Using viruses to introduce genes that are known to control pluripotency (i.e. embryonic state) of cells some Harvard researchers managed to take skin cells from a women suffering from Amyotrophic Lateral Sclerosis (ALS - Lou Gehrig's disease) and make them into first stem cells and then neurons.
Cambridge, MA, July 31, 2008 - Less than 27 months after announcing that he had institutional permission to attempt the creation of patient and disease-specific stem cell lines, Harvard Stem Cell Institute (HSCI) Principal Faculty member Kevin Eggan today proclaimed the effort a success - though politically imposed restrictions and scientific advances prompted him to use a different technique than originally planned.
The breakthrough by Eggan and colleagues at Harvard and Columbia University marks the first time scientists are known to have produced human stem cell lines coaxed from the cells of adult patients suffering from a genetically-based disease. The affected patients had Amyotrophic Lateral Sclerosis (ALS), commonly known as Lou Gehrig's disease.
The ability to induce pluripotency on demand is impressive. The research into what causes cells to be embryonic stem cells and to be other kinds of stem cells is beginning to bear fruit. As scientists learn more about the internal genetic state of cells they will find easier and safer ways to control cell state and to produce therapies for almost all diseases.
The initial intent is to use these cells to study ALS. The longer term intent is to create neural stem cells that could be used to repair brains that are decaying due to ALS.
The work, published in today's on-line edition of the journal Science, provides "proof of concept" for the belief of scientists and fervent hope of patients that in the not-too-distant future it may be possible to treat patients suffering from chronic diseases with stem cell-based treatments created from their own adult cells. However, Eggan believes that the first therapeutic use of these newly derived stem cells will in fact be to use them to study the root cause of this disease and to screen for drugs that may provide benefit in patients.
This method does not currently produce cells that are safe to use in therapy. The viruses are a rather blunt instrument for introducing genes into cells and the cells run the risk of becoming cancerous. We need improved ways to do gene therapy and to regulate the epigenetic state of cells. That will all come with time. But the faster it comes the more likely you won't die from some disease before rejuvenation therapies become available.
"This is a seminal discovery," said Valerie Estess, director of research for Project A.L.S. "The ability to derive ALS motor neurons through a simple skin biopsy opens the doors to improved drug discovery. For the first time, researchers will be able to look at ALS cells under a microscope and see why they die. If we can figure out how a person's motor neurons die, we will figure out how to save motor neurons."
Some brain stem cell researchers have identified molecules that keep stem cells in a basically sleeping deactivated state and they think this points toward how to activate stem cells to do brain repairs.
Boston, MA-Scientists at Schepens Eye Research Institute have identified specific molecules in the brain that are responsible for awakening and putting to sleep brain stem cells, which, when activated, can transform into neurons (nerve cells) and repair damaged brain tissue. Their findings are published online this week in the Proceedings of the National Academy of Science (PNAS).
A previous paper by the same group found stem cells in many more parts of the brain than stem cells were previously know to exist. This suggests more parts of the brain are repairable via mechanisms already there if we can only find ways to get control of those mechanisms.
An earlier paper (published in the May issue of Stem Cells) by the same scientists laid the foundation for the PNAS study findings by demonstrating that neural stem cells exist in every part of the brain, but are mostly kept silent by chemical signals from support cells known as astrocytes.
"The findings from both papers should have a far-reaching impact," says principal investigator, Dr. Dong Feng Chen, who is an associate scientist at Schepens Eye Research Institute and an assistant professor of ophthalmology at Harvard Medical School. Chen believes that tapping the brain¹s dormant, but intrinsic, ability to regenerate itself is the best hope for people suffering from brain-ravaging diseases such as Parkinson¹s or Alzheimer¹s disease or traumatic brain or spinal cord injuries.
Until these studies, which were conducted in the adult brains of mice, scientists assumed that only two parts of the brain contained neural stem cells and could turn them on to regenerate brain tissue-- the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ). The hippocampus is responsible for learning and memory, while the SVZ is a brain structure situated throughout the walls of lateral ventricles (part of the ventricular system in the brain) and is responsible for generating neurons reponsible for smell. So scientists believed that when neurons died in other areas of the brain, they were lost forever along with their functions.
Molecules named ephrin-A2 and ephrin-A3 inhibit neural stem cell growth. So inhibitors of those molecules might help to activate stem cells for brain repair. Sonic hedgehog (which the press release below misspells as sonic hedghoc) stimulates neural stem cell growth. Inhibit the ephrins and stimulate sonic hedgehog and the result would be much more neural stem cell growth.
In the second (PNAS) study, the team went on to discover the exact nature of those different chemical signals. They learned that in the areas where stem cells were sleeping, astrocytes were producing high levels of two related molecules--ephrin-A2 and ephrin-A3. They also found that removing these molecules (with a genetic tool) activated the sleeping stem cells.
The team also found that astrocytes in the hippocampus produce not only much lower levels of ephrin-A2 and ephrin-A3, but also release a protein named sonic hedghoc that, when added in culture or injected into the brain, stimulates neural stem cells to divide and become new neurons.
What I'd like to know: As the brain ages do the astrocyte support cells excrete more ephrin-A2 and ephrin-A3 and less sonic hedgehog? Maybe the aging brain becomes less able to do repair because evolutionary natural selection selected for stem cell inhibition as an anti-cancer strategy. Therapies to activate brain stem cells might increase risk of brain tumors. Of course, if you have Parkinson's Disease your trade-off might weigh to taking that risk as likely to deliver the best net benefit.
The eventual development of techniques to create youthful neural stem cells will provide stem cells that can be safely stimulate to grow without running a cancer risk. But How to replace the old stem cells with young ones? It is not enough to add the newer younger stem cells to the brain (and just getting the new stem cells into all the spots in the brain they need to go is a challenge). We need to get rid of the old stem cells so that a drug that boosts stem cell growth will only stimulate the new stem cells and not the old stem cells too.
I wrote a post back in November 2004 about the ability of sonic hedgehog to triple brain stem cell growth. The use of sonic hedgehog for this purpose is well known among the researchers in this area.
NEW YORK, March 23, 2008—Research led by investigators at Memorial Sloan-Kettering Cancer Center (MSKCC) has shown that therapeutic cloning, also known as somatic-cell nuclear transfer (SCNT), can be used to treat Parkinson’s disease in mice. The study’s results are published in the March 23 online edition of the journal Nature Medicine.
For the first time, researchers showed that therapeutic cloning or SCNT has been successfully used to treat disease in the same subjects from whom the initial cells were derived. While this current work is in animals, it could have future implications as this method may be an effective way to reduce transplant rejection and enhance recovery in other diseases and in other organ systems.
In therapeutic cloning or SCNT, the nucleus of a somatic cell from a donor subject is inserted into an egg from which the nucleus has been removed. This cell then develops into a blastocyst from which embryonic stem cells can be harvested and differentiated for therapeutic purposes. As the genetic information in the resulting stem cells comes from the donor subject, therapeutic cloning or SCNT would yield subject-specific cells that are spared by the immune system after transplantation.
The new study shows that therapeutic cloning can treat Parkinson’s disease in a mouse model. The scientists used skin cells from the tail of the animal to generate customized or autologous dopamine neurons—the missing neurons in Parkinson’s disease. The mice that received neurons derived from individually matched stem cell lines exhibited neurological improvement. But when these neurons were grafted into mice that did not genetically match the transplanted cells, the cells did not survive well and the mice did not recover.
This work builds on earlier work by the same team where they didn't make stem cells for each target animal. With this latest work they avoided the immune rejection problem that by starting with a genome from the target animal and then creating embryonic stem cells with that animal's genome.
Some religious people find cloning to create embryonic stem cells morally unacceptable because an embryo gets destroyed in the creation of the stem cells in most cases. But for a moment leave aside the ethical objections for use of this procedure with humans. The fact remains that given immune compatible cells properly prepared to become dopamine neurons it is possible to do brain repair and a limited form of brain rejuvenation.
Some see rejuvenation therapies as distant prospects. But I do not see why stem cell therapies lie only in the distant science fiction future. A therapy that works for mice today is going to work for humans within a timespan quick enough for many of us alive today.
New UC Irvine research is among the first to demonstrate that neural stem cells may help to restore memory after brain damage.
In the study, mice with brain injuries experienced enhanced memory – similar to the level found in healthy mice – up to three months after receiving a stem cell treatment. Scientists believe the stem cells secreted proteins called neurotrophins that protected vulnerable cells from death and rescued memory. This creates hope that a drug to boost production of these proteins could be developed to restore the ability to remember in patients with neuronal loss.
Youthful stem cell therapy to replace aged stem cell reservoirs in the brain will be one of the methods for slowing and eventually reversing brain aging. Success in mice is a good sign for future stem cell therapies for human brains.
Mice with damage to the hippocampus who were given stem cells formed new memories just as well as undamaged mice did.
Three months after implanting the stem cells, the mice were tested on place recognition. The researchers found that mice with brain injuries that also received stem cells remembered their surroundings about 70 percent of the time – the same level as healthy mice. In contrast, control mice that didn’t receive stem cells still had memory impairments.
PITTSBURGH — Carnegie Mellon University's Stefan F. Zappe is using adult neural stem cells to develop a new stem cell-based drug delivery therapy that may ultimately help treat a variety of inherited genetic disorders like Hunter syndrome.
Zappe, an assistant professor of biomedical engineering at Carnegie Mellon, and his graduate student Sasha Bakhru, are creating genetically engineered adult neural stem cells for delivery to patients' brains, where they will be programmed to produce an essential missing protein. In Hunter syndrome, for example, patients are lacking the enzyme iduronate-2-sulfatase that helps cells break down certain waste products. One in every 130,000 boys is born with the rare but deadly genetic disorder.
Successful development of this therapy will move us much closer toward being able to do one form of brain rejuvenation: take out the extracellular and intracellular junk that accumulates with age. A neural stem cell therapy that can get rid of wastes that accumulate due to a genetic defect would provide many of the biotechnological pieces needed to create a neural stem cell therapy to get rid of wastes that accumulate due to old age. For example, genetically engineered neural stem cells could clear out beta amyloid plaques which accumulate in the brains of Alzheimer's Disease sufferers.
Keep in mind that they have a lot of problems to solve before they come up with an effective therapy for the disease they are targeting. But the pursuit of treatments for existing neural genetic diseases is sending scientists down roads where they will solve many of the problems which stand in the way of effective rejuvenation therapies.
This team has developed microcapsules to deliver the stem cells into the brain.
To support their therapeutic goals, Zappe and his team have developed cell-instructive microcapsules that contain neural stem cells. These microcapsules efficiently control whether stem cells proliferate (multiply), differentiate into more specialized cell types like neurons and to what extent implanted stem cells will be allowed to migrate to the host tissue.
Zappe will be using these caviar-sized capsules specifically for rapid manipulation of stem cells outside the body and for reliable delivery of stem cells to the brain. The acute inflammatory response that usually occurs from implantation would normally cause implanted neural stem cells to differentiate into mature cell types that are not able to migrate extensively. Encapsulated stem cells will be protected from such premature differentiation.
Once the brain has healed from the initial implant of the encapsulated stem cells, the stem cells are genetically engineered to produce an enzyme that eats the microcapsule, freeing the neural stem cells. The stem cells can then migrate deep into the surrounding brain tissue where they provide the missing enzyme.
They have a lot of work cut out for them. It might take them well over 10 years to succeed. But once they and other researchers like them succeed in sending genetically engineered stem cells into various nooks and crannies of the brain the techniques they develop for doing this will be reusable for therapies aimed at rejuvenating aging brains.