of the journal, provides proof of principle that alternative sources of stem cells can be created.
The team, which included scientists from Scripps Research, Peking University, and the University of California, San Diego, conducted the studies to establish novel rat induced pluripotent stem cell lines (riPSCs) and human induced pluripotent stem cell lines (hiPSCs) by using a specific cocktail of chemicals combined with genetic reprogramming, a process whereby an adult cell is returned to its early embryonic state. Pluripotency refers to the ability of a cell to develop into each of the more than 200 cell types of the adult body.
The ability to create pluripotent stem cells (i.e. cells just as flexible as cells removed from embryos) from adult cells promises to allow us to create immunologically compatible replacement organs and stem cell therapies.
(Boston) -- A Boston University School of Medicine-led research team has discovered a more efficient way to create induced Pluripotent Stem (iPS) cells, derived from mouse fibroblasts, by using a single virus vector instead of multiple viruses in the reprogramming process. The result is a powerful laboratory tool and a significant step toward the application of embryonic stem cell-like cells for clinical purposes such as the regeneration of organs damaged by inherited or degenerative diseases, including emphysema, diabetes, inflammatory bowel disease, and Alzheimer's Disease.
Their research titled "iPS Cell Generation Using a Single Lentiviral Stem Cell Cassette" appears on line in the journal Stem Cells.
Prior research studies have required multiple retroviral vectors for reprogramming -- steps that depended on four different viruses to transfer genes into the cells' DNA – essentially a separate virus for each reprogramming gene (Oct4. Klf4, Sox2 and cMyc). Upon activation these genes convert the cells from their adult, differentiated status to what amounts to an embryonic-like state.
Research papers on easier and better ways to create pluripotent stem cells keep coming and coming. Restrictions on creation of pluripotent stem cells from embryos are going to matter less and less as these alternative ways to create such cells keep getting better.
Just a year ago Jamie Thomson's lab at U Wisc showed how to insert 4 genes to convert adult skin cells into pluripotent stem cells that are just as flexible as embryonic stem cells (i.e. they can become all the cell types in the body). Thomson commented more recently that his lab could have done the work 5 years sooner if he'd only believed it was not a hard problem. Well, the technique for doing this has just gotten easier and safer. MIT Whitehead Institute researchers have shown they can use a single virus to deliver 4 genes in a safer way to convert cells into the pluripotent state.
CAMBRIDGE, Mass. (Dec. 15, 2008) — Whitehead Institute researchers have greatly simplified the creation of so-called induced pluripotent stem (iPS) cells, cutting the number of viruses used in the reprogramming process from four to one. Scientists hope that these embryonic stem-cell-like cells could eventually be used to treat such ailments as Parkinson's disease and diabetes.
The earliest reprogramming efforts relied on four separate viruses to transfer genes into the cells' DNA--one virus for each reprogramming gene (Oct4, Sox2, c-Myc and Klf4). Once activated, these genes convert the cells from their adult, differentiated status to an embryonic-like state.
However, this method poses significant risks for potential use in humans. The viruses used in reprogramming are associated with cancer because they may insert DNA anywhere in a cell's genome, thereby potentially triggering the expression of cancer-causing genes, or oncogenes. For iPS cells to be employed to treat human diseases, researchers must find safe alternatives to reprogramming with such viruses. This latest technique represents a significant advance in the quest to eliminate the potentially harmful viruses.
Bryce Carey, an MIT graduate student working in the lab of Whitehead Member Rudolf Jaenisch, spearheaded the effort by joining in tandem the four reprogramming genes through the use of bits of DNA that code for polymers known as 2A peptides. Working with others in the lab, he then manufactured a so-called polycistronic virus capable of expressing all four reprogramming genes once it is inserted into the genomes of mature mouse and human cells.
The ability to convert adult cells into pluripotent cells has practical benefits aside from getting around political opposition to human embryonic stem cell work. The ability to create stem cells from adult cells without using a human egg also gets around the limited supply of human eggs as well as making it possible to use the same mitochondria as exist in the donor adult cells. So this opens up the possibility of creating pluripotent stem cells that immunologically and functionally match each person's existing cells.
I am eager to see the development of cell therapies derived from pluripotent stem cells. We all have parts that are wearing out. I see people around me with chronic knee pain, back pain, and other joint and connective tissue problems and think how much better their lives will be once we can repair their worn out knees, spinal disks, elbows, shoulders, and other worn out mechanical parts. I look at people who need to restore their receded gums, replace tissue scarred from burns, or who just have aged and easily scratched skin and think how better off they'd be with some rejuvenated tissues. I think about people who suffer from failing hearts, kidneys, or livers and imagine a future where we can grow replacement organs from stem cells. I want that future to arrive as soon as possible.
A year ago James Thomson's lab at U Wisc Madison used the genes OCT4, SOX2, NANOG, and LIN28 to turn adult cells into pluripotent stem cells. It was an experiment that the scientists could have done years sooner if they'd only thought the problem could be that easy. Since then other researchers have found safer ways to do the cell conversion. Here's yet another paper showing a way to convert adult fibroblast cells into pluripiotent stem cells by substituting small molecules for those of the genes used by Thomson's lab.
In the study, the scientists screened known drugs and identified small molecules that could replace conventional reprogramming genes, which can have dangerous side effects. This new process offers a new way to generate stem cells from fibroblasts, a general cell type that is abundant and easily accessible from various tissues, including skin.
The study was published in the November 6, 2008 edition (Volume 3, Issue 5) of the journal Cell Stem Cell.
"Our study shows for the first time that somatic or general cell types can be reprogrammed with only two genes and small molecules, and that these small molecules can replace one of the two most essential reprogramming genes," said Sheng Ding, a Scripps Research scientist and Associate Professor in the Department of Chemistry, who led the study with colleagues from Scripps Research and the Max Planck Institute for Molecular Biomedicine in Germany. "In this case, we replaced the Sox2 gene, which had previously always been regarded as absolutely essential for the reprogramming process."
A reduction in the number of genes used probably decreases the risk that the converted cells will go cancerous.
For the first time, the new study showed that BIX, an inhibitor of enzymes involved in regulating gene expression, enables fibroblast cell reprogramming in the absence of Sox2 gene overexpression. However, by itself, BIX's reprogramming efficiency is relatively low.
"As a result, we performed a second screen to find a compound that would synergize with BIX to further increase the reprogramming efficiency of general cells" Ding said. "Besides providing an improvement in reprogramming, we believed that these newly identified molecules might lead to discovery of different reprogramming mechanisms."
The second screen identified BayK, a calcium channel agonist, which was selected because it had no observable reprogramming activity on general cells in the absence of BIX. In addition, BayK was not known to affect the cell directly at the epigenetic level—changes in gene expression without any DNA or DNA-associated packaging protein modification—but rather at the cell signal transduction level.
The scientists found that when transduced general cells were treated with both BIX and BayK, a significant increase in the number of pluripotent cells resulted compared to transduced general cells treated with BIX alone.
Expect more research papers that reduce the risk and difficulty of converting adult cells to pluripotent stem cells. Your own cells will become convertible into cells usable in therapies.
ANN ARBOR, Mich.---Like a sentry guarding the castle walls, a molecular messenger inside adult stem cells sounds the alarm when it senses hazards that could allow the invasion of an insidious enemy: Cancer.
The alarm bell halts the process of cell division in its tracks, preventing an error that could lead to runaway cell division and eventually, tumor formation.
"Our work suggests that to be able to prevent abnormal cell proliferation, which could lead to cancer, stem cells developed this self-checking system, what we're calling a checkpoint," said Yukiko Yamashita of the University of Michigan's Life Sciences Institute.
"And if it looks like the cell is going to divide in the wrong way, the checkpoint senses there's a problem and sends the signal: 'Don't divide! Don't divide!'" said Yamashita, a research assistant professor of life sciences and an assistant professor of cell and developmental biology at the U-M Medical School.
The mechanisms which the body has for protecting against cancers are problematic for the development of stem cell therapies. Our stem cells become less able to divide as they age. Research done in mice shows that blood in the aged contains compounds that suppress stem cells. Maybe some of the factors that stop the cell division mentioned above are coming from the blood or surrounding tissues. We need to understand in detail each of the mechanisms by which stem cells become less able to divide with age.
Stem cells can be genetically engineered to ignore some of the factors that suppress stem cell replication. But this approach seems problematic. Aging isn't the only cause of the body's production of compounds that suppress growth. Stem cells that ignore growth suppression signals might cause problems similar to those caused by cancers.
In a promising finding for the field of regenerative medicine, stem cell researchers at Children's Hospital of Pittsburgh of UPMC have identified a source of adult stem cells found on the walls of blood vessels with the unlimited potential to differentiate into human tissues such as bone, cartilage and muscle.
The scientists, led by Bruno Péault, PhD, deputy director of the Stem Cell Research Center at Children's Hospital, identified cells known as pericytes that are multipotent, meaning they have broad developmental potential. Pericytes are found on the walls of small blood vessels such as capillaries and microvessels throughout the body and have the potential to be extracted and grown into many types of tissues, according to the study.
Sources of adult stem cells have obvious applications for the creation of therapies. But a discovery such as this one has other benefits which are less immediately obvious. Notably, we need to know all the cell types in our bodies and their distribution and function in order to know all the cell types we need to target with rejuvenation therapies. Obviously, if a discovery such as this one is possible to make in 2008 we do not know all the cell types we have or all the places these cell types are found.
The ability to isolate all the stem cells and progenitor cells from human bodies makes it easier to study key cell types to measure how much they've aged. For example, we need to know whether stem cell aging plays a big role in artery clogging with atherosclerotic plaques. If we could grow large numbers of youthful pericytes outside of the body would injecting these cells into the body cut the risks of stroke and heart attack? Or are the existing pericytes getting suppressed by chemicals that build up in the blood as we age?
Since pericytes are found in so many tissue types they will be easy to extract.
"This finding marks the first direct evidence of the source of multipotent adult stem cells known as mesenchymal stem cells. We believe pericytes represent one of the most promising sources of multipotent stem cells that scientists have been searching for in the quest to make regenerative medicine possible," Dr. Péault said. "The encouraging aspect of this source is that blood vessels are the one structure that all tissues in the human body have in common. These cells can be extracted easily and painlessly from convenient sources such as fat tissue, dental pulp, umbilical cord and placental tissue, then grown in culture to large numbers and, possibly, re-injected into the patient to heal a broken bone, a failing joint or an injured muscle."
Results of the study are published in the September issue of the journal Cell Stem Cell.
Could pericytes or cells grown from pericytes be injected into joints to repair worn cartilage? We are all wearing out. Many of us will some day start feeling pains from cartilage wearing (and some of you already feel such pains). So the ability to manipulate pericytes to get them to do our bidding will probably some day help us avoid a lot of suffering.
Update: Some Stanford researchers also just discovered a muscle stem cell that exists among muscle satellite cells.
A single cell can repopulate damaged skeletal muscle in mice, say medical school scientists who devised a way to track the cell's fate in living animals. The research is the first to confirm that the so-called satellite cells, which encircle muscle fibers, harbor an elusive muscle stem cell.
Identifying and isolating such a cell in humans would have therapeutic implications for disorders such as muscular dystrophy, muscle injury and muscle wasting due to aging, disuse or disease.
"We were able to show at the single-cell level that these cells are true, multipotent stem cells," said Helen Blau, PhD, the Donald E. and Delia B. Baxter Professor of Pharmacology. "They fit the classic definition: they can both self-renew and give rise to specialized progeny." Blau is the senior author of the study, published Sept. 17 in the online issue of Nature.
Alessandra Sacco, PhD, senior research scientist in Blau's laboratory and the article's first author, added, "It's been known that these satellite cells are crucial for the regeneration of muscle tissue, but this is the first demonstration of self-renewal of a single cell."
The transplanted individual cells went on to replicate into thousands and even tens of thousands of cells. But these researchers were not able to tell which satellite cells are really stem cells. So they have more work to do in order to know when a particular cell is really a stem cell.
I am especially interested to learn whether these stem cells, satellite cells, and other progenitor cells show signs of serious aging. Or do muscles, blood vessels, and other tissue decay because the signaling gets lost or muffled that should tell the stem cells to produce replacement repair cells?
Harvard researchers have improved a technique for converting adult cells into induced pluripotent stem (iPS) cells. Pluripotent stem cells can become all other cell types in the body.
Now researchers led by Konrad Hochedlinger of the Massachusetts General Hospital, Boston, have used the same four genes to create iPS cells, but carried instead by adenoviruses. These don't normally integrate into the genome of cells that they infect and therefore present little risk of cancer.
Many gene therapy techniques boost the risk of cancer. The initial method used to introduce genes to reprogram adult cells into stem cells ran the risk of creating cancerous cells. This newer technique lowers that risk substantially.
This method for creating pluripotent stem cells has a few advantages over using embryos. Most obviously, the political ethical opposition to human embryo destruction is avoided. Second, the stem cells can be produced from one's own body and so they are more likely to be immunologically compatible. Third, the cost might go lower.
"This is certainly a major stem cell milestone," said Advanced Cell Technologies chief scientific officer Bob Lanza, who was not involved in the research. "It’s the first ray of light that iPS cells could soon be used to treat patients."
These iPS cells -- short for induced pluripotent stem cell -- debuted less than a year ago: By using viruses to insert key developmental genes, researchers coaxed human skin cells into an embryonic state, capable of growing into almost any other type of tissue.
This moves us a lot closer toward having useful stem cell therapies. We need those therapies in order to reverse the aging process and rejuvenate our bodies.
ROCHESTER, Minn. -- Mayo Clinic investigators have demonstrated that stem cells can be used to regenerate heart tissue to treat dilated cardiomyopathy, a congenital defect. Publication of the discovery was expedited by the editors of Stem Cells and appeared online in the "express" section of the journal's Web site at http://stemcells.alphamedpress.org/.
And yet people do not complain that mice get all the great medical treatments first. Why is that? My theory: the mice have somehow brainwashed us. PETA (People for the Ethical Treatment of Animals) are really a secret organization of people who are immune to mouse brainwashing. They pose as animal rights activists. But in reality they are human rights activists trying to move humans ahead of mice in priority for treatment development. If the mice find out that I've told you this then I'll probably have to get some cats as bodyguards.
The key here is that the scientists used embryonic stem cells. This seems pretty straightforward to try in humans except for the regulatory obstacles that stand in the way.
The team reproduced prominent features of human malignant heart failure in a series of genetically altered mice. Specifically, the "knockout" of a critical heart-protective protein known as the KATP channel compromised heart contractions and caused ventricular dilation or heart enlargement. The condition, including poor survival, is typical of patients with heritable dilated cardiomyopathy.
Researchers transplanted 200,000 embryonic stem cells into the wall of the left ventricle of the knockout mice. After one month the treatment improved heart performance, synchronized electrical impulses and stopped heart deterioration, ultimately saving the animal's life. Stem cells had grafted into the heart and formed new cardiac tissue. Additionally, the stem cell transplantation restarted cell cycle activity and halved the fibrosis that had been developing after the initial damage. Stem cell therapy also increased stamina and removed fluid buildup in the body, so characteristic in heart failure.
Embryonic stem cells are pluripotent. That means they can become all other cell types. Another way to create pluripotent stem cells without using an embryo will eventually make it possible to create pluripotent stem cells that do not raise big ethical opposition.
The use of stem cells to do repairs will be easier for some organs than others. I'm hopeful from reports like the one above that most heart problems will be among the easier problems to solve.
Looking ahead 20 years I'm most worried about cancer and brain aging. I would be surprised if organ failures will still kill a lot of people in industrialized countries 20 years from now. Will cancer become easily curable in 20 years? Maybe. But brain aging is going to be the hardest problem to solve.
Jane Gitschier, with the UCSF Departments of Medicine and Pediatrics, interviewed U Wisc stem cell researcher Jamie Thomson for PLoS Genetics. Thomson was the first person to derive a human embryonic stem cell line and has other firsts to his credit. The whole interview is worth a read. But the most interesting point to me related to how Thomson's lab first figured out how to create human pluripotent stem cells (capable of becoming all cell types) without using embryonic cells as a starting point. Thomson could have made the induced pluripotent stem cell breakthrough 5 years sooner but the problem seemed it must be really hard to solve and so he didn't immediately try the easiest ways to make this happen.
Gitschier: And now, you've developed a new technology that may obviate some of these political and funding issues: Induced pluripotent stem [IPS] cells. Set the stage for that for me.
Thomson: The stage was Dolly really—that changed the mindset of developmental biologists in a big way, including mine. About 5 years ago, I hired the post-doc [Junying Yu] who was the first author on our paper [published in 2007]. My conversation with her at the time was that we have to try this, even though it probably isn't going to work. And it's probably like a 20-year problem, because the thought back then was that it has just got to be really complicated. All those little factors, and how can you manipulate all of those? It didn't really seem sensible.
I thought by doing such a combinatorial screen, we might get PARTIAL reprogramming in some way.
Gitschier: Describe what you mean by combinatorial screen.
Thomson: I'll tell you what we did, and it was very similar to what Yamanaka did in the mouse. We were doing it at the same time, but he got ahead of us because mouse work is actually much faster than human work, although we actually had a partially defined system with a more complicated set of factors prior to publication of his mouse work.
Back in the '70s, it was found that if you fuse blood cells with embryonic carcinoma [EC] cells—ES cells hadn't been derived yet—that within that heterokaryon, the dominant phenotype could either be the blood cell or the EC cell, but it was often the EC cell. So that was early evidence for reprogramming.
We started to do similar experiments several years ago, in which we took ES cell–derived blood cells. We had a well-defined, cloned, expandable hematopoietic cell type that we used in cell fusions for a model for reprogramming, and we showed that the dominant phenotype was the ES cell.
We did gene expression analysis of both those cell types and started to clone genes that were specifically enriched in ES cells. So Junying cloned between 100 and 200 genes, and she started taking pools of them to test for reprogramming ability and we used a knock-in human ES cell line that turns green and gets drug resistant when it reprograms to an ES cell state. Last summer, Junying kept paring it down until there were four factors, and we repeated it in different cell types.
It was kind of a dumb thing to do—it worked and that is nice. If you look at the factors we found, OCT4, SOX2, and NANOG—they're everybody's favorite genes already—these are key pluripotency genes. But we had this mindset, which was so strong, that it HAD to be complicated, we just never tested them! It would have been a lot easier to just test them 5 years ago and gotten it done in a month or two!
Gitschier: These IPS cells won't be restricted in terms of federal funding?
Thomson: No. That changes everything.
This breakthrough speeds up progress toward the development of useful stem cell therapies because it opens up the funding floodgates for working with human pluripotent stem cells by producing them in a way that doesn't involve use of a human fetus. But the gene twiddling involved in this technique might not produce cells safe enough for injection into humans. More refined ways to manipulate adult cells to revert them into an embryonic state might be necessary to produce cells that won't go cancerous.
Scientists have identified about two dozen genes that control embryonic stem cell fate. The genes may either prod or restrain stem cells from drifting into a kind of limbo, they suspect. The limbo lies between the embryonic stage and fully differentiated, or specialized, cells, such as bone, muscle or fat.
By knowing the genes and proteins that control a cell's progress toward the differentiated form, researchers may be able to accelerate the process – a potential boon for the use of stem cells in therapy or the study of some degenerative diseases, the scientists say.
Their finding comes from the first large-scale search for genes crucial to embryonic stem cells. The research was carried out by a team at the University of California, San Francisco and is reported in a paper in the July 11, 2008 issue of "Cell."
This understanding will lead scientists to eventually be able to turn adult cells into embryonic stem cells. This will also lead to techniques to instruct embryonic stem cells to become more differentiated (specialized). So if kidney tissue is needed it will become possible to instruct the stem cells to become kidney cells. Ditto other cell types as needed.
By injecting purified stem cells isolated from adult skeletal muscle, researchers have shown they can restore healthy muscle and improve muscle function in mice with a form of muscular dystrophy. Those muscle-building stem cells were derived from a larger pool of so-called satellite cells that normally associate with mature muscle fibers and play a role in muscle growth and repair.
In addition to their contributions to mature muscle, the injected cells also replenished the pool of regenerative cells normally found in muscle. Those stem cells allowed the treated muscle to undergo subsequent rounds of injury repair, they found.
"Our work shows proof-of-concept that purified muscle stem cells can be used in therapy," said Amy Wagers of Harvard University, noting that in some cases the stem cells replaced more than 90 percent of the muscle fibers. Such an advance would require isolation of stem cells equivalent to those in the mouse from human muscle, something Wagers said her team is now working on.
Suppose this team manages to isolate muscle stem cells from human muscles and manages to get to replicate outside of the body. Add in a gene therapy to fix a mutation that causes muscular dystropy and it should be possible to inject these stem cells back into muscles and cause a gradual improvement in symptoms.
What I'd really like to see: Apply this approach to old folks who have old shriveled muscles. Imagine the development of a technique to separate the stem cells that have the most DNA damage from those stem cells that are still in good shape. Then grow up the stem cells that are still fairly young and inject them back into a person. The result might be a partial rejuvenation of aged muscles.
Think that if only we could create youthful stem cells and then inject them into various parts of the our aging bodies the youthful stem cells would repair us? I've previously reported on work by Thomas Rando's group at Stanford that found something in old blood suppresses stem cells and prevents them from creating new cells for repair. That's a huge obstacle in the of way of use of stem cells for rejuvenation and repair. But a new report from Berkeley (from a team that not coincidentally includes a person who used to work with Rando at Stanford) attempts to genetically engineer stem cells to basically ignore the signals that old bodies use to tell stem cells not to do repairs.
Berkeley - Old muscle got a shot of youthful vigor in a stem cell experiment by bioengineers at the University of California, Berkeley, setting the path for research on new treatments for age-related degenerative conditions such as muscle atrophy or Alzheimer's and Parkinson's diseases.
In a new study to be published June 15 in an advanced online issue of the journal Nature, researchers identified two key regulatory pathways that control how well adult stem cells repair and replace damaged tissue. They then tweaked how those stem cells reacted to those biochemical signals to revive the ability of muscle tissue in old mice to repair itself nearly as well as the muscle in the mice's much younger counterparts.
Irina Conboy, an assistant professor of bioengineering and an investigator at the Berkeley Stem Cell Center and at the California Institute for Quantitative Biosciences (QB3), led the research team conducting this study.
There's a big problem with ignoring those signals that suppress cell division: When cells totally ignore signals that inhibit growth those cells are called cancer cells. We need growth regulation. But not too much or too little or at the wrong time.
The Berkeley researchers are trying to deal with the problem of old blood suppressing repair by younger cells. But that old blood contains cell division suppressor molecules
"We don't realize it, but as we grow our bodies are constantly being remodeled," said Conboy. "We are constantly falling apart, but we don't notice it much when we're young because we're always being restored. As we age, our stem cells are prevented, through chemical signals, from doing their jobs."
The good news, the researchers said, is that the stem cells in old tissue are still ready and able to perform their regenerative function if they receive the appropriate chemical signals. Studies have shown that when old tissue is placed in an environment of young blood, the stem cells behave as if they are young again.
"Conversely, we have found in a study published last year that even young stem cells rapidly age when placed among blood and tissue from old mice," said Carlson, who will stay on at UC Berkeley to expand his work on stem cell engineering either as a QB3 fellow or a postdoctoral researcher. He will be supervised by Conboy; Tom Alber, professor of biochemistry; and David Schaffer, associate director of the Berkeley Stem Cell Center and professor of chemical engineering.
Thomas Rando at Stanford and Irina Conboy (who was at Stanford working with Rando) have been working on the problem of what causes stem cells to stop doing repairs in old body. Rando is looking at a molecule called Wnt as a suppressor of old stem cells. This latest report from Conboy builds in years of work trying to puzzle out why our repair capabilities decline with age.
In this latest round of work the researchers blocked a pathway of cellular growth inhibition. As we age the concentration of a growth-promoting molecule called notch declines while a growth inhibiting molecule called TGF-beta goes up in concentration. So they lowered concentration of the molecule pSmad3 which TGF-beta promotes. By lowering pSmad3 they got excellent muscle tissue repair in the mice.
But what would happen if researchers blocked the adult stem cells in old tissues from reacting to those TGF-beta signals? The researchers put that question to the test in a living organism by comparing the muscle regeneration capacity of old, 2-year-old mice, comparable in age to a 75- to 80-year-old human, with that of 2-month-old mice, similar in age to a 20- to 25-year-old human.
For a group of the old mice, the researchers disabled the "aging pathway" that tells stem cells to stop dividing by using an established method of RNA interference that reduced levels of pSmad3. The researchers then examined the muscle of the different groups of mice one to five days after injury to compare how well the tissue repaired itself.
As expected, the researchers found that muscle tissue in the young mice easily replaced damaged cells with new, healthy cells. In contrast, the areas of damaged muscle in the control group of old mice were characterized by fibroblasts and scar tissue.
However, muscles in the old mice whose stem cell "aging pathway" had been dampened showed levels of cellular regeneration that were comparable to their much younger peers, and that were 3 to 4 times greater than those of the group of "untreated" old mice.
The researchers cautioned that shutting down the TGF-beta/pSmad3 pathway altogether by turning off the gene that controls it could lead to many health problems. The ability to suppress cell division is critical in controlling the development of tumors, for instance.
This report does not outline a solution to the problem of growth inhibition of stem cells in aging bodies. Blocking the suppressor molecules will enhance growth of stem cells needed for repair. But the effect will be too widespread. Cells that ought not divide will get activated. Some of those activated cells might be cancerous.
These researchers are working on a hard problem. The pathways for cellular growth control are complex. The bloodstream in older bodies carries growth inhibiting compounds that deliver a net benefit by reducing cancer risk. If we had great cures for cancer then we might be able to block those inhibiting compounds. But absent those great cures for cancer we need ways to selectively inhibit old stem cells but not younger stem cells.
Heart rejuvenation is fundamentally a DNA programming problem. With enough knowledge about how to run the DNA software we can make stem cells become replacement cells in cardiac muscle and in the rest of the body.
SAN FRANCISCO, CA –March 5, 2008--Researchers at the Gladstone Institute of Cardiovascular Disease (GICD) and the University of California, San Francisco have identified for the first time how tiny genetic factors called microRNAs may influence the differentiation of pluripotent embryonic stem (ES) cells into cardiac muscle. As reported in the journal Cell Stem Cell, scientists in the lab of GICD Director, Deepak Srivastava, MD, demonstrated that two microRNAs, miR-1 and miR-133, which have been associated with muscle development, not only encourage heart muscle formation, but also actively suppress genes that could turn the ES cells into undesired cells like neurons or bone.
“Understanding how pluripotent stem cells can be used in therapy requires that we understand the myriad processes and factors that influence cell fate,” said Dr. Srivastava. “This work shows that microRNAs can function both in directing how ES cells change into specific cells—as well as preventing these cells from developing into unwanted cell types.”
These microRNAs trigger gene activity that turns the embryonic stem cells into cardiac muscle. With more knowledge about the activity of hundreds (or perhaps thousands) of microRNAs we will be able to make large numbers of tissue types from stem cells. It is a matter of discovering a large number of possible ways to instruct cells to do our bidding.
How long will it take to figure which microRNA can tell which cell type to become which other cell type? I'm thinking that microfluidics will speed up this process by automating the testing of large numbers of microRNAs with large numbers of cell types. The rate of advance in stem cell manipulation will accelerate every year as microfluidic devices and other tools for lab automation allow the solution space to be searched orders of magnitude more rapidly.
Donovan and Leslie Lock, assistant adjunct professor of biological chemistry and developmental and cell biology at UCI, previously identified proteins called growth factors that help keep cells alive. Growth factors are like switches that tell cells how to behave, for example to stay alive, divide or remain a stem cell. Without a signal to stay alive, the cells die.
The UCI scientists – Donovan, Lock and Kristi Hohenstein, a stem cell scientist in Donovan’s lab – used those growth factors in the current study to keep cells alive, then they used a technique called nucleofection to insert DNA into the cells. Nucleofection uses electrical pulses to punch tiny holes in the outer layer of a cell through which DNA can enter the cell.
With this technique, scientists can introduce into cells DNA that makes proteins that glow green under a special light. The green color allows them to track cell movement once the cells are transplanted into an animal model, making it easier for researchers to identify the cells during safety studies of potential stem cell therapies.
Scientists today primarily use chemicals to get DNA into cells, but that method inadvertently can kill the cells and is inefficient at transferring genetic information. For every one genetically altered cell generated using the chemical method, the new growth factor/nucleofection method produces between 10 and 100 successfully modified cells, UCI scientists estimate.
Gene therapy has been a great disappointment. Back in the mid 1990s gene therapy research seemed more promising. This gene therapy method is for cells that can be removed from the body. So it is useful for preparing stem cells (and probably non-embryonic stem cells) to accept DNA. But it is not a general solution for gene therapy.
This report is especially interesting because the improvement by orders of magnitude. To get from where we are to where we need to be with gene therapy and stem cell therapy we need many advances that bring orders of magnitude improvements in our ability to manipulate cells and genes
Confirming work reported a few months ago by other researchers, a group at UCLA have demonstrated that adult human skin cells can be reprogrammed to act like embryonic stem cells.
UCLA stem cell scientists have reprogrammed human skin cells into cells with the same unlimited properties as embryonic stem cells without using embryos or eggs.
Led by scientists Kathrin Plath and William Lowry, UCLA researchers used genetic alteration to turn back the clock on human skin cells and create cells that are nearly identical to human embryonic stem cells, which have the ability to become every cell type found in the human body. Four regulator genes were used to create the cells, called induced pluripotent stem cells or iPS cells.
The UCLA study confirms the work first reported in late November of researcher Shinya Yamanaka at Kyoto University and James Thompson at the University of Wisconsin. The UCLA research appears Feb. 11, 2008, in an early online edition of the journal Proceedings of the National Academy of the Sciences.
The implications for disease treatment could be significant. Reprogramming adult stem cells into embryonic stem cells could generate a potentially limitless source of immune-compatible cells for tissue engineering and transplantation medicine. A patient’s skin cells, for example, could be reprogrammed into embryonic stem cells. Those embryonic stem cells could then be prodded into becoming various cells types – beta islet cells to treat diabetes, hematopoetic cells to create a new blood supply for a leukemia patient, motor neuron cells to treat Parkinson’s disease.
“Our reprogrammed human skin cells were virtually indistinguishable from human embryonic stem cells,” said Plath, an assistant professor of biological chemistry, a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and lead author of the study. “Our findings are an important step towards manipulating differentiated human cells to generate an unlimited supply of patient specific pluripotent stem cells. We are very excited about the potential implications.”
This research helps to get around the opposition to embryonic stem cell research. But these results also demonstrate progress in understanding cellular differentiation. Scientists first had to discover genes that play a role keeping cells in the embryonic state before they could know how to turn very differentiated (specialized) cells into much more flexible wider purpose cells
Our biggest obstacle for turning stem cells into useful therapies probably is our limited understanding of how cells regulate their conversion into a large assortment of specialized cell types. If we knew much more about how cells regulate themselves we'd have a much better idea of how to intervene to control them for therapeutic purposes.
In a paper to be published Nov. 22 in the online edition of the journal Science, a team of University of Wisconsin-Madison researchers reports the genetic reprogramming of human skin cells to create cells indistinguishable from embryonic stem cells.
The new study was conducted in the laboratory of UW-Madison biologist James Thomson, the scientist who first coaxed stem cells from human embryos in 1998. It was led by Junying Yu of the Genome Center of Wisconsin and the Wisconsin National Primate Research Center.
For several years I've been expecting clever scientists to figure out ways to basically program around the limitations on embryonic stem cell research. By finding ways to turn the knobs on genetic switches in the cell it was inevitable that scientists would figure out how to make cells change state into embryonic cells. They will next find more genetic knobs to turn in order to convert embryonic cells into precisely desired cell types and they will even find ways convert between various non-embryonic cell types while totally avoiding an intermediate state where the cells are like embryonic cells. Cells are just complex state machines. The next few decades of advance in biotechnology can be seen as a series of advances in techniques for causing desired and useful cell state transitions.
Shinya Yamanaka of Kyoto University led a separate team that also accomplished this same goal of reprogramming adult skin cells to turn them into pluripotent stem cells
The same feat is reported in the journal Cell by Prof Yamanaka with colleagues in Japan and America, the scientist who pioneered this approach of "nuclear reprogramming" in mice. He too reports that a simple recipe turns human skin cells into embryonic stem cell-like cells, he calls "iPS" cells.
From about 50,000 human cells treated with four factors introduced by a virus, his team obtained 10 distinct kinds of embryonic like cells.
"This efficiency may sound very low," said Prof Yamanaka but in practice it means a single experiment in a Petri dish will yield several lines of embryo like cells, while cloning would require dozens of human eggs to achieve the same feat.
Doug Melton, a stem-cell researcher at Harvard University, heralded the breakthrough.
Yamanaka, of Kyoto University in Japan, last year was the first to reveal the successful creation of reprogrammed cells in mice; he and two other research groups published improvements on that step this July. Many scientists thought it would take years to do the same with human cells.
"We appear to be closer than we ever thought we might be to a day when we could use this alternative method," Melton said in prepared remarks.
Though Thomson and Yamanaka both reprogrammed human skin cells using four genes, their methods differed slightly. They used different viruses to deliver the genes. Both used genes called Oct4 and Sox2, but Thomson used two others called Nanog and Lin28, while Yamanaka used c-Myc and Klf4.
These results aren't surprising. The most important difference between embryonic cells and adult cells is whch genes are activated. These scientists basically figured out how to apply a software patch to human cells that made them express genes that make them act like embryonic cells. Scientists have already identified these genes as active in early stage embryonic stem cells and have experimented with activating them in mouse cells.
"While this is exciting basic research, it could still take years to get this to work in humans in a way that could be used clinically," said Robert Lanza, chief scientific officer of Advanced Cell Technology in Worcester, Mass. "I cannot overstate that this is early-stage research and that we should not abandon other areas of stem cell research."
It seems unlikely that these cells have been pushed into a state that is exactly like the state of an embryonic stem cell. That state might have very subtle aspects that are important in ways we have not yet discovered. The cells created by these two new methods might suffer lingering effects from the introduced genes and a technique to silence those genes at some later step might be needed. But then cloning didn't produce perfect embryonic stem cells either.
Christian opponents of embryonic stem cell research are celebrating this discovery since the result reduces the advantage of working with embryo-derived cells.
Today, Family Research Council President Tony Perkins praised the research of Dr. James Thomson and Dr. Shinya Yamanaka. Thomson, the first to grow human embryonic stem cells, and Yamanaka from Japan, published results in the journals Science and Cell, respectively, showing that embryonic-type stem cells can be produced directly from ordinary human skin cells, without first creating or destroying human embryos
Wesley J. Smith, the Discovery Institute's Senior Fellow in Bioethics and author of Consumer's Guide to a Brave New World, hailed the breakthrough as demonstrating that ethical science is also good science: "Everyone should applaud this tremendous scientific achievement. We now have the very real potential of developing thriving and robust stem cell medicine and scientific research sectors that will bridge, rather than exacerbate, our moral differences over the importance and meaning of human life."
They are happy about this result because it probably will make the use of embryonic stem cells unnecessary. But the result also seems to show that the difference between embryonic stem cells and other cells is just different settings on a few genetic switches in the cell. So doesn't this result make embryonic stem cells seem less magical and less supernatural?
CAMBRIDGE, Mass. (October 10, 2007) – The protein Oct4 plays a major role in embryonic stem cells, acting as a master regulator of the genes that keep the cells in an undifferentiated state. Unsurprisingly, researchers studying adult stem cells have long suspected that Oct4 also is critical in allowing these cells to remain undifferentiated. Indeed, more than 50 studies have reported finding Oct4 activity in adult stem cells.
But those findings are misleading, according to research in the lab of Whitehead Member Rudolf Jaenisch.
In a paper published online in Cell Stem Cells on October 10, postdoctoral fellow Christopher Lengner has shown that Oct4 is not required to maintain adult stem cells in their undifferentiated state in mice, and that adult tissues function normally in the absence of Oct4. Furthermore, using three independent detection methods in several tissue types in which Oct4-positive adult stem cells had been reported, Lengner found either no trace of Oct4, or so little Oct4 as to be indistinguishable from background readings.
This means that pluripotency, the ability of stem cells to change into any kind of cell, is regulated differently in adult and embryonic stem cells.
“This is the definitive survey of Oct4,” says Jaenisch, who is also an MIT professor of biology. “It puts all those claims of pluripotent adult stem cells into perspective.”
Why does this matter one whole heck of a lot? If we could turn adult stem cells into pluripotent stem cells (i.e. into stem cells that can then become all other types of cells in the body) then we might not need embryonic stem cells for that purpose. If we could reduce the need for embryonic stem cells then research into pluripotent stem cells would probably progress more rapidly.
Cellular differentiation is the process by which stem cells become specialized cell types such as muscle cells, nerve cells, skin cells, and liver cells. Research into genes that control differentiation is also generally useful for efforts to develop replacement organs and other replacement body parts. We need to know how all the genes that regulate differentiation interact with each other in complex signaling networks. We also drugs, gene therapies, techniques that can control the process of cellular differentiation. The ability to control cellular differentiation will give us replacement parts as our bodies wear out.
Once we can coax stem cells to go into places in the body and repair decayed tissue we are well on the way toward achieving the ability to do full body rejuvenation. Granted, we'll need other capabilities as well. But the ability to coax and direct stem cells is going to be one of the key pieces of the rejuvenation puzzle. With that in mind, this report about a special class of adult stem cells which can repair muscles is intriguing. Adult myoendothelial stem cells isolated from blood vessel walls can form muscle strands.
In a study using human muscle tissue, scientists in Children's Stem Cell Research Center - led by Johnny Huard, PhD, and Bruno Péault, PhD - isolated and characterized stem cells taken from blood vessels (known as myoendothelial cells) that are easily isolated using cell-sorting techniques, proliferate rapidly and can be differentiated in the laboratory into muscle, bone and cartilage cells.
These characteristics may make them ideally suited as a potential therapy for muscle injuries and diseases, according to Drs. Huard and Péault. Results of the study are published in the September issue of the journal Nature Biotechnology.
"Finding this population of stem cells in a human source represents a major breakthrough for us because it brings us much closer to a clinical application of this therapy," said Dr. Huard, the Henry J. Mankin Professor and vice chair for Research in the Department of Orthopaedic Surgery at the University of Pittsburgh School of Medicine. "To make this available as a therapy, we would take a muscle biopsy from a patient with a muscle injury or disease, remove the myoendothelial cells and treat the cells in the lab. The stem cells would then be re-injected into the patient to repair the muscle damage. Because this is an autologous transplant, meaning from the patient to himself, there is not the risk of rejection you would have if you took the stem cells from another source."
Muscles shrivel with age. Can myoendothelial stem cells restore muscles to something approaching their youthful glory? One problem is going to be that the myoendothelial stem cells will also age and myoendothelial stem cells isolated from a 70 or 80 year old might grow slowly and form tired muscle fibers.
But combine isolation of myoendothelial stem cells from an old body with some gene therapies to repair those stem cells and youthful stem cells for body repair could become available. How to develop those cellular rejuvenating gene therapies will probably turn out to be the hardest problem to solve to make adult stem cells fully useful in rolling back the ravages of aging.
Other types of adult stem cells can also form muscle. But the other types of adult stem cells form muscle much less efficiently.
Working in dystrophic mice while searching for a cure for Duchenne muscular dystrophy (DMD), Dr. Huard's laboratory team first identified a unique population of muscle-derived stem cells with the ability to repair muscle 8 years ago.
Dr. Péault, a professor in the Department of Pediatrics, Cell Biology and Physiology at the University of Pittsburgh School of Medicine, recognized the importance of determining the origin of these muscle-derived stem cells. His team applied, among others, techniques of confocal microscopy and cell sorting by flow cytometry which led to the discovery in human muscle biopsies that these myoendothelial cells are located adjacent to the walls of blood vessels.
According to their study, myoendothelial cells taken from the blood vessels are much more efficient at forming muscle than other sources of stem cells known as satellite and endothelial cells.A thousand myoendothelial cells transplanted into the injured skeletal muscle of immunodeficient mice produced, on average, 89 muscle fibers, compared with 9 and 5 muscle fibers for endothelial and satellite cells, respectively. Myoendothelial cells also showed no propensity to form tumors, a concern with other stem cell therapies.
These researchers are chasing after better treatments for Duchenne muscular dystrophy (DMD). The development of stem cell treatments for DMD will inevitably lead to stem cell treatments to treat aged muscles. That is the way many rejuvenation therapies will come about. Efforts to repair damage caused by trauma, infection, and genetic defects will produce therapies that work to repair the damage caused by aging.
Melbourne, Australia; 20 August 2007: Australia's adult stem cell company, Mesoblast Limited (ASX:MSB;USOTC:MBLTY), today announced that preclinical trials of its patented adult stem cells had shown that the therapy significantly protected knee cartilage against damage in osteoarthritis.
Millions of people have osteoarthritis of the knee.
More than 10 million people in the US currently suffer from osteoarthritis of the knee, making it the most common joint disease. Osteoarthritis results in loss of cartilage which cannot repair itself after injury and for which there is no effective therapy. Current treatments attempt to alleviate painful symptoms but are unable to preserve the cartilage lining the joint. Moreover, many of the currently used pharmaceutical therapies are associated with severe side-effects and can even cause death. Joint replacement is often the only option for restoring function.
You may have knee osteoarthritis some day even if you don't now. Or you'll have it in your back or hands or shoulders or hips or some combination thereof. Your parts are wearing out. You need replacement parts.
People and dogs really suffer from decaying joints. We need stem cell therapies for joint rejuvenation and repair.
With the support of the Australian Government's Commercial Ready Grant award, Mesoblast's cartilage trials evaluated the effectiveness and safety of the company's allogeneic (donor unrelated) adult stem cells to treat osteoarthritis of the knee in 48 sheep arthritic joints. The results showed that joint cartilage in osteoarthritic knees of animals receiving Mesoblast's stem cells had significantly greater thickness, reduced breakdown, and greater biomechanical strength three months after injection into the knee than did control joints receiving injections of hyaluronic acid.
The trial's principal investigator, Professor Rick Read at the Murdoch University in Western Australia, said: "We are delighted with the significant cartilage protective effects of Mesoblast's allogeneic cells in our large animal model of knee osteoarthritis, without any adverse events of the cells at all".
We need this technology to work in humans. The benefits will be enormous. We need it faster.
For several years here I've argued the ethical conflict over human embryonic stem cell research would get resolved by discovery of techniques to dedifferentiate adult cells (make cells less specialized and more flexible). Well, at least with mice a method has been discovered to do exactly that. The use of gene therapy to turn on 4 genes in adult mouse cells transforms those cells to make them as flexible as embryonic stem cells.
Now, in three papers published simultaneously this week, Yamanaka and two other groups report that by turning on expression of the same four chemicals in adult mouse cells, the cells run their differentiation process backwards, reverting to an ESC-like state (Nature, DOI:10.1038/nature05934 and DOI:10.1038/nature05944; Cell Stem Cell, DOI:10.1016/j.stem.2007.05.014). "We have shown that cells can be generated by these four factors, that are indistinguishable from embryonic stem cells," says Konrad Hochedlinger of the Harvard Stem Cell Institute, who wrote one of the papers (watch a video of Marius Wernig - first author on the same paper - describing the cells - 3.8 MB, .wmv).
These cells are pluripotent which means they are capable of turning into all the cell types in a body. Need new parts to replace old worn out organs, blood vessels, muscles, tendons, and joint tissue? Pluripotent cells will some day serve as starter cells for the growth of replacement parts. Replacement cells and organs will usher in the age of regenerative medicide and eventually full body rejuvenation.
What was the enabler that made these experiments possible? The discovery by Yamanaka's team that 4 genes could cause a cell to become pluripotent. As scientists discover more about which genes control cellular differentiation (how cells change to take on specialized jobs) more ways to manipulate cell type will come from use of this knowledge.
Using artificial viruses called vectors, the team activated the same four genes in a batch of mouse skin cells. These genes, Oct4, Sox2, c-Myc and Klf4, are called transcription factors, meaning that they regulate large networks of other genes. While Oct4 and Sox2 are normally active in the early stages of embryogenesis, they typically shut down once an embryo has developed beyond the blastocyst stage.
It says something about the immaturity of gene therapy techniques in the year 2007 that only 1 in 1000 cells exposed to viruses with the 4 genes got reprogrammed by the attempt to add genes to the cells.
“We were working with tens of thousands of cells, and we needed to devise a precise method for picking out those rare cells in which the reprogramming actually worked,” says Wernig. “On average, it only works in about one out of 1,000 cells.”
To test for reprogramming, the team decided to zero in on Oct4 and another transcription factor called Nanog. These two hallmarks for embryonic stem cell identity are only active in fully pluripotent cells. The trick would be to figure out a way to harvest Oct4- and Nanog-active cells from the rest of the population.
Nicholas Wade of the New York Times claims the technique, once replicated with human cells, will clost less and take less effort than cloning to create embryonic stem cells.
The technique, if adaptable to human cells, is much easier to apply than nuclear transfer, would not involve the expensive and controversial use of human eggs, and should avoid all or almost all of the ethical criticism directed at the use of embryonic stem cells.
“From the point of view of moving biomedicine and regenerative medicine faster, this is about as big a deal as you could imagine,” said Irving Weissman, a leading stem cell biologist at Stanford University, who was not involved in the new research.
Replicating this study with human cells poses some problems which scientists must solve. But some of the scientists are optimistic about solutions:
A third issue is that two of the genes in the recipe can cause cancer. Indeed 20 percent of Dr. Yamanaka’s mice died of the disease. Nonetheless, several biologists expressed confidence that all these difficulties would be sidestepped somehow.
“The technical problems seem approachable — I don’t see anyone running into a brick wall,” said Owen Witte, a stem cell biologist at U.C.L.A. Dr. Jaenisch, in a Webcast about the research, predicted that the problems of adapting the technique to human cells would be solvable but he did not know when.
The threat of cancer is a big problem with stem cells. We need better methods of doing gene therapy so that stem cells can get genetically altered to repair all genes that prevent cells from growing uncontrollably.
Thanks to Brock Cusick for the tip.
ANAHEIM, Calif., May 21 -- Women with stress urinary incontinence (SUI) treated using muscle-derived stem cell injections to strengthen their sphincter muscles experience long-term improvements in their condition, according to a study led by researchers at the University of Pittsburgh School of Medicine and Sunnybrook Health Sciences Centre in Toronto. The study, which followed patients for more than one year, suggests that the approach is safe, improves patients’ quality of life and may be an effective treatment for SUI. The findings will be presented at the Tissue Engineering and Regenerative Medicine in Urology press briefing at the annual meeting of the American Urological Association (AUA) in San Diego, and will be published in Abstract 1331 in the AUA proceedings.
The results of this study illustrate a pattern: Stem cell therapies for maladies of aging bodies look like rejuvenation therapies. The development of stem cell therapies to treat various problems will produce treatments that do rejuvenation. As long as civilization isn't destroyed by a natural disaster such as an asteroid or massive volcanic eruption the development of rejuvenation therapies is inevitable.
Someone might object and argue that this treatment has a very narrow effect on one location in the body. But these researchers are developing a rather general capability where they can supply replacement muscle cells where lack of muscle cells is the problem. Well, as we grow old our muscle cells become hobbled by damage and die. This happens in all our muscles. The ability to grow stem cells and turn them into muscle cells is a key capability needed to rejuvenate our bodies.
In the study, Dr. Carr and colleagues took biopsies of skeletal muscle tissue from eight female patients and isolated and expanded the stem cells from the tissue in culture. In an outpatient setting, the patients then received injections of the muscle-derived stem cells into the area surrounding the urethra. Each patient received an equal dose of stem cell injections using three different injection techniques – a transurethral injection with either an 8-mm or 10-mm needle or a periurethral injection.
Five of the eight women who participated in the study reported improvement in bladder control and quality of life with no serious short- or long-term adverse effects one year after the initial treatment.
A future enhancement of this treatment will be to take the muscle stem cells, treat them with gene therapies to correct accumulated DNA damage, and then grow them up for injection. Eventually scientists will even discover genetic variations that enhance muscle performance and the stem cells will get genetically engineered to form better muscle cells than we were born with.
Skeletal progenitor cells differentiate into cartilage cells when one master gene actually suppresses the action of another, said Baylor College of Medicine researchers in a report that appears online in the journal Proceedings of the National Academy of Sciences.
Skeletons are made of bone and cartilage cells that are differentiated from the same multipotent stem cell, said Dr. Brendan Lee, associate professor of molecular and human genetics at BCM, director of the Skeletal Dysplasia Clinic at Texas Children’s Hospital and a Howard Hughes Medical Institute investigator. This same stem cell gives rise to bone, cartilage, fat and fibroblasts.
“The big question is what are the master genes that make a stem cell go one way versus another,” said Lee.
Both SOX9 and RUNX2 are master transcription factors involved in the process of differentiating bone and cartilage.
SOX9 and RUNX2 are obvious candidates for drug development. A drug that could block SOX9 would probably cause skeletal progenitor cells to become bone cells. That'd be handy for bone repair and bone restoration for people suffering osteoporosis. A drug that could turn on SOX9 could produce cartilage to replace aged or damaged cartilage.
The master protein SOX9 directs skeletal progenitor cells to become cartilage and another master protein, RUNX2, directs such cells to become bone, However, he said, the primordial skeletal cell has both RUNX2 AND SOX9.
“We then asked a simple question: Could these master transcription factors (that direct the expression of other genes) directly affect one another’s function"” he said. After studies in the laboratory, with mice and with humans, the answer was yes.
“SOX9 appears to be the dominant player,” said Lee. “When it is present in a progenitor cell, it turns off RUNX2 and allows the cell to become cartilage.”
That does not answer the question of how such cells become bone.
“Clearly, something must turn off SOX9,” said Lee. “That’s the next question we have to answer.”
These two genes are part of a much larger set of genes that control cell differentiation (i.e. the process by which cells turn into all the specialized cell types on the body). Advances in biotechnology are accelerating the rate at which scientists working in labs can figure out how all these genes work. The more they learn the better able they will be to intervene and turn cells into any types needed for repair and rejuvenation.
Here's the paper: Dominance of SOX9 function over RUNX2 during skeletogenesis.
Using mouse embryonic stem cells Harvard researchers funded by the Howard Hughes Medical Institute have created a first draft map of how a set of proteins interact with each other to maintain embryonic stem cell state.
Howard Hughes Medical Institute (HHMI) researchers have created a map that charts the largely unexplored protein landscape that regulates a stem cell's ability to differentiate into multiple types of mature cells.
Understanding this protein network in greater detail could give stem cell biologists a new set of tools to coax mature cells to revert to an embryonic state, said the researchers. Reprogramming adult cells in this way could provide an alternative source of stem cells to use in regenerating tissues damaged by disease or trauma, rather than employing embryonic cells, they said.
HHMI investigator Stuart Orkin and his colleagues at Children's Hospital Boston and Harvard Medical School published their findings November 8, 2006, in an advanced online publication in the journal Nature.
They've also shown that depletion of concentration of a few of the proteins causes the cells to start showing signs that they are becoming more differentiated (specialized) to become cell types that carry out specific functions.
All these proteins will become targets for drug development to block or enhance their effects in order to shift cells into other states. Scientists will build on this work to create more detailed maps of how these proteins interact to control cell state. Likely still other proteins will be found to also interact with these proteins to control cell state. An increasingly more detailed map of relations between these proteins will provide a guide for where to intervene to control stem cell state. This report is a great foundation for further work along this line.
Orkin hopes the map will help guide the development of improvements in methods to better control reprogramming of cell state.
Orkin said that thus far experiments aiming at reprogramming mature cells into a stem cell-like state have yielded cells that imperfectly resemble embryonic stem cells. “However, with this new understanding of the network of regulatory factors, it might be possible to refine this approach to reprogramming,” he said.
He's being overly modest here. Of course this map will be useful for development of techniques to control cell state.
Note how these researchers think of the proteins in cells as forming complex circuits just as computer chips have complex circuits.
The regulatory network that maintains a stem cell's ability to become many different cell types - a characteristic called pluripotency - also prevents the cell from inappropriately differentiating into a mature cell, while keeping it poised to undergo maturation when required. This precise control relies on intricate circuits of interacting proteins that both regulate one another and govern the activity of genes.
While I sometimes write posts about promising individual stem cell treatments no one announcement of a promising treatment or even a dozen such announcements will amount to much of a breakthrough given our current deficient state of knowledge on how cells work. The real breakthroughs that will provide us with the most power to produce treatments are going to come from the development of knowledge on how cells control their differentiation (i.e. how cells specialize to become heart muscle cells or liver cells or other specialized types). So this announcement is much more important than the average report about stem cell advances.
Once scientists understand the complex circuitry governing cell differentiation the next set of real important breakthroughs (though mostly invisible to the general public) will come. Scientists will seek to intervene in those cellular circuits and to do so they will develop techniques to tweak those circuits in highly precise and controlled ways.
Cells in the embryonic state are several state changes away from any other state such as muscle cell or artery lining cell or liver cell. Once we have detailed knowledge of the circuits that control cell state the need for embryonic stem cells will go way down. It will become possible to start with a cell in any state and tweak it to shift into any other state.
Previous research has shown that the Nanog gene is a key regulator of whether a stem cell acts like an embryonic stem cell. Orkin's team used this previously discovered knowledge about Nanog to use it as a starting point to map the cell differentiation regulatory circuitry.
As the jumping-off point of their mapping effort, Orkin and his colleagues used a protein called Nanog, which other researchers' experiments had indicated was central to regulation of stem cell pluripotency. The researchers first tagged Nanog so that when they removed it from cells, they would simultaneously remove any proteins that were attached to it.
These experiments enabled them to identify numerous proteins that interact with Nanog, including some already known to regulate pluripotency. To confirm that the proteins they had found functioned to maintain stem cell pluripotency, they depleted the levels of several proteins in embryonic cells and observed that the cells then expressed markers of differentiation.
Drugs could emulate the depletion of a protein by blocking its activity. So each of these several proteins are obvious targets for drug development. To change stem cells into specialised cells or vice versa we need drugs that will bind to these regulatory proteins to turn them on or disable them. Scientists will gradually assemble large toolsets of molecules that can bind to regulatory proteins and by using them in different combinations and orders they will be able to change any cell type to any other cell type.
The researchers have created an initial map of how the proteins interact to maintain embryonic stem cell state.
Next, the researchers created a protein interaction map that showed the relationships among the various proteins. The map will provide stem cell biologists with an important guide for future studies, said Orkin. “Even though some of these factors were known to be important in pluripotency, exactly how they work and who they talk to and interact with was completely unknown,” he said.
This research is important for another reason: These scientists did not try to study one or two proteins at a time. If they did we'd have to wait another century before rejuvenation therapies become possible. The development of assay tools which allow measurement of many proteins or many genes at once has allowed scientists to study complex networks of interactions. Since cells contain many kinds of components functioning in complex networks this ability to collect more data about more target cell components at once is essential if we are to have a chance of benefitting from stem cell therapies.
Embryonic stem cells can serve as a renewable source of replacement tissue to rescue visual function in rats with degenerative eye disease similar to age-related macular degeneration, a leading cause of blindness in humans, according to a report to be published in the Fall 2006 (Volume 8, Number 3) issue of Cloning and Stem Cells, a peer-reviewed journal published by Mary Ann Liebert, Inc. The paper is available online ahead of print at www.liebertpub.com/clo
Robert Lanza, M.D. and Irina Klimanskaya, Ph.D. at Advanced Cell Technology (Worcester, MA), and Raymond Lund, Ph.D. and colleagues at the University of Utah Health Science Center (Salt Lake City) generated retinal pigment epithelium (RPE)--the cells that support photoreceptor function in the eye--from human embryonic stem cell lines grown in culture in the laboratory. They transplanted the engineered tissue into the eyes of rats that had a defect in their RPE. This defect results in the loss of photoreceptors and visual function.
The authors reported 100% improvement in visual performance (spatial acuity) in treated animals compared to an untreated control group, and the transplanted RPE cells did not cause any pathology. In the treated rats, spatial acuity, or the ability to see fine detail, was approximately 70% that of normal rats (that had no RPE defect).
"These observations are very exciting as they show that one day it will be possible to treat diseases of human eyes with cells," says Ian Wilmut, Ph.D., Editor-In-Chief of Cloning and Stem Cells and director of the Centre for Regenerative Medicine, in Edinburgh, Scotland. "They also emphasize the great potential benefit of research with human embryo stem cells, in this case for cell therapy."
Macular degeneration is the leading cause of blindness in persons over age 60 in the United States and affects more than 30 million people worldwide. Embryonic stem cells would offer a readily available, safe, and reproducible source of replacement tissue to restore photoreceptors damaged or destroyed by disease and to restore a range of visual functions.
"One important advantage offered by hES-derived cells over other cells developed to mimic or replace lost retinal pigment epithelium is that they more closely resemble primary human RPEs," stated Raymond D. Lund, Ph.D., Professor at the Moran Eye Center, University of Utah Health Science Center, Salt Lake City and the study's lead author. "Another significant advantage of using these cells is that a range of lines can be derived allowing the opportunity to 'tissue match' donor cells with recipient, a real advantage given that RPE cells are highly immunogenic and susceptible to rejection without some form of immunosuppression."
"Embryonic stem cells promise to provide a well-characterized and reproducible source of replacement cells for clinical studies," stated Robert Lanza, M.D., Vice President of Research & Scientific Development at ACTC and senior author of the paper. "All 18 human embryonic stem cell lines we studied reliably produced retinal cells that could potentially be used to treat retinal degenerative diseases, such as macular degeneration. We showed that these cells have the capacity to rescue visual function in animals that otherwise would have gone blind. Importantly, the cells did not appear to cause any unwanted pathological responses in the animals following transplantation."
Once useful human therapies are available which have been created using hESC the people making ethical arguments against the use of hESC are going to face much more opposition than they do today. The hypothetical future promise of hESC doesn't today motivate people to support hESC research as much as the availability of real treatments will.
The opponents of the use of hESC really ought to push harder to increase funding to develop other methods to create flexible and youthful stem cells. If they fail to do that they will find they are fighitng for a losing cause.
In a move that might provide a away around ethical objections to other ways to create human embryonic stem cells scientists were able to extract human embryonic stem cells from embryos that had ceased to grow
The journal STEM CELLS(R) today announced that scientists were able, for the first time, to derive pluripotent human embryonic stem cells (hESCs) from non-viable early human embryos.
The team, led by Professor Miodrag Stojkovic, derived hESCs using surplus and donated embryos that had stopped their cleavage. The scientists demonstrated that these non-viable embryos could be used under suitable laboratory conditions for derivation of hESCs and for study of early human development.
This progress, published in STEM CELLS(R), encourages other scientists to perform hESC research using both viable and non-viable pre-implantation embryos in their attempt to understand and fight debilitating diseases.
'This should get round opposition to stem cell science because live embryos will no longer need to be used in all experiments,' said Professor Miodrag Stojkovic, the researcher who carried out the experiments at the Centre for Stem Cell Biology at Newcastle University last year.
The embryos used were from attempts at in vitro fertilization where the embryos stopped growing even before implantation.
Stojkovic's experiments were carried out while he was working at the Centre for Stem Cell Biology at Newcastle last year. In a paper, published last week online on the website of the journal Stem Cells, Stojkovic reveals he and his colleagues took 13 embryos, created by IVF. All 13 had stopped developing a few days after conception. 'They were in a very early stage of development,' said Stojkovic, now head of Sintocell, the Serbian medical research centre.
The team then waited 24 hours to check that the embryos were no longer dividing before beginning their experiments.
But other stem cell scientists and ethicists quickly raised a host of reasons that the advance may have little practical impact on the stormy research field. Among them are concerns that cells from dead embryos may be genetically abnormal, and the lack of a definitive test for proving that an embryo has no lingering potential for life.
How to get around the genetic abormality problem? In theory doctors could take embryos from pregnant women who die from trauma such as from car accidents. The removal of cells from embryos to use for therapy development would be analogous to using organs. But I'm guessing that the early stage pregnancies where the embryos still have pluripotent (highly flexible) stem cells aren't going to be recognized either by the mother or by emergency room workers.
It could turn out that some of the IVF embryos stop dividing for epigenetic (chemical state around the genes rather than the genes themselves) reasons. If that turns out to be the case then some stem cells extracted using this technique might turn out to be in good genetic shape.
The full paper is available with free access.Here's the abstract excerpted from the paper (PDF format).
Human embryonic stem cells (hESC) hold huge promise in modern regenerative medicine, drug discovery, and as a model for studying early human development. However, usage of embryos and derivation of hESC for research and potential medical application has resulted in polarised ethical debates since the process involves destruction of viable developing human embryos. Here we describe that not only developing embryos (morulae and blastocysts) of both good and poor quality but also arrested embryos could be used for the derivation of hESC. Analysis of arrested embryos demonstrated that these embryos express pluripotency marker genes such OCT4, NANOG and REX1. Derived hESC lines also expressed specific pluripotency markers (TRA-1-60, TRA-1-81, SSEA4, alkaline phosphatase, OCT4, NANOG, TERT and REX1) and differentiated under in vitro and in vivo conditions into derivates of all three germ layers. All the new lines including line derived from late arrested embryo have normal karyotype. These results demonstrate that arrested embryos are additional valuable resources to surplus and donated developing embryos and should be used to study early human development or derive pluripotent hESC.
Biotech company Advanced Cell Technology (ACT) has announced development of a technique that can extract pluripotent human embryonic stem cells from a human embryo without destroying the embryo. In theory this technique provides a way to get human embryonic stem cells without destroying what some religious people think is a human life.
Alameda, CA, August 23, 2006 – Advanced Cell Technology, Inc. (OTC Bulletin Board: ACTC.OB) today reported that company scientists have successfully generated human embryonic stem cells (hES cells) using an approach that does not harm embryos. The technique is reported in an article appearing online (ahead of print) in the journal Nature. The article describes a method for deriving stem cells from human blastomeres with a single-cell biopsy technique called Preimplantation Genetic Diagnosis (PGD). This technique is used in in vitro fertilization (IVF) clinics to assess the genetic health of preimplantation embryos. The cell lines produced using this technique appear to be identical to hES cell lines derived from later stage embryos using techniques that destroy the embryo’s developmental potential. ACT had previously reported the successful use of a similar technique in mice in Nature in October 2005.
“Until now, embryonic stem cell research has been synonymous with the destruction of human embryos,” stated Robert Lanza, M.D., Vice President of Research & Scientific Development at ACT, and the study’s senior author. “We have demonstrated, for the first time, that human embryonic stem cells can be generated without interfering with the embryo’s potential for life. Overnight culture of a single cell obtained through biopsy allows both PGD and the development of stem-cell lines without affecting the subsequent chances of having a child. To date, over 1,500 healthy children have been born following the use of PGD.” Current technology derives hES cells from the inner cell mass of later-stage embryos known as blastocysts, destroying their potential for further development. ACT’s approach generates human embryonic stem cells from a single cell obtained from an 8-cell-stage embryo. The researchers used left-over embryos from fertility clinics which use IVF to create embryos for implantation. To create hES cell lines, the researchers used single cells obtained from unused embryos produced by IVF for clinical purposes. Nineteen stem-cell outgrowths and two stable hES cell lines were obtained. These cell lines were genetically normal and retained their potential to form all of the cells in the human body, including nerve, liver, blood, vascular, and retinal cells that could potentially be used to treat a range of human diseases.
“Until now, embryonic stem cell research has been synonymous with the destruction of human embryos,” stated Robert Lanza, M.D., Vice President of Research & Scientific Development at ACT, and the study’s senior author. “We have demonstrated, for the first time, that human embryonic stem cells can be generated without interfering with the embryo’s potential for life. Overnight culture of a single cell obtained through biopsy allows both PGD and the development of stem-cell lines without affecting the subsequent chances of having a child. To date, over 1,500 healthy children have been born following the use of PGD.”
Current technology derives hES cells from the inner cell mass of later-stage embryos known as blastocysts, destroying their potential for further development. ACT’s approach generates human embryonic stem cells from a single cell obtained from an 8-cell-stage embryo.
The researchers used left-over embryos from fertility clinics which use IVF to create embryos for implantation.
To create hES cell lines, the researchers used single cells obtained from unused embryos produced by IVF for clinical purposes. Nineteen stem-cell outgrowths and two stable hES cell lines were obtained. These cell lines were genetically normal and retained their potential to form all of the cells in the human body, including nerve, liver, blood, vascular, and retinal cells that could potentially be used to treat a range of human diseases.“One of the major ethical objections of those who oppose the generation of human embryonic stems cells is that all techniques, until now, have resulted in the destruction of the embryo,” stated Ronald Green, Ph.D., Director of Dartmouth College’s Ethics Institute and Chairman of ACT’s Ethics Advisory Board. “This technique overcomes this hurdle and has the potential to play a critical role in the advancement of regenerative medicine. It also appears to be a way out of the current political impasse in this country and elsewhere.”
But the new method, reported yesterday by researchers at Advanced Cell Technology on the Web site of the journal Nature, had little immediate effect on longstanding objections of the White House and some Congressional leaders yesterday. It also brought objections from critics who warned of possible risk to the embryo and the in vitro fertilization procedure itself, in which embryos are generated from a couple’s egg and sperm.
Regarding possible risks: Trying to get a pregnancy started the natural way poses large risks to the eggs that get fertilized using old fashioned sexual procreation. Perhaps half of all conceptions spontaneously abort with most never even recognized as pregnancies.
The incidence of spontaneous abortion is estimated to be 50% of all pregnancies, based on the assumption that many pregnancies abort spontaneously with no clinical recognition.
I predict that advances in reproductive biotechnology will eventually lead to the ability to create embryos and start pregnancies that have a far higher chance of going to term than pregnancies started the natural way.
Many scientists would like to take human embryonic stem cells (hESC) and find ways to instruct the cells to become whatever cell type that is needed. But restrictions on funding hESC work has slowed that avenue of investigation. Well, scientists at the University of Florida may have found a way to avoid the need for hESC to create neurons or neural progenitor cells for therapeutic purposes.
GAINESVILLE, Fla. -- University of Florida researchers have shown ordinary human brain cells may share the prized qualities of self-renewal and adaptability normally associated with stem cells.
Writing online today (Aug. 16) in Development, scientists from UF's McKnight Brain Institute describe how they used mature human brain cells taken from epilepsy patients to generate new brain tissue in mice.
Furthermore, they can coax these pedestrian human cells to produce large amounts of new brain cells in culture, with one cell theoretically able to begin a cycle of cell division that does not stop until the cells number about 10 to the 16th power.
They can grow large numbers of neurons. But how hard will it be to instruct those neurons to go into the brain and take up positions that replace lost neurons? For example, people with Parkinson's Disease have lost a lot of dopaminergic neurons. But neurons grown in culture aren't helpful unless they can be made to take up residence in those regions of the brain that have lost neurons and then once there the neurons would need to form appropriate connections with other neurons. Still, this is a hopeful result.
"We can theoretically take a single brain cell out of a human being and - with just this one cell - generate enough brain cells to replace every cell of the donor's brain and conceivably those of 50 million other people," said Dennis Steindler, Ph.D., executive director of UF's McKnight Brain Institute. "This is a completely new source of human brain cells that can potentially be used to fight Parkinson's disease, Alzheimer's disease, stroke and a host of other brain disorders. It would probably only take months to get enough material for a human transplant operation."
The findings document for the first time the ability of common human brain cells to morph into different cell types, a previously unknown characteristic, and are the result of the research team's long-term investigations of adult human stem cells and rodent embryonic stem cells.
Every sperm is sacred,
Every sperm is great,
If a sperm is wasted,
God gets quite irate.
Let the heathen spill theirs,
On the dusty ground,
God shall make them pay for,
Each sperm that can't be found.
Every sperm is wanted,
Every sperm is good,
Every sperm is needed,
In your neighbourhood.
Every neuron is sacred? Does every neuron contain part of a soul? If you torture a human neuron in lab culture are you torturing a human?
Well, whether or not human neurons are sacred they can grow in mouse brains. They also can grow in culture. Once sperm can be created from regular cells and grown in large numbers in culture dishes will those spem be sacred too?
Human neurons in the brain of a mouse or rat will not make that animal think human thoughts. Their skulls are far too small to provide enough space for enough human neurons to form links that make higher level thought possible.
With the introduction of just four factors, researchers have successfully induced differentiated cells taken from mouse embryos or adult mice to behave like embryonic stem cells. The researchers reported their findings in an immediate early publication of the journal Cell.
The cells--which the researchers designate "induced pluripotent stem cells" (iPS)--exhibit the physical, growth, and genetic characteristics typical of embryonic stem cells, they reported. "Pluripotent" refers to the ability to differentiate into most other cell types.
"Human embryonic stem cells might be used to treat a host of diseases, such as Parkinson's disease, spinal cord injury, and diabetes," said Shinya Yamanaka of Kyoto University in Japan. "However, there are ethical difficulties regarding the use of human embryos, as well as the problem of tissue rejection following transplantation into patients."
Those problems could be circumvented if pluripotent cells could be obtained directly from the patients' own cells.
"We have demonstrated that pluripotent stem cells can be directly generated from fibroblast cultures by the addition of only a few defined factors," Yamanaka said. Fibroblasts make up structural fibers found in connective tissue.
Pluripotent stem cells can become any type of cell in the body. Adult stem cells are not as flexible. But currently the only way to get pluripotent stem cells is from embryonic cells. That raises ethical opposition in some quarters. Pluripotent stem cells created from adult cells would avoid most of the political resistance and at the same time be more immunologically compatible.
If this approach works for humans as well then some day we'll be able to have pluripotent stem cells made from our own cells. Then those cells could be used to grow replacement parts such as internal organs or injected into joints to supply joint material to those suffering from arthritis.
The researchers chose factors to introduce into adult cells by looking at which genes are turned on in embryonic stem cells. Note that advances in biotechnology in recent years have made it a lot easier to measure the levels of activity of many genes at once.
The researchers selected 24 genes--all previously found to play a role in early embryos and embryonic stem cell identity--as candidate factors that might give body cells the ability to become other cell types.The researchers found that four of those factors, known as Oct3/4, Sox2, c-Myc, and Klf4, could lend differentiated fibroblast cells taken from embryonic or adult mice the pluripotency normally reserved for embryonic stem cells.
They further reported that transplantation of the iPS cells under the skin of mice resulted in tumors containing a variety of tissues representing the three primary types found in mammalian embryos. Those primary "germ layers" in embryos eventually give rise to all an animal's tissues and organs.
The researchers still need to repeat this experiment with human cells to find out if this method will work for human cells as well. If they succeed then this discovery could open the gates for much higher levels of research funding for pluripotent stem cells.
Embryonic stem cells converted into astrocyte cells repaired damaged rat spinal cords and allowed the rats to walk normally again.
Researchers believe they have identified a new way, using an advance in stem-cell technology, to promote recovery after spinal cord injury of rats, according to a study published in today's Journal of Biology.
Scientists from the New York State Center of Research Excellence in Spinal Cord Injury showed that rats receiving a transplant of a certain type of immature support cell from the central nervous system (generated from stem cells) had more than 60 percent of their sensory nerve fibers regenerate. Just as importantly, the study showed that more than two-thirds of the nerve fibers grew all the way through the injury sites eight days later, a result that is much more promising than previous research. The rats that received the cell transplants also walked normally in two weeks.
The University of Rochester Medical Center, Rochester, N.Y., and Baylor College of Medicine, Houston, collaborated on the work. Researchers believe they made an important advance in stem cell technology by focusing on a new cell type that appears to have the capability of repairing the adult nervous system.
"These studies provide a way to make cells do what we want them to do, instead of simply putting stem cells into the damaged area and hoping the injury will cause the stem cells to turn into the most useful cell types," explains Mark Noble, Ph.D., co-author of the paper, professor of Genetics at the University of Rochester, and a pioneer in the field of stem cell research. "It really changes the way we think about this problem."
The breakthrough is based on many years of stem cell biology research led by Margot Mayer-Proschel, Ph.D., associate professor of Genetics at the University of Rochester. In the laboratory, Mayer-Proschel and colleagues took embryonic glial stem cells and induced them to change into a specific type of support cell called an astrocyte, which is known to be highly supportive of nerve fiber growth. These astrocytes, called glial precursor-derived astrocytes or GDAs, were then transplanted into the injured spinal cords of adult rats. Healing and recovery of the GDA rats was compared to other injured rats that received either no treatment at all or treatment with undifferentiated stem cells.
The rats without the GDA cell transplant did not show any nerve fiber regeneration and still had difficulty walking four weeks after surgery.
Note the use of embryonic stem cells. As more therapies are developed in animal models using embryonic stem cells the pressure to allow more research on human embryonic stem cells is going to build. The political opponents of human embryonic stem cell (hESC) research who want to be able to resist this pressure ought to add a couple of billion dollars a year to the money available for adult stem cell treatment.
Mind you, I'm not taking sides in that fight. Rather, I'm always on the look-out for more arguments for why research funding ought to be increased. I figure if hESC opponents can be convinced that they need to fund far more rapid development of alternatives to hESC-based therapies then the total amount of money available to develop rejuvenation therapies will increase.
Researchers at the Medical College of Georgia have demonstrated the ability of a commercial human stem cell line to partially repair surgically induced stroke-like damage in rat brains.
A single dose of adult donor stem cells given to animals that have neurological damage similar to that experienced by adults with a stroke or newborns with cerebral palsy can significantly enhance recovery from these types of injuries, researchers say.
Using a commonly utilized animal model for stroke, researchers administered a dose of 200,000-400,000 human stem cells into the brain of animals that had experienced significant loss of mobility and other functions. The stem cells used in the study were a recently discovered stem cell type, referred to as multipotent adult progenitor cells, or MAPCs.
Treated animals experienced at least 25 percent greater improvement in motor and neurological performance than controls, said Dr. Cesario V. Borlongan, neuroscientist at the Medical College of Georgia and the Veterans Affairs Medical Center in Augusta.
Improvement in function continued for the length of the study. This suggests that even greater improvement would have been seen over additional months. Also, it opens up the possibility that additional treatment doses might yield even greater improvement.
Following the stroke, both control animals and those that received a single injection of stem cells were evaluated for a period of up to 2 months. Improvements in stem cell treated animals included enhanced performance across the range of tests, which examined strength, balance, agility and fine motor skills, and also included greater recovery of injured tissue.
“A single dose of the cells produce robust behavioral recovery at an early period post-transplantation and the recovery was durable, lasting up to two months, which was the entire length of this study,” Dr. Borlongan said. “Furthermore, animals continued to show improvement over time.” In the newborn model of ischemic injury, enhanced recovery was found within two weeks.
Even though less than 1 percent of the transplanted cells were present two months later, animals receiving treatment developed new neurons, apparently formed from endogenous stem cells. “The mechanism that we are putting forward is these donor cells are secreting nourishing trophic factors that are helping the host brain cells survive and stimulating stem cells from the host to multiply,” Dr. Borlongan said.
I can imagine such a treatment providing benefit even to those who do not suffer from stroke or cerebral palsy. Aged brains with slowly dividing stem cells could get partially rejuvenated if injected stem cells could stimulate existing cells to divide.
This method of treatment for stroke does not repair the core location of damage. However, repair on the periphery could prevent the core damage area from getting even larger and could make the difference between, for example, being wheelchair bound or walking with a cane. Or it could mean the difference between drooling out the side of one's mouth or being able to keep one's mouth closed.
In the adult stroke model, MCG researchers found giving stem cells increased the number of injured cells that survived in the area just outside the area of greatest damage, also referred to as the ischemic core, by 5-20 percent.
“Up to this point, all the treatment approaches, including transplantation and tPA, cannot get rid of that ischemic core,” Dr. Borlongan said. “But outside of that core there is a lining, what we call the penumbra, and that penumbra, if you do not treat it over time, becomes part of the core. We are showing, that even one week after a stroke, we are able to increase the number of cells surviving along that penumbra and that is how we feel it is producing significant recovery, by rescuing cells within the penumbra.”
What we most need are stem cell therapies, gene therapies, and still other therapies that will go into the vascular system and repair blood vessels that put us at risk of stroke. Any therapy aimed at restoring function after a stroke won't be able to put back neurons that held memories or that were trained to do complex physical movements such as, say, playing a musical instrument. Better not to lose the neurons in the first place.
The stem cells used in this experiment came from a Cleveland Ohio biotech company named Athersys.
Athersys, Inc., a Cleveland-based biopharmaceutical company pursuing cell therapy programs in cardiovascular disease, stroke, cancer and other diseases, funded the research in which previously frozen human or rodent multipotent adult progenitor cells, which the company calls MultiStem™, were thawed and injected directly into the brain.
Researchers believe that MultiStem™ cells are able to deliver a therapeutic benefit in multiple ways, for example by producing factors that limit tissue damage and stimulate repair, according to Dr. Gil Van Bokkelen, the company’s chairman and chief executive officer. In addition, MultiStem™ cells can safely mature into a broad range of cell types and can be produced on a large scale, something which should ease the move toward clinical studies and eventual clinical use. “Given the number of stroke victims each year, it would be a big step forward if a safe and effective stem cell therapy could be produced, conveniently stored, and efficiently delivered on a widespread basis. We believe that we can achieve that with MultiStem™,” commented Dr. Van Bokkelen.
As stem cell therapies become used to treat a wider range of diseases and disorders the revenue from sales will feed back toward the development of improvements and the development of stem cell therapies for yet more conditions and problems. We are on the threshold of a virtuous cycle of stem cell development funded by the enormous amounts of money in the medical industry. Sales of stem cell therapies will replace far less effective therapies and also shift money away from nursing homes and palliative treatments.
Update: Another study using stem cells to repair neuron damage found that a special gel can align the growth of neural stem cells to help bridge spinal cord injury gaps.
The second study addressed a significant problem in the use of stem cells for spinal cord repair, that of directing cells to align in the proper direction along the cord. Misdirected or undirected cell orientation limits the ability of injured nerves to reconnect with other nerve cells further down the spinal cord. “A regrowth-directing structured scaffold is required for spinal cord repair,” said lead study author Norbert Weidner, MD, of the University of Regensburg, Germany.
The research group tested anisotropic capillary hydrogels (ACH) made of a seaweed derivative, which have an internal structure that preferentially guides axons (nerve cell extensions) in one direction. In brain slice cultures, they showed that ACH promoted regrowth of existing axons and improved their ability to reconnect with their target nerve cells. They then tested this strategy in adult rats with damaged spinal cords, where ACH promoted directional regrowth across the scaffold. Ongoing studies demonstrate that ACH can be "seeded" with neural stem cells, which now align properly and may further enhance the regenerative capacity of ACH.
To give you some measure of the potential benefit of a treatment that could repair damaged spinal cords in the United States about a quarter million people have spinal cord injuries and the average age at the time of injury is about 28 years old. So a lot of people will gain decades of greater mobility and richer lives when their spinal cord injuries become repairable. The economic value of effective spinal cord repair techniques will be enormous.
The researchers, from the Georg August University in Gottingen, isolated sperm-producing cells from the testes of adult mice.
They were able to show that, under certain culture conditions, some of them grew into colonies much like embryonic stem cells.
They called these cells multipotent adult germline stem cells (maGSCs).
Like ES cells, maGSCs can spontaneously differentiate into the three basic tissue layers of the embryo - and contribute to the development of multiple organs when injected into embryos.
I wonder how old the mice were. Would such results be achievable from old mice?
Also, adult stem cell lines tend to grow more slowly (even orders of magnitude more slowly) Than embryonic stem cell lines. So how fast do these msGSC lines replicate? Can they grow fast enough to be used to grow replacement organs for example?
Gerd Hasenfuss from the Georg-August-University of GÃ¶ttingen and colleagues report the results in Nature1. Their work shows the extraction of the cells from male mice, but it should be possible to produce similar results with samples taken from human testicles through a biopsy, says Wolfgang Engel, a human geneticist also at the Georg-August-University of GÃ¶ttingen and a co-author on the paper.
The cells have been shown to have some of the same characteristics as embryonic stem cells, but not all, notes Chris Higgins, director of the Medical Research Council's Clinical Sciences Centre at Imperial College London, UK. "There needs to be further research before we really get excited about it."
The discovery that cells which behave like ESCs can now be obtained from adult mice may now open up the possibility of a similar â€œethicalâ€? source from grown men.
â€œWeâ€™re in the process of doing this in humans, and weâ€™re optimistic,â€? says Gerd Hasenfuss of the Georg-August University of GÃ¶ttingen, Germany, and head of the team which pioneered the breakthrough.
Here is a report I really hope holds up. PrimeGen Biotech of Irvine California claims they've already produced pluripotent stem cells from human adult testes.
-- PrimeCell(TM) -- First Human Adult Stem Cell Showing Ability to Differentiate into Any Cell in the Body -- Paves Way for Cellular Replacement Therapies to Cure a Multitude of Diseases
-- Does Not Require Generation or Destruction of an Embryo
In a breakthrough for stem cell research and cellular replacement therapies, PrimeGen Biotech LLC (www.primegenbiotech.com) today announced that its researchers have successfully developed the first human adult therapeutic germ stem cell. Derived from adult stem cells but with the advantageous genetic characteristics of embryonic stem cells, PrimeCells have successfully been transformed into human heart, brain, bone and cartilage cells -- cardio, neuro, osteo and chondrocytes.
Therapeutically reprogrammed from germ line stem cells found in the testes of adult human males, PrimeCell(TM) is the first non-embryonic stem cell showing the potential to become any type of cell from any organ, something previously thought possible only for embryonic stem cells -- the definition of true pluripotency.
This week, the company's researchers are scheduled to present a summary of their complete data and manuscript in a poster presentation at the Serono Symposia International's Therapeutic Potential of Stem Cells In Reproductive Medicine conference in Valencia, Spain. PrimeGen first presented its preliminary human experimental data at the 1st International Symposium on Germ Cells, Epigenetics, Reprogramming and Embryonic Stem Cells, held in November 2005 in Kyoto, Japan.
Scientists will find ways around the use of embryonic stem cells and will develop other means to make highly flexible cells. The restrictions on human embryonic stem cell research are going to seem like a speed bump 5 or 10 years from now. I'm not saying that to attack or defend those restrictions. I just think the restrictions aren't going away but they can be worked around. People who fight for lifting those restrictions ought to fight for a lot more research funding to find ways around the restrictions.
"The medications and interventional therapies available so far are intended only to limit further damage to the heart," said Andreas Zeiher, professor at J.W. Goethe University in Frankfurt, Germany, and a senior author of the study.
"In contrast, progenitor cell therapy has the potential not only to limit further damage, but to regenerate heart function," he said.
The improvement was small.
But patients who received the bone marrow cell infusion saw an improvement in their left ventricular ejection fraction -- a measure of heart efficiency -- on average, of 5.5 percent. Those getting placebo saw a 3 percent improvement.
The hearts of treated patients also swelled less and had better blood supply.
More than 200 individuals who had had a heart attack were enrolled in the trial. Half of the participants received infusions of their own bone marrow progenitor cells into their hearts while the other half received placebo infusions.
Both groups had similar left ventricular function (LVEF), a surrogate predictor of a patient's prognosis after a heart attack, at the beginning of the trial: 47 percent in the placebo group and 48 percent in the bone marrow cell group.
What we really need: Therapies that can prevent heart attacks in the first place. In most cases such therapies will involve clearing arterial plaque, prevention of plaque formation, and growth of new blood vessels. You can do some of that now with better diet and statin drugs to lower cholesterol.
Heart specialist Sebastiano Marra at Turin University in Italy found that injection of cytokine hormones into the body after a heart attack marshals stem cells to repair the heart and leads to better outcomes.
In the new technique, hormones called cytochines are injected into the body during the 24 hours after emergency heart surgery and immediately spur the production of stem cells in spinal fluid.
The stem cells race to rescue the damaged heart, Marra said.
"The acute inflammation of the heart attracts the stem cells whose role in the body is to repair cardiac tissue," said Marra, who operated on the patients at Turin's Molinette Hospital.
Tests on eight patients who were operated on immediately after a heart attack have produced "amazing" results, he said.
"They were soon back on their bicycles or going to swimming pools." Compared to experimental methods used so far, the Turin technique is far less invasive, Marra continued.
Mind you, this is a news report on only 8 patients and not a journal article with a larger number of patients with controls and a detailed comparison of outcomes. Still, the approach is at least plausible. Stimulation of the production of stem cells is already used to make stem cells from donors to treat leukemia. But Marra is trying to stimulate stem cells within the same body that needs them for heart muscle repair.
The technique might work less well in the really old because stem cell reservoirs in older people are aged and do not divide as quickly. However, one study found that elements in the blood of the old mice caused their stem cells to grow less rapidly. So it isn't so much that the stem cells are old but that they are getting signals telling them not to grow. Perhaps cytokines or other compounds can override those suppressor signals. So Marra's approach might work even for old folks.
Thanks to Brock Cusick for the pointer.
Researchers at the UC Irvine Reeve-Irvine Research Center have used adult human neural stem cells to successfully regenerate damaged spinal cord tissue and improve mobility in mice.
The findings point to the promise of using this type of cells for possible therapies to help humans who have spinal cord injuries. Study results appear online in the Proceedings of the National Academy of Sciences Early Edition.
In their study, Brian Cummings, Aileen Anderson and colleagues injected adult human neural stem cells into mice with limited mobility due to spinal cord injuries. These transplanted stem cells differentiated into new oligodendrocyte cells that restored myelin around damaged mouse axons. Additionally, transplanted cells differentiated into new neurons that formed synaptic connections with mouse neurons.
The ability to grow new myelin sheath would also be very beneficial to patients suffering from multiple sclerosis.
Myelin is the biological insulation for nerve fibers that is critical for maintenance of electrical conduction in the central nervous system. When myelin is stripped away through disease or injury, sensory and motor deficiencies result and, in some cases, paralysis can occur. Previous Reeve-Irvine research has shown that transplantation of oligodendrocyte precursors derived from human embryonic stem cells restores mobility in rats.
“We set out to find whether these cells would be able to respond to the injury in an appropriate and beneficial way on their own,” Cummings said. “We were excited to find that the cells responded to the damage by making appropriate new cells that could assist in repair. This study supports the possibility that formation of new myelin and new neurons may contribute to recovery.”
Coordinated walking ability was restored.
Mice that received human neural stem cells nine days after spinal cord injury showed improvements in walking ability compared to mice that received either no cells or a control transplant of human fibroblast cells (which cannot differentiate into nervous system cells). Further experiments showed behavioral improvements after either moderate or more severe injuries, with the treated mice being able to step using the hind paws and coordinate stepping between paws whereas control mice were uncoordinated.
The cells survived and improved walking ability for at least four months after transplantation. Sixteen weeks after transplantation, the engrafted human cells were killed using diphtheria toxin (which is only toxic to the human cells, not the mouse). This procedure abolished the improvements in walking, suggesting that the human neural stem cells were the vital catalysts for the maintained mobility.
The lack of need to condition the stem cells to become specific types of cells makes this a simpler approach to apply than attempts which used less differentiated human embryonic stem cells.
This study differs from previous work using human embryonic stem cells in spinal cord injury because the human neural stem cells were not coaxed into becoming specific cell types before transplantation.
If human cells can improve movement in mice the likelihood that these same cells would deliver a similar benefit in humans with spinal cord injuries seems high.
The British newspaper The Guardian reports that the stem cells came from neural tissue of aborted fetuses.
Neuroscientist Aileen Anderson and her team at the Reeve-Irvine Research Centre at the University of California, Irvine, used stem cells taken from the neural tissue of aborted foetuses. When injected into the body, they can develop into any type of nervous tissue.
Can anyone confirm this? Neither the UC Irvine press release or the press release of the company that supplied the stem cells (see below) make any mention of this fact.
The company that supplied the stem cells to the UC Irvine researchers is Palo Alto California based StemCells Inc. The StemCells Inc. press release mentions that the Christopher Reeve Foundation was one of the sources of funds for this research (bringing to mind that South Park episode where Reeve's character ate fetal brains and became extremely vigorous as a result)
PALO ALTO, Calif., (September 19, 2005) – StemCells, Inc. (Nasdaq: STEM) today announced results of a published study that demonstrates that the Company’s proprietary human neural stem cells restore the lost motor function of mice with spinal cord injuries. This study is also the first to show the causal relationship between transplanted human neural stem cells and long-term recovery of motor function: The human neural cells were subsequently ablated in some of the mice, and their improved motor function was lost.
The study was conducted by Drs. Aileen Anderson, Brian Cummings and their colleagues from the Reeve Irvine Research Center at the University of California, Irvine. It will be published today online in the Early Edition of the Proceedings of the National Academy of Sciences of the United States of America (PNAS), and will appear in the September 27, 2005 print issue. The study was funded in part by a Small Business Innovative Research Grant from the National Institute of Health (NIH) to StemCells, Inc. Support was also provided by the Christopher Reeve Foundation through its International Research Consortium on Spinal Cord Injury.
The CEO of StemCells Inc. says these are still early days. But what obstacle exists for trying out these stem cells in paralyzed humans right now?
“While we are early in our quest to find a stem cell therapy for spinal cord injury, the design of this study raises the bar for evaluating experimental cell-based therapies in this extremely debilitating medical condition,” said Martin McGlynn, President and Chief Executive Officer of StemCells. “The study clearly demonstrates that our proprietary human neural stem cells make functional new neural cells, and are responsible for the restoration of hind limb function in this animal model of spinal cord injury.”
In the StemCells Inc. press release they refer to the cells as having been isolated from "normal brain tissue".
StemCells, Inc. is a development stage biotechnology company focused on the discovery, development and commercialization of stem cell-based therapies to treat diseases of the nervous system, liver and pancreas. The Company’s stem cell programs seek to repair or repopulate neural or other tissue that has been damaged or lost as a result of disease or injury. StemCells is the first company to directly identify and isolate human neural stem cells from normal brain tissue. These stem cells are expandable into cell banks for therapeutic use, which demonstrates the feasibility of using normal, non-genetically modified cells as cell-based therapies. StemCells is the only publicly traded company solely focused on stem cell research and development and has more than 40 U.S. and 100 non-U.S. patents, as well as 100 patent applications pending worldwide.
On one hand abortion is already legal in the United States and has been for decades. So use of neural stem cell tissue from aborted fetuses does not result in more fetuses getting killed. On the other hand, abortion opponents will surely get angry at the idea of remains of aborted fetuses getting used to develop medical treatments.
Put aside the ethical considerations. Think about the medical implications. The scientific lesson here is that types of neural stem cells already exist that can at least partially and substantially repair spinal cord injury. The delivery of those cells does not require creation of a futuristic high tech artificial biochemical environment in the spine (say complex chemical gradients varying through time) or an elaborate system for controlling the migration and differentiation of the cells. Given the development of the right sort of neural stem cells a substantial amount of spinal repair becomes possible pretty easily.
The technical point here, even for abortion opponents, is that if a way to make the right sorts of neural stem cells can be found then stem cells can fix damaged spines. Granted, some people would prefer a different way to make these stem cells. I expect other ways will be found. But once stem cells can get programmed to the right epigenetic state then the cells will repair spinal cords. That's good news.
Update: Be sure to read the comments on this post. Garson Poole points to the use of premature births that die as a source of cells. This neatly sidesteps opposition to abortion. The use of organs from people who unexpectedly die is morally accepted across the political spectrum (with the exception of perhaps a couple of religious demoninations that do not oppose this choice by others). So why not the same with premature births?
An international team of researchers has discovered that human embryonic stem cell lines accumulate changes in their genetic material over time.
The findings do not limit the utility of the cells for some types of research or for some future clinical applications, the researchers say, but draw attention to the need to closely monitor stem cell lines for genetic changes and to study how these alterations affect the cells' behavior. The researchers' work is described in the Sept. 4 online edition of Nature Genetics.
"This is just the first step," says Aravinda Chakravarti, Ph.D., one of the research team's leaders and professor and director of the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins. "While this is a snapshot of the genomic changes that can happen, it's certainly not everything going on. We still need comprehensive analyses of the changes and what they mean for the functions of embryonic stem cells."
"Embryonic stem cells are actually far more genetically stable than other stem cells, but our work shows that even they can accumulate potentially deleterious changes over time," adds Anirban Maitra, M.B.B.S., an assistant professor of pathology at Johns Hopkins who shares first authorship of the paper with Dan Arking, Ph.D., an instructor at Hopkins. Both are members of the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins. "Now it will be important to figure out why these changes occur, how they affect the cells' behavior and how time affects other human embryonic stem cell lines."
My guess is they compared versions of the stem cell lines that had been frozen years ago with other versions of those same lines that had been kept growing in cell culture dividing many times since each embryonic stem cell line was created. Those sort of sub-lines of the original stem cell lines that have divided more have more mutations. Note that this is not surprising. Cells grown in culture are not growing in ideal conditions and when cells divide they do so imperfectly anyhow.
The researchers in the United States, Singapore, Canada and Sweden compared "early" and "late" batches of each of nine federally approved human embryonic stem cell lines. Twenty-nine human embryonic stem cell lines from seven different companies are approved by the United States National Institutes of Health under President George W. Bush's policy restricting federal funding of this research to cell lines in existence before his announcement of the policy at 9 p.m. ET, Aug. 9, 2001. The dozens of human embryonic stem cell lines developed since that announcement cannot be used in federally funded research.
Most of the "late" batches of stem cells -- those grown in the lab a year to three years longer than their early counterparts -- displayed gross changes in the number of copies of chromosomes or parts of chromosomes, in the marks that control whether a gene is used by the cell, or in the sequence of DNA found in the cell's mitochondria.
Some of the changes found resemble changes seen in cancer cells.
"The majority of the lines we tested had genetic changes over time," says Chakravarti. "Whenever you have something in a culture dish, it can change, and it will be important to identify, keep track of and understand these changes."
At this point, the precise effects of these changes on the cells aren't known, but some of the changes resemble those seen in cancerous cells. At any rate, the changes presumably became entrenched in a particular cell line because they conferred some advantage as the cells were grown in laboratory dishes. Whether the changes affect the stem cells' abilities to become other cell types is also unknown.
In the body aged adult stem cells that accumulate dangerous mutations are suspected by many scientists as being major sources of cancer. Adult stem cells grown in culture will mutate just as these embryonic stem cells have done. Therefore this result does not demonstrate a problem specific to embryonic stem cells and should not be seen as a useful debate point by opponents of human embryonic stem cell research.
Note how the scientists can not say for sure whether any of the mutations in these human embryonic stem cells put them at risk of causing cancers. One reason for this lack of certainty is that all the genetic mutations that contribute to cancer are not yet known. The other reason is that even if all those mutations were known some might be hard to test for. To defeat cancer and fully realize the potential of both adult and embryonic stem cells we need cheaper and better technologies for DNA sequencing and DNA testing.
Gene chips were essential tools for this research. Better tools mean better and faster research.
Although research with human embryonic stem cells is still in the lab -- not the clinic -- focusing on what the cells can do and how they are controlled, the hope is that in the future these cells might help replace or repair tissues lost to disease or injury. Because embryonic stem cells can become any type of cell found in the body, in theory they could replace certain pancreas cells in people with type I diabetes, or regenerate brain cells lost in a person with Parkinson's disease, for example.
The analyses of the embryonic stem cell lines and the computer comparisons of the mounds of resulting data required the efforts of scientists at four academic centers, two federal laboratories and three companies. Critical to the team's success was prescient support of cutting-edge technology development by the National Institutes of Health, support that enabled development of the technological infrastructure necessary for large-scale comparative research, particularly the Human Genome Project, says study co-author Mahendra Rao, M.B.B.S., Ph.D., of the Laboratory of Neurosciences at the National Institute on Aging.
The scientists used so-called GeneChip microarrays, or oligonucleotide arrays, to determine whether there were genetic differences between the early and the late batch of each of the stem cell lines, including whether any genes were present in extra copies. Depending on the gene affected, extra copies could lead to accelerated cell growth, increased cell death, or no measurable effect at all.
Epigenetic changes in the form of methylation patterns on the DNA backbone were also seen along with the genetic mutations. Note that epigenetic changes are also thought to contribute to the development of cancer.
In addition to probing changes in the nuclear and mitochondrial DNA sequences and copy numbers, the researchers examined whether the cells' genetic material had shifts in marks that sit on genes and are passed from cell to cell during cell division. These so-called epigenetic marks -- in this case methyl groups on a gene region known as the promoter -- help control whether a gene is used by a cell to make proteins. The researchers determined the methylation status of 14 genes in each of the batches of stem cells; three of the genes did show different methylation patterns in late batches compared to early batches.
What creates the differences between embryonic stem cells, adult stem cells, and various specialized functional cell types throughout the body? Epigenetic changes. If we had the ability to precisely change methylation patterns in any way desired then we probably could convert any cell type to any other cell type. The point is that epigenetic state is important and the development of better abilities to test and change epigenetic state would greatly help in the development of stem cell therapies.
The embryonic stem cells also had deletion and duplication mutations.
The scientists' analysis revealed that five of the nine cell lines had extra or fewer copies of at least one section of their genetic material in the late batch compared to the same cell line's early batch. Two of the nine lines had changes in their mitochondrial DNA over time, and all nine stem cell lines exhibited some shift in methylation of at least one of three genes. One of these genes, called RASSF1A, is also methylated in many cancers, but what effect the methylation has on the stem cells is unknown.
The team is already planning to conduct similar analyses of the remaining NIH-approved cell lines, but analysis of stem cell lines not available for use with federal funds will also be needed, the team members say.
These results suggest that existing embryonic stem cell lines are going to have limited utility in the development of therapies. Lots of research can still be conducted on these stem cell lines. But I'd be very reluctant to have any of these mutated embryonic stem cells injected into yours truly. Also, years will go by before these stem cells can get massaged into useful forms for therapies and they will accumulate even more mutations in that time.
Stem cell lines created just when they are needed (whether embryonic or slightly more differentiated adult stem cell lines) would reduce the risk of mutations. However, even "just in time" stem cell lines would need extensive genetic testing because whichever cell would be used for the starter nucleus might contain mutations that put the resulting stem cell line at heightened risk of creating a cancer.
It is possible that future gene therapies will allow at least partial repair of these cell lines. But those gene therapies could be many years into the future.
Biogerontologist Aubrey de Grey's proposal for dealing with the cancer risk from stem cell lines is to knock out the telomerase gene so that any cancer would eventually be halted by telomere decay. The downside of such an approach is that the youthful stem cell line would not function for as long in the body before needing yet another replenishment by another youthful stem cell line. But maybe that would be worth the lowered cancer risk.
Stanford researchers have discovered a way to get adult stem cells to divide that probably will simultaneously lower the risk of the stem cells going cancerous.
Out of the tousled tresses of a long-locked mouse, Stanford researchers have discovered a technique to turn on certain adult stem cells at will. Their new method not only transforms shorthaired mice into shaggy critters but also could open the door to finding ways to use stem cells to treat a host of tissue-related diseases and conditions, including cancer.
"Any area that requires tissue regeneration could be potentially impacted by this finding," Dr. Steven Artandi, an assistant professor of medicine (hematology), said of the research, which was published in the Aug. 18 issue of the journal Nature. Artandi is the senior author of the paper that focuses on stem cells in the mice's skin tissue, though it has implications for other stem cells as well.
The key to controlling these stem cells lies within an enzyme, telomerase, which has long been known to play a crucial role in keeping chromosomes intact when stem cells divide and in the formation of cancer. There is recent evidence, though, that the enzyme may play additional roles in the cell that are not well understood.
To better understand the role of telomerase, Artandi's lab developed a genetically modified mouse, which enabled them to stuff additional telomerase into the mouse's cells. The added enzyme was equipped with a genetic switch that would activate telomerase, or more specifically a telomerase component called TERT, when the mouse was fed a chemical trigger.
TERT activates stem cell growth.
Similar to the board game Mouse Trap, in which one trigger sets off a chain of events ending in the capture of a mouse, the chemical trigger fired up the TERT, which kicked the stem cells into action, which built up the hair follicles, which started growing hair nonstop, which ultimately yielded the shaggy mouse.
You might be thinking: Hey, some day will a variation on this technique but developed for humans regrow hair on receding hairlines?
Adult stem cells in hair follicles are only intermittently active, so hair normally grows in corresponding spurts. When active, the stem cells proliferate and expand, building up the follicle and producing cells that make new hair. After a while, the follicle reverts to a resting state and hair growth ceases. But all that changed when Artandi and Kavita Sarin, lead author of the paper and a Stanford graduate student in genetics, flipped the switch on the TERT gene. The stem cells woke up and stayed up.
The finding is particularly striking because the TERT protein was acting independently from its normal role in the telomerase complex. "TERT can activate stem cells and cause them to proliferate," Artandi said. The introduced TERT was present in other tissues besides the mouse's skin, where it was also affected by the chemical trigger. "We see other effects as well from TERT activation, and we're working on those tissues right now," Artandi said.
Here's the extremely exciting part of this technique: Essentially they created a telomerase knock-out stem cell line. Without the ability to regrow telomeres the stem cells probably lack the ability to develop into cancers. Without telomerase acting to grow longer telomeres (caps on the ends of chromosomes) cancer cells might eventually run out of telomeres therefore stop dividing.
Telomerase consists of the protein TERT and an RNA component, TERC. Together, they enable telomerase to perform what until now has been its only clear function: patching up chromosomes after the rigors of cell division.
Chromosomes are never completely copied during cell division but are shortened a bit at each end, where material is left out of end caps called telomeres. Eventually, when the telomeres dwindle too far down, the cell stops dividing or dies.
Though present in only modest quantities in most cells, telomerase is abundant and vital in stem cells, where ample stores of telomerase keep the telomeres nice and long, allowing the cells to keep dividing without limit.
This endless dividing of cells is fine when it's just happening in stem cells. We rely on those new cells to repair injured and worn out tissues throughout our bodies. But in 90 percent of human cancers, telomerase—normally so rare outside of stem cells—is plentiful and active, facilitating the uncontrolled growth of tumors.
"We're interested in what telomerase is doing in cancer," Sarin said. That and the hope of learning more about stem cells—as well as learning more about what TERT might be up to aside from telomere rebuilding—is what prompted the study.
The ability to turn on adult stem cell division by knocking out one component of telomerase while increasing the availability of another teolomerase component simultaneously increases the supply of adult stem cells available for stem cell therapy and decreases the odds of getting cancer from stem cells.
To be certain it was TERT alone that was triggering the stem cells, Artandi's team crossbred mice to eliminate the presence of the RNA component, TERC. Since TERC is crucial to rebuilding telomeres, when the mice grew shaggy even with no TERC around, it was clear the follicle stem cell stimulation was due solely to TERT and that the telomere repair function of telomerase played no role.
"This is really an unanticipated effect for TERT, one that's independent of the conventional telomerase complex," Artandi said.
The findings have gotten the attention of other telomerase researchers. "It's very interesting and very tantalizing," Carol Greider, one of the co-discoverers of telomerase, was quoted as saying in an article in the New York Times on the findings. Greider is at Johns Hopkins School of Medicine and was not involved in the study.
Artandi and Sarin stressed that the potential for therapeutic treatments arising from their work is highly speculative at this stage. That caveat aside, they noted many diseases and conditions could benefit from renewed tissue, including chronic ulcers of the skin, Parkinson's disease, Type-1 diabetes, osteoarthritis and some spinal injuries. Deafness caused by the loss of hearing hair cells, the sensory cells that respond to sound, also could benefit.
Said Artandi: "It's a very long list, and it really touches on many of the principal diseases that affect people, especially with advancing age."
Researchers have developed a new technique for creating human embryonic stem cells by fusing adult somatic cells with embryonic stem cells. The fusion causes the adult cells to undergo genetic reprogramming, which results in cells that have the developmental characteristics of human embryonic stem cells.
This approach could become an alternative to somatic cell nuclear transfer (SCNT), a method that is currently used to produce human stem cells. SCNT involves transferring the nuclei of adult cells, called somatic cells, into oocytes in which scientists have removed the nuclei.
The immediate use of this technique will be for research on how to reprogram adult cells into a fully dedifferentiated state.
The researchers said that -- while the technique might one day be used along with SCNT, which involves the use of unfertilized human eggs -- technical hurdles must be cleared before the new technique sees widespread use. It is more likely that the new technique will see immediate use in helping to accelerate understanding of how embryonic cells "reprogram" somatic cells to an embryonic state.
The researchers published their findings in the August 26, 2005, issue of the journal Science. Senior author Kevin Eggan and Howard Hughes Medical Institute investigator Douglas A. Melton, both at Harvard University, led the research team, which also included Harvard colleagues Chad Cowan and Jocelyn Atienza.
In theory, researchers can induce embryonic stem cells to mature into a variety of specialized cells. For that reason, many researchers believe stem cells offer promise for creating populations of specialized cells that can be used to rejuvenate organs, such as the pancreas or heart, that are damaged by disease or trauma. Stem cells also provide a model system in which researchers can study the causes of genetic disease and the basis of embryonic development.
This result was already demonstrated with mouse adult somatic cells and mouse embryonic cells. So, again, the result isn't a surprise.
Eggan, Melton and their colleagues decided to pursue their alternative route after other researchers had shown that genetic reprogramming can occur when mouse somatic cells are fused to mouse embryonic stem cells. The scientists knew that if their studies were successful, it would provide the research community with a new option for producing reprogrammed cells using embryonic stem cells, which are more plentiful and easier to obtain than unfertilized human eggs.
Human skin cells were used.
In the studies published in Science, the researchers combined human fibroblast cells with human embryonic stem cells in the presence of a detergent-like substance that caused the two cell types to fuse. The researchers demonstrated that they had achieved fusion of the two cell types by searching the fused cells for two distinctive genetic markers present in the somatic fibroblast and stem cells. The researchers were also able to further confirmed that fusion occurred by studying the chromosomal makeup of the fused cells. Their analyses showed that the hybrid cells were "tetraploid" – meaning they contained the combined chromosomes of both the somatic cells and the embryonic stem cells.
The fact that the resulting cells have nucleuses from both cells means these cells probably can not be used for therapy.
One of the key findings from the study was that the fusion cells have the characteristics of human embryonic stem cells. "Our assays showed that the hybrid cells, unlike adult cells, showed the development potential of embryonic stem cells," said Eggan. "We found they could be induced to mature into nerve cells, hair follicles, muscle cells and gut endoderm cells. And, since these cell types are derived from three different parts of the embryo, this really demonstrated the ability of these cells to give rise to a variety of different cell types."
But this is an important step toward the goal of making pluripotent stem cells (i.e. stem cells that can become any cell type) without destroying embryocs.
Furthermore, Eggan noted that genetic analyses of the fused cells revealed that the somatic cell genes characteristic of adult cells had all been switched off, while those characteristic of embryonic cells had been switched on. "With the exception of a few genes one way or the other -- which is perhaps because these cells are now tetraploid -- the hybrid cells are indistinguishable from human embryonic stem cells," he said.
"The long term goal for this experiment was to do cell fusion in a way that would allow the elimination of the embryonic stem cell nucleus to create an embryonic stem cell from the somatic cell," said Melton. "This paper reports only the first step toward that goal, because we end up with a tetraploid cell. So, while this does not obviate the need for human oocytes, it demonstrates that this general approach of cell fusion is an interesting one that should be further explored."
The researchers also performed fusion experiments using pelvic bone cells as the somatic cells and a different human embryonic cell line, to demonstrate that their technique was not restricted to one adult cell type or embryonic cell line.
In both cases, the researchers observed extensive reprogramming of the somatic cells. "We were surprised at how complete the reprogramming was," said Eggan. "I think we were expecting that there would be more 'memory' of the adult state than the embryonic in the hybrid cells. It was quite clear that when we looked at these hybrid cells, they had completely reverted to an embryonic state."
The challenge is how to eliminate the extra nucleus.
Melton said that the remaining technical hurdle is figuring out a way to eliminate the embryonic stem cell nucleus in the hybrid cell, causing it to have a normal number of chromosomes. One problem, said Melton, is that the nucleus in stem cells is large, occupying nearly the entire cell. Thus, it is not practical to physically extract the nucleus, as is currently done with oocytes, which have a relatively small nucleus. An alternative approach of destroying the embryonic stem cell nucleus with chemicals or radiation would induce the cell's suicide program, called apoptosis, he said.
Melton emphasized that "at this at this stage in our understanding, the hard fact is that the only way to create an embryonic stem cell from a somatic cell is by nuclear transfer into oocytes. Taking advantage of this current capability -- such as colleagues in South Korea and other countries are doing -- is critical if we are to maintain the progress necessary to realize the extraordinary clinical potential of this technology."
But this technique has immediate value in research to figure out how a cell nucleus gets reprogrammed into a less differentiated state.
Eggan added that the most realistic current promise of the fusion technique is in studying the machinery of genetic reprogramming of somatic cells by embryonic cells. "It is extremely difficult to study the reprogramming process using eggs, because in the case of humans it is very difficult to obtain eggs in any quantity and difficult or impossible to genetically manipulate them," he said. "But embryonic stem cells can be grown in large quantities. We can isolate the components of the reprogramming machinery, and we can genetically manipulate the cells to analyze the reprogramming process."
The ability to understand the process of dedifferentiation of a nucleus into a pluripotent state would provide an excellent basis for the development of more precise and reliable techniques for producing pluripotent cells. The use of Somatic Cell Nuclear Transfer (SCNT) to put adult cells into denucleated eggs is really a hack and a hack that does not work well.
Leave aside fact that some people have ethical objections to SCNT. Some animals created via SCNT have health problems. We need much greater control of cellular dedifferentiation than SCNT provides. We need to understand what SCNT does to cells. But now scientists can study what cell fusion does to adult cells and this will make the study of the process of dedifferentiation easier to do.
Other researchers already claim to have solved the problem of the extra chromosomes. Yuri Verlinsky and his colleagues at the Reproductive Genetics Institute in Chicago, US, claimed in May to have achieved the same as Eggan, but by reprogramming with ESCs stripped beforehand of their nuclear DNA. Without this extra genetic baggage, the cells have real potential for therapy.
They claim to have a research paper explaining how they did this headed for release.
They do not mention that several teams, including ones in Illinois and Australia, have said in recent interviews that they are making progress removing stem cell DNA from such hybrid cells. None of those teams has published details of their results. But several leading researchers have said they believe it will be feasible to remove the extra DNA.
Technical means will be developed to avoid ethical objections to the use of embryos to extract embryonic stem cells. Promoters of stem cell research would do well to refocus their efforts toward supporting a large increase in funding stem cell research in general rather than fight the human embryonic stem cell political battle.
Cellular dedifferentiation means turning a cell from a specialized state (e.g. muscle cell or liver cell) into an unspecialized cell that has the ability to become other cell types. At the most extreme dedifferentiated state embryonic stem cells are so dedifferentiated that they have the ability to become all more specialized cell types. This extreme state is called pluripotency. Ethical opposition to the use of cells harvested from human embryos to create pluripotent cell lines has led scientists to look for other ways to create pluripotent stem cells. A major figure in stem cell research says a number of labs are getting close to announcing successful techinques for dedifferentiating cells.
"Just a few years ago, it was beyond the reach of the existing science at the time ... almost like alchemy, where you're trying to turn lead into gold," said Dr. Robert Lanza, vice president of medical and scientific development at Massachusetts-based Advanced Cell Technology.
But today, new tools have changed the landscape: "Our group, and I know at least two or three others, are playing with different techniques, and it's very clear that something is going on here. We're definitely getting reprogramming," Lanza said.
The article cites a number of experimental approaches being pursued to cause dedifferentiation. However, I expect better methods which provide more precise control and more consistent outcomes to eventually replace some of the earlier techniques.
Success may come soon. Lanza says look for research reports on dedifferentiation in the next year.
What's more, researchers are hinting that yet more dramatic studies will be coming out in the weeks and months ahead.
"You'll start seeing publications in the next year," Advanced Cell Technology's Lanza said.
I've long argued that dedifferentiation is a solvable problem and that it would not take decades to solve. Plus, solving it will provide a great deal of information with many practical uses. W
Lanza is a very credible source for such an optimistic assertion as Lanza and ACT colleagues were the first to clone a human embryo in 2001. In other words, he's an accomplished stem cell researcher and has a major human embryonic stem cell research achievement to his credit.
Even if you resent or disagree with the religious folks who morally oppose the harvesting of embryonic stem cells from human embryos you should see Lanza's latest claim as good news. If fully pluripotent stem cells (i.e. capable of becoming all cell types) can be created without destroying embryos then a larger fraction of the populations of Western countries will support research into uses of pluripotent stem cells. Increases in public support for stem cell research of any type are beneficial to the cause of developing rejuvenating therapies and disease cures.
US President George W. Bush's chief bioethicist Leon Kass is even willing to accept removal of a single cell from an embryo to create pluripotent stem cell lines of the technique can be demonstrated to pose no risk to the eventual baby that could develop from such an embryo.
The next alternative is to use a biopsy, that is, cell removal from still-living embryos, presumably in ways that will not do damage to that embryo. We now practice, at least on a small scale, what’s called preimplantation genetic diagnosis, where couples are at risk of a child with a genetic disease known to run in the family. At the roughly eight-cell stage, one or even two cells are taken out for genetic testing. And maybe 10,000 babies have already been born, more or less healthy, following this procedure. ... If you take out a couple of cells and you test them, and the embryo is shown not to carry the genetic disease of concern, that embryo is then transferred to a woman, and if all goes well, nine months later you’ve got a baby free of the disease. The thought is that maybe you biopsy these embryos, and you take out the individual cells, not for genetic testing, but to try to produce stem cell lines from them.
No one has yet converted a single blastomere from an eight-cell embryo into a stem cell line. That’s a scientific challenge. But the council was quite concerned about the ethics of this. We didn’t think that one could justify putting a child-to-be at additional risk, not for its own benefit. Until it could be proved by animal studies, or by much longer studies of preimplantation genetic diagnosis, that embryo biopsy is really risk-free to the child who results from all of this, the council is unprepared to pronounce this particular approach as ethically acceptable at this time.
While that techinque may turn out to be useful it still involves going down a path of fertilizing an egg from a woman with a sperm from a man to start a pregnancy in order to get a pluripotent stem cell line. But that cell line does not genetically match any single existing person's DNA sequence. What we really need most of all is the ability to turn our own cells into more flexible and youthful cells so that we can create fully immunologically compatible cells. Plus, if I'm going to have neural stem cells injected to help rejuvenate my brain I don't want someone else's stem cells which have different characteristics due to genetic differences and which therefore might gradually alter my personality.
Adult stem cells are hard to grow. But MIT Whitehead Institute researchers have discovered that turning on a gene that is active in the early embryo causes adult stem cells to grow rapidly.
While research on human embryonic stem cells gets most of the press, scientists are also investigating the potential therapeutic uses of adult stem cells. Although less controversial, this research faces other difficulties. Adult stem cells are extremely difficult to isolate and multiply in the lab.
Now, as reported in the May 6 issue of Cell, researchers led by Rudolf Jaenisch of the Whitehead Institute have discovered a mechanism that might enable scientists to multiply adult stem cells quickly and efficiently.
"These findings provide us with a new way of looking at adult stem cells and for possibly exploiting their therapeutic potential," says Jaenisch, who also is a professor of biology at MIT.
I have repeatedly argued that it is just a matter of time before scientists find ways to turn adult stem cells into cells that can become any other cell type. This latest research from MIT is certainly a step in that direction. Note that these scientists used existing knowledge that the gene Oct4 is known to be active in embryonic stem cells. They turned that same gene on in adult stem cells. So this research is a clear step in the direction of making adult stem cells more like embryonic stem cells.
This research focuses on a gene called Oct4, a molecule that is known to be active in the early embryonic stage of an organism. Oct4's primary function is to keep an embryo in an immature state. It acts as a gatekeeper, preventing the cells in the embryo from differentiating into tissue-specific cells. While Oct4 is operating, all the cells in the embryo remain identical, but when Oct4 shuts off, the cells begin growing into, say, heart or liver tissue.
Konrad Hochedlinger, a postdoctoral researcher in Jaenisch's lab, was experimenting with the Oct4 gene, curious to see what would happen in laboratory mice when the gene was reactivated in adult tissue in which it had long been dormant. Hochedlinger found that when he switched the gene on, the mice immediately formed tumors in the gut and in the skin where the gene was active. When he switched the gene off, the tumors subsided, demonstrating that the process is reversible.
Discovering that simply flipping a single gene on and off had such an immediate effect on a tumor was unexpected, even though Oct4 is known to be active in certain forms of testicular and ovarian cancer. Still, the most provocative finding was that "Oct4 causes tumors by preventing adult stem cells in these tissues from differentiating," says Hochedlinger. In other words, with Oct4 active, the stem cells could replicate themselves indefinitely, but could not produce mature tissue.
One of the main obstacles with adult stem cell research is that,
This experiment showed that when Oct4 was reactivated, the adult stem cells in those tissues continued to replicate without forming mature tissue. In a mammal's body, this type of cell behavior causes tumors. But under the right laboratory conditions, it could be a powerful tool.
"This may allow you to expand adult stem cells for therapy," Hochedlinger said. "For instance, you could remove a person's skin tissue, put it in a dish, isolate the skin stem cells, then subject it to an environment that activates Oct4. This would cause the cells to multiply yet remain in their stem cell state. And because this process is reversible, after you have a critical mass of these cells, you can then place them back into the person where they would grow into healthy tissue."
"This could be very beneficial for burn victims," Jaenisch said.
The difference between adult and embryonic stem cells is just that they are in different regulatory states. Think of the genome of a cell as having a big set of switches on it with the pattern of which switches are set On and Off being one way in embryonic cells and other ways in other cell types. One reason I haven't been pessimistic about limitations on human embryonic stem research is that I expect scientists working with adult stem cells to find ways to change their regulatory state (i.e. their pattern of On and Off for their genetic switches) into the same states as is found in embryonic stem cells.
The irony of religious opposition to human embryonic stem cell research is that it logically leads scientists to look harder for ways to make adult stem cells act more like embryonic stem cells. The inevitable outcome of this search will be development of techniqes that convert adult stem cells into cells that can be turned into all other cell types - just as embryonic stem cells can. The ability of embryonic stem cells to turn into all other cell types is called pluripotency. Once non-embryonic stem cells can be made pluripotent then the religious opponents of human embryonic stem cell research are going to have to decide whether they believe all pluripotent stem cells are mini-humans or not.
Even if work with all human pluripotent stem cells is outlawed regardless of what cell type is converted into the pluripotent state or how it is turned into the pluripotent state that still won't stop scientists from manipulating adult stem cels into all other cell types. Such a ban would be just another regulatory barrier that could be programmed around with genetic engineering. Scientists could respond to that ban by fiding some difference between fully pluripotent cells and slightly differentiated cells and convert cells into slightly differentiated (i.e. slightly specialized) states rather into the fully pluripotent state.
So far the acrimonious debate about human embryonic stem cells has caused a big increase in adult stem cell funding by the US federal government (over $500 million per year in total stem cell research funding) and the passage of an initiative in California to spend $300 million per year on stem cells without a restriction on human embryonic funding. So obviously funding levels have risen greatly. The rate of advance is accelerating. But I'd like to see even greater acrimonious debate so that we can get total funding over $1 billion. Come on, get mad at each other. We need more funding!