July 23, 2004
Fetuses Give Pregnant Women Stem Cell Therapy
Diana W. Bianchi, M.D. of the Tufts University Sackle School of Graduate Biomedical Research has found that cells from fetuses during pregnancy cross over into mothers and become a large assortment of types of specialized cells in the mothers and persist for years.
Bianchi and her colleagues retrieved cells from the tissue samples of 10 women who had male sons and compared them to tissue samples from 11 women who had never had male offspring. The reason the researchers chose women with male offspring is that it would be easy to detect cells from male offspring because male cells carry the Y chromosome, while female cells do not.
The tissue samples were from the thyroid, cervix, liver, lymph node, intestine, spleen and gallbladder. Skin samples were also collected from 11 women in a control group.
Bianchi said that not only did they find fetal cells present in the mothers' tissue samples, but that the fetal cells had taken on the characteristics of the mother's cells.
This result is very important for the stem cell debate. (same article here)
The findings could also affect the national debate over stem cells, she said, in that they raise the possibility of obtaining stem cells, which can change into many tissues of the body, without the ethical issues involved in creating or destroying human embryos. President Bush has sharply restricted federal funding for research on human embryonic stem cells to keep the government from supporting research that he believes destroys human life.
Pregnant or previously pregnant women could potentially be a source of pluripotent stem cells.
Likewise, the author of the Tufts study, Dr. Diana Bianchi, said another potential source of stem cells is women who have been pregnant.
"Studies have virtually ignored the role of pregnancy, but women who have been pregnant potentially have cells with therapeutic potential from their fetus," she said.
It is possible that many years after a pregnancy there are no longer cells in the mother's body that are fetal and capable of becoming all cell types. But a better point at which to try to catch fetal cells from the blood stream of women would be while they are still pregnant or perhaps shortly after giving birth. If fully pluripotent stem cells can be isolated from the blood of pregnant women then this may well provide a source for such cells that will not raise religious hackles.
Back in 1996 Bianchi first found fetal cells in mothers. But those cells were blood cells only. Her finding that fetal cells are becoming other cell types strongly suggests that fetal cells that are fairly undifferentiated are crossing over into women from fetuses and then differentiating (specializing) into various adult cell types. If those fetal cells that are crossing over are capable of converting into a large variety of specialized cell types then they are quite possibly the equivalent of pluripotent embryonic stem cells.
A confirmation of this result poses what seems to me an ethical problem for the religious opponents of embryonic stem cell research. If developing embryos effectively are donating human embryonic stem cells (hESC) to mothers and literally doing cell therapy to mothers then this natural process is doing something that at least some hESC therapy opponents consider to be morally repugnant.
It will be interesting to see where the various hESC research opponents come down on this result. Will they oppose the extraction of embryonic stem cells from a mother's blood while she is pregnant. If so, on what moral basis?
My guess is that a large fraction of the hESC research opponents will decide that extraction of hESC from a mother's blood is morally acceptable. No fetus will be killed by the extraction. The cells so extracted are not cells that would go on to become a complete new human life. If a sizable portion of the religious hESC opponents can be satisfied by this approach for acquiring hESC then Bianchi's research may well lead to a method to get hESC that will open the gates to a much larger effort to develop therapies based on hESC.
If blood samples from pregnant women are also a source of "morally uncontaminated" embryonic stem cells, then the bars on federal research money cannot help but fall without making Bush look very, very bad.
Wow! This is a cool.
Take a few cells. Culture them with the right growth factors and you have a new stem cell line. Modify ‘em, grow significant quanties, and pump ‘em back into the body.
Almost makes me want to get pregnant. (Damn Y chromosome.)
Engineer-poet said: '...a source of "morally uncontaminated" embryonic stem cells, then the bars on federal research money cannot help but fall without making Bush look very, very bad.'
Actually, quite the contrary. If this research pans out, the religious right can claim victory. "Victory?" you might say? Bush and his bioethics council can say "See, we told you so. Our ban on new stem cell lines prevented the destruction of hundreds, possibly thousands of embryos, and a way was found to do this research without slaughtering the innocent." I hate Bush just as much as the next person here, but mark my words, they will spin this into a media victory. A victory that, if it can keep them from losing the Presidency this November, will probably lead to a total ban on cloning, including therapeutic cloning.
However, don't get me wrong. Even the total ban on cloning isn't as bad as the ban on new stem cell lines, at least not for a few more years. We can do the research without the cloning, though the results won't be as good as they could be with. By the time Bush gets kicked out in 2009 (assuming he gets re-elected, which I am still holding hope won't happen), there will be several cures in stage III trials, and perhaps some awaiting FDA approval. By then, the public will have had another four years to wake up to the reality that stem cell research will save millions of lives. Not maybe. It will be inarguable. It will have been proven for disease after disease. The ban, if passed, will fall by the end of the decade, or at the latest, by the beginning of the next. And given that FDA approval will take this long or longer anyway, the delays won't cost hundreds of millions of lives, just a few tens of millions (some consolation, huh?).
This article provides another example of cells found within adults that can be used to repair tissues. The cells were found circulating in the blood of the mother years after the birth of the child. The topic of stem cells has been intensely politicized. In part, this is because powerful political factions have selected this research area to engage in a venomous proxy campaign between pro-life/anti-abortion and pro-choice/pro-abortion ideologies.
The actual science is being distorted and down played. Consider this article from Wired News titled "Stem-Cell Cash on a Winding Road".
The article is supposed to be about about stem-cell research but it completely suppresses all mention of adult (post-natal) stem cells. Bizarre! It is political reporting with a veneer of science.
The FuturePundit blog has covered stories about adult stem cells and embryonic stem cells. I think that it is clear that adult stem cells would in most cases be vastly superior therapeutically if they can be made to work. Adult stem cells collected from a patient, cultured with growth factors, selected and reintroduced would provide an exact immunological match. Progress has been rapid and enormous. Here is a small set of links:
TriStem claims it has developed a very rapid way to convert blood cells to less differentiated stem cells.
Adult stem cells are an effective treatment for patients who have had a heart attack.
Adult stem cells in human fat convert into human bone cells.
Adult stem cells in human fat convert into cartilage.
Adult stem cells from fat can be turned into fully functioning brain cells.
Tooth Stem Cells Could Treat Parkinson's. Dental pulp-derived stem cells can protect and promote the survival of dopaminergic neurons - brain cells involved in movement.
Stem cells from umbilical cord blood infiltrate damaged heart tissue and become the cells needed to stop further damage.
Garson Poole, I agree adult stem cells are more promising for curing disease. (No immune problem and being more “differentiated” they take on the proper roles.)
I’m not so sure about anti-aging therapies.
First, adult cells are older. There is evidence that old stem cells are less effective at repair than young cells. (Who knows why? DNA damage? Improper gene silencing? Cell internal environment? Defective mitochondria?)
Second, embryonic stem cell transplants might be better accepted by the host immune system. I expect to see enhanced stem cell lines developed for many purposes. Rather than make the changes to an individual’s adult stem cells, I expect companies to develop several generic stem cell lines that work in most people. Treatment for the masses.
Adult stem cells isolated from a person and then grown to be delivered back to the same person are much less likely to invoke an immune response than cells from another person.
As for whether the adult stem cells can be rejuvenated: With time, certainly. But will it take longer to figure out how to rejuvenate adult stem cells or to figure out how make embryonic stem cells immunologically compatible? I do not know.
But if embryonic stem cells can be harvested from the blood of pregnant women the question of whether to use embryonic or adult stem cells will become purely scientific. I do not expect most current opponents of embryonic stem cells to object to the harvesting of embryonic stem cells from the blood of pregnant women. Though I could be wrong on that point. The key here might be in how the stem cells get labelled. If scientists would simply call these cells pluripotent stem cells and only refer to cells taken from the embyro as embryonic then many the religious folks will find this method of acquiring stem cells to be ethically acceptable.
I agree with Poole that most early stem cell therapy successes will use adult stem cells.
Educating Immune System May Ease Future Use Of Stem Cells
Since we don’t yet know why adult stem cells are old and significant progress has been made on the immune problem, I believe embryonic stem cells will likely be used for rejuvenation.
Deriving embryonic stem cells from a pregnant woman’s blood is excellent news.
If I were female and pregnant I’d definitely want my fetus’s stem cells to be extracted from my blood, cultured, and saved for future therapies.
Something in the generation of sperm and egg cells, the fertilization of the egg (involving competition among millions of sperm), or the early womb environment rejuvenates cells. Accomplishing the same feat for adult stem cells might be difficult.
Randall Parker said:
I do not expect most current opponents of embryonic stem cells to object to the harvesting of embryonic stem cells from the blood of pregnant women. Though I could be wrong on that point.
I think you are correct. The opposition to "embryonic stem cells" seems to rest primarily on the desire to avoid the destruction of embryos. In the article we are commenting on, the cells are harvested from the blood of an adult woman. The collected cells are originally from a male fetus but the fetus is not destroyed. In fact, the fetus might already be a healthy child when the cells are collected.
One website that opposes the use of embryonic stem cells called "DoNoHarm" http://www.stemcellresearch.org/ appears to be in favor of this type of research. They have a link to an article about the work at http://health.myway.com/art/id/519953.html and at http://news.bostonherald.com/localRegional/view.bg?articleid=34668
There already is an industry storing stem cells from umbilical cord blood http://www.cordblood.com/
These cells are arguably "fetal" stem cells but I do not think there is much opposition to their use.
Fetal cells are collected and typically destroyed during the diagnostic process called amniocentesis. This does not kill the fetus (at least it usually does not - miscarriages are possible). The procedure is legal and widely used. So I do not think the collection and use of fetal cells will be widely opposed when the fetus (or embryo) is not destroyed.
Selecting a good name for the cells would be useful. The name "pluripotent stem cells" sounds good. Additional complexity and obscurity might help ;-). How about cross-membrane maternally derived multipotent progenitor cells?
One problem with any type of stem cell is that it might have mutations in cell growth regulatory systems. Already quite a few genes have been identified that get mutated in ways that contribute to cancer. Any stem cell line will need to be screened for all known regulatory and repair gene mutations. Also, general appearance of the chromosomes would need to be checked for breakage and iiregularities.
If we can verify that a given adult cell line doesn't have any harmful mutations then we can apply therapies to the line that will help to rejuvenate it. One big thing that would need to be done would be lengthen telomeres. Another might be to make sure all the mitochondrial DNA is unmutated. That might be tricky to do. A cell has many mitochondria in it. A better solution would be to put mitochondrial genes into the nucleus. But they can't be moved directly without some tweaking because they need to be modified so their gene products will be transported back into mitochondria after synthesized. That is a challenge due to chemical properties of the proteins made by the mitochondrial DNA genes.
Anyway, some day we will be able to rejuvenate adult stem cell lines. It is a matter of when, not if. That is easier to do than it is to rejuvenate an entire body for a number or reasons. Cells are easier to manipulate than complete tissues. Some forms of problems in tissues are not a problem in individual cells. For instance, extracellular junk is not a problem and dividing cell lines will dilute accumulated lysosomal junk. Also, we can select amount large numbers of cells to choose ones that are in the best shape to start from.
“Also, we can select amount large numbers of cells to choose ones that are in the best shape to start from.”
I’m guessing that this is the mechanism that animals presently use to filter harmful mutations.
First, sperm and egg cells have to be viable. Since they only have one chromosome copy, many lethal mutations will be eliminated. (But only those needed to support single cell function.)
Second, sperm compete to impregnate so the winner is one of millions. I’d expect this to be a good filter of mitochondria but the sperm supplies very little of the mitochondria to a fertilized egg. (If I were designing the process I’d want the sperm mitochondria to predominate.)
Third eggs compete for maturity. While not as intense as sperm competition, this might be the stage where the mitochondrial population improves. (My intuition says this step isn’t sufficient to filter out bad mitochondria. Perhaps that is why many genetic diseases seem to have a mitochondrial link.)
Fourth, the early cells must produce trillions of cells. Perhaps this process favors good mitochondria. The cells that through random distribution of mitochondria accumulate better mitochondria might provide more of the body’s cells. Thus the cells that end up producing the germ cells might have better mitochondria than the first fertilized egg.
Fifth, the fetus has to successfully develop. This process filters genes and regulatory sequences that weren’t needed by the gametes.
Finally, we have Darwinian selection outside the womb.
Note that cloning doesn’t replicate this filtering process. The success rate for cloned embryos is low but seems to be improving as the technology advances. Does this mean that the above process isn’t important? Does it mean that cloned animals have significantly more recessive lethal mutations? (There are also problems with gene silencing in clones but I’m more interested in how the genome is maintained from one generation to the next.)
Is anyone working on such problems?
Understanding the natural process might help in devising a biotech process for maintaining a high quality stem cell line. Note that just observing the cells won’t prove that the genome isn’t degrading. Only a subset of the genome would be active and recessive mutations (most common since they are often loss of function mutations) might have no visible effect.
Opps, I should have commented that I agree that Randall’s suggestion of monitoring for the most common known defects by testing sample cells would play an important role.
If we take large numbers of stem cells from adult humans we can select among them using an automated screening mechanism to choose cells that are least damaged. We'd need to take each cell, isolate it, induce it to divide. have it grow into large numbers, extract subsets, test the subsets using DNA sequencing and other techniques. Then use those results to pass on whether the starting cell was a good starting point. Repeat as nececessry with dozens, hundreds, or thousands of cells taken from various parts of the body.
Of course, to do very rigorous testing in a cost-effective way requires advances in instrumentation. But surely those advances are coming. Microfluidics and other techniques will lower the costs and support the level of scaling needed to sort through a large number of cells to find good starter cells to then dedifferentiate and convert into other cell types. We will be able to do all that within 10-20 years and sooner for some applications.
Cheap, accurate, and complete genome DNA sequencing for single cells may be awhile in arriving. Still I wouldn’t bet against it. I believe the trends favor your prediction.
The stem cell lines would be carefully nurtured with anti-oxidants and grow factors to minimize genetic damage so frequent testing might not be necessary to maintain genome quality.
I’d still like to know how animals keep the germ cell line relatively free of errors. I was speculating above but I don’t know that anyone has verified in an animal how the process works. (I know the germ cell lines have extra DNA repair enzymes. I want to know what selective mechanisms might also be working.)
Some of my speculation is based on comments Aubrey de Grey made in a newsgroup years ago. I haven’t seen anything in a biology text or article to confirm or contradict these guesses.
The problem of adult vs. embryonic stem cells is vexing. Two developments have to be made before this problem will go away. A method must be developed to transform adult stem cells into "embryonic" stem cells, back and forth. The other is to figure out exactly what the biochemical mechanism of aging is so that we can rejuvenate them into a youthful condition, just like the embryonic ones. People tell me that we are, at most, 5 years from being able to do both of these. The key is to make whatever kind of stem cells we want without making the embryo. Once we have accomplished this, I think that the religious people will shut up.
Clearly this is possible because our bodies do this all of the time. We just need to figure out how to do this with a microfluidics device. Rapid whole genome sequencing from a single cell will take time, but is definitely coming (probably within 10 years). What should be obvious to everyone is that aging is strictly a somatic-cell phenomenon. It does not occur in the germ-line. I think that Aubry de Grey is correct about the cause of aging (60% is due to mitochondrial mutations and the remaining 40% is due to one or more of the remaining six causes).
Since I have entered the biotech instrumentation industry (biochip scanners, micro-arrayers, etc), I can tell you that this technology is also following a development curve similar to that of the semiconductor IC Moore's Law. All of these instruments are based on electronics, nanosensors, and MEMS technologies like microfluidics. It is also very embryonic (no pun intended). The MEMS technology has yet to progress to the point where several functions (sequencing, analysis, and synthesis) are combined into a single microfluidics device. However, this technology is coming very fast. The reason is that I am aware of over 20 microfluidics MEMS device manufacturers. That means that there are probably 40 such start ups operating now. They have to differentiate themselves in order to stay business.
Much of the biomedical fabrication techniques that require a room-sized biotech lab will be doable by a single MEMS device in 10-15 years. I honestly believe that, if it has not been done by then, that it will be relatively easy for a lone researcher to develop his/her own anti-aging therapies in their own lab by 2035, using this kind of micro or nano based instrumentation.
I have a little knowledge about TriStem. I suspect that their claims are inflated. They have not allowed any other labs to duplicate their work, which makes me suspicious. Scrips Institute has developed a compound, called reversine, that can take regular cells and de-differentiate them into a more stem-cell like state. How far back the de-differentiation process can be done is still being researched.
I honestly do believe that by 2050, aging will become as much an artifact of history then as polio is to us today. I see no reason why we should have to put up with this disgusting, disabling process any longer than necessary. Aubry is right. It should not be tolorated in polite company.
Kurt: “What should be obvious to everyone is that aging is strictly a somatic-cell phenomenon. It does not occur in the germ-line.”
Clearly animals are born young and not old. What isn’t clear is how this feat is accomplished.
The germ cell line is special in that it has extra nuclear DNA repair enzymes. However there are types of DNA damage that the enzymes don’t repair. And those enzymes don’t stop mitochondrial DNA damage. Even germ cells age. (Old sperm and old eggs lead to increased birth defects in offspring.)
Some aspects of aging aren’t a problem for the fertilized egg cell. Cellular garbage is diluted to non-existence by rapid division. Likewise protein cross linkage is no problem since all structures are new. Aging due to whole body hormonal imbalance is not a problem since the body is new. The gamete/fertilization process resets gene silencing and the regulatory state. Telomer length is maintained.
That still leaves the problem of the germ line DNA defects that do occur in both nuclear and mitochondrial DNA. Obviously some are passed to offspring in the form of both harmful and beneficial mutations. My question is “Are large numbers of bad mutations filtered out by the gamete/fertilization process?”
How do single-celled life forms stay “young”? To me the answer seems clear, extreme environmental selection pressure. Harmful mutations decrease fitness and are rapidly eliminated. (Twenty minutes between generations and vast populations equals extreme selection pressure.)
Large life forms are under much less environmental selection pressure. So how is genome quality maintained?
I’ve already stated some of my guesses. Basically the sex process of gametes, sperm competition, and fertilization forces a selective competition that maintains genome quality.
(As a measure of “selection pressure” consider the percent “junk” DNA in a genome. Bacteria have almost no “junk” DNA, yeast has a moderate amount of “junk” DNA, while almost all human DNA is “junk”.)
Outstanding work Dr. Bianchi. You are my new hero! Onward, and upward we all go because of you Dr.
Just wanted to thank you guys for proving that it is, in fact, possible to have an intelligent discussion on these matters. Great website!
I was just woundering if anyone could tell me why Blood Type A- is a risk for a pregnant woman. If you know anything that could help me understand this please e-mail me. I would greatly appreciate it.