Blood, Teeth and Stem Cells

The Bayblab has been a bit neglected lately, but that doesn't mean we're not still blogging. Head over to the Stem Cell Network blog to check out some new posts. I have a couple of recent pieces up. The first is about a potential new dental implant that uses a special scaffold to attract and differentiate stem cells, growing new teeth in place. The second is a first look at a new paper that challenges some assumptions about hematopoiesis.

Stem Cell Tourism in China

I've written before about StemEnhance, a piece of pseudomedicine that purports to improve "wellness" by stimulating stem cell release from the bone marrow. In that post I questioned whether the supplement a)did what they claimed and b)whether, if it worked as advertised, the mobilization of stem cells would have a positive, negative or no effect.

Well now, instead of $60 a bottle for algae extract, you can drop a grand on a flight to China and another $20000 to be injected with umbilical cord cells - guaranteeing an at least temporary boost of stem cells in the body. (Nevermind that these cells are foreign and will be attacked by the immune system) Of course the same questions remain: Will this kind of treatment have positive, negative or no effect? Dr. Hu, the chairman of the company selling this treatment claims that 70% of the 3000 patients who have had these injections for a variety of conditions have seen an improvement. On the other hand, the NPR article (linked above) points out:

No rigorous, controlled clinical trials were carried out before the treatment was offered to patients. No research has yet been published in established peer-review journals overseas. And no one knows for sure what the possible risks might be.

So once again, we have an untested, unproven therapy. Let's look at the possible scenarios:

1) The injections work. People's varying conditions are being improved. Great! Test it. Prove it. Show it's safe. Yes trials are expensive, but why wouldn't you want to do it to silence skeptics, better understand what's going on and potentially improve this kind of treatment. However, the likelihood of this therapy working as advertised is small.

Bruce Dobkin is director of the neurologic rehabilitation and research program at the University of California, Los Angles. In response to questions from NPR, he writes in an e-mail that "it is extreme nonsense to think that cells can be incorporated into the complex nervous system and do so much, when we cannot even get cells in mice and rats to do very much.

There's also no evidence that umbilical cord stem cells can become the kind of neurons these doctors are claiming, nor evidence that they'll even get to the desired site to begin with.

2) The injections have negative effects. Regardless of whether these injections are a useful treatment, there's the very real posibility that there could be serious consequences that haven't been discovered (no testing means no awareness of effects good or bad). Immune response. Cancer. Take your pick.

3) The injections have no effect at all. Thanks for your 20 grand! Goodbye.

This kind of treatment may hold some future promise, but once again someone is putting the cart before the horse when it comes to stem cell treatments. Do the research, then treat. And don't ask desperate families to plonk down crazy amounts of money for what is generously described as experimental treatment. Sadly, this makes StemEnhance look good by comparison.

More blog reaction here and here.

Can mammals renew their eggs?

I've talked about this subject in the past, and we briefly mention it in the upcoming podcast, but where are we with the question of whether a germline stem cell exists in female mammals? PLOS as a great article which summarizes the ongoing debate on whether a woman is born with a limited pool of eggs that will last for her reproductive life or whether that pool is continuously renewed... Obviously the presence of a hematopoietic stem cell which has the ability to form eggs, as Jonathan Tilly believes, would radically change the way we view conditions such as infertility, menopause and bone marrow transplants. As mentioned in this article, it's still too early to call, considering so little of the work has been replicated. Additionally, while bone marrow transplants in irradiated females is sufficient to reestablish fertility, none of the ovulated eggs match the donor, despite such eggs being supposedly present in the ovary.

In addition to this story being interesting, it highlights how reproducibility is so seldom tested in the current constrained funding environment. In fact it seems that this situation is particularly true of the whole field of stem cell biology...

“What anyone publishes is not really the corpus of scientific knowledge unless it can be verified,” says Gosden. “You don't get a paradigm change until you have a consensus of expert opinion,” he says, and that is certainly not the case here. This follows physicist and science historian Thomas Kuhn's view of scientific revolutions—that many inconsistencies must build up in a field of science before a paradigm shift can occur.

The Kuhn model of paradigm shifts describes how most central ideas in science get revised or overturned, but there is another model that some would argue is equally valid, if rarer: the “lone voice in the wilderness” of a single scientist pushing a revolutionary idea forward. There are notable examples of lone voices who both succeeded and failed in overturning an idea. Stanley Prusiner's hypothesis that aberrant protein structures called prions could cause infection initially lost him his bid for tenure at the University of California at San Francisco and significant funding from the Howard Hughes Medical Institute, but eventually won him a Nobel prize in physiology or medicine in 1997. The cold fusion work of the late 1980s, which was never replicated to the satisfaction of the nuclear physics community, eventually resulted in Martin Fleischmann and Stanley Pons dropping out of academia.

“There's a fine line between being a maverick and a genius prescient person,” says Durant. Currently, Tilly is gingerly straddling that line, which can mean the difference between receiving the highest scientific honors or the scorn of your peers."

Rethinking transplants

The NEJM has a series of articles on transplantation without the maintenance of immunosupression.The idea is that along with the transplanted organ, say a kidney, you give some of the donor's hematopoietic stem cells. If the stem cell graft is successful it will result in a chimeric immune system which tolerates the transplanted organ despite being HLA mismatched. However, one wonders why the stem cell itself isn't rejected, since immunosupressive drugs are only given for a short period of time, so that the graft takes :

"Five patients with end-stage renal disease received combined bone marrow and kidney transplants from HLA single-haplotype mismatched living related donors, with the use of a nonmyeloablative preparative regimen. Transient chimerism and reversible capillary leak syndrome developed in all recipients. Irreversible humoral rejection occurred in one patient. In the other four recipients, it was possible to discontinue all immunosuppressive therapy 9 to 14 months after the transplantation, and renal function has remained stable for 2.0 to 5.3 years since transplantation. The T cells from these four recipients, tested in vitro, showed donor-specific unresponsiveness and in specimens from allograft biopsies, obtained after withdrawal of immunosuppressive therapy, there were high levels of P3 (FOXP3) messenger RNA (mRNA) but not granzyme B mRNA."

The cool thing is that this can spontaneously occur, such as this case of a young girl who received a liver transplant. Somehow either a liver stem cell or a resident cd34+ cell was a ble to colonise her bone marrow and turned her into a partial chimera, thus removing the need for lifelong immunosupression:

"Complete hematopoietic chimerism and tolerance of a liver allograft from a deceased male donor developed in a 9-year-old girl, with no evidence of graft-versus-host disease 17 months after transplantation. The tolerance was preceded by a period of severe hemolysis, reflecting partial chimerism that was refractory to standard therapies. The hemolysis resolved after the gradual withdrawal of all immunosuppressive therapy."

Bayblab Podcast Episode 14

The famous bayblab podcast is now full of holiday cheer and back where it belongs: at a pub! This time we discuss what's new in cancer research, talk about the psychology of quacks who sell fake stem cell remedies and reveal shocking lab tales of promiscuity in the dark room which may explain why Bayman is absent.

Jaenisch On Iran

Rudolf Jaenisch, arguably the foremost stem cell researcher in the world, certainly doesn't shy away from politics. Last time I saw him speak, his lab had engineered the "ethical" stem cell, but he also dedicated quite a few slides to ridiculing US anti-stem cell research policies. Now he's tackling American anti-Iran extremism, with this article on his recent trip to a stem cell conference in Tehran:

"Delays and setbacks are built into the scientific process no matter where it occurs, but researchers in Iran face an additional burden imposed, largely, by politics. Cell biologists lack even the machines that sort cells by surface-protein markers because the necessary US-made equipment cannot be imported. They cannot perform many experiments that we consider routine, but rely on collaborators who have the necessary equipment. Even when equipment has been procured, Iranian researchers face logistics that prevent them from getting on with their experiments.

It seems to me that these restrictions are not in anyone's interest. Scientists themselves exacerbate the situation, fuelled by misinformation that they put themselves at personal risk by travelling to Iran. Of course, people who would not be able to refrain from political discussion or dress as expected would be wise not to go. But the vast majority of scientists would find themselves surrounded, as I was, by courteous, hospitable, well-informed men and women who relish interaction with other scientists. Unfounded apprehensions about the risks of travelling to Iran effectively add a scientific embargo to the politcal one.

"There are clear differences between our countries, but these fade in the laboratory as we approach scientific questions. Furthermore, attitudes and policies that stifle scientific work and collaboration hinder not only science, but also international relations. When we don't have an exchange of ideas, we foster fanaticism and intolerance; this is something that science could help to counteract."

I think it's commendable that Jaenisch has the guts to take positions that powerful people in his country might disagree with, rather than bury his head in the sand alongside many of his colleagues.

Obesity IS a Disease

Stem cells are at it again, but this time they're responsible for obesity. At a recent meeting of the American Chemical Society, data was presented demonstrating that infection with with a common virus - Adenovirus-36 - caused adult stem cells from adipose tissue to change into fat storing cells. Animals infected with the virus pack on the pounds, and obese people are 3 times as likely to have been infected by Ad-36 according to the report. Adenovirus-36 has also been shown to increase insulin sensitivity and reduce leptin expression - two other factors that can influence obesity. Researchers are talking about coming up with an 'obesity vaccine' to combat this form of obesity, further chiseling away at the notion of personal responsibility when dealing with one's health.

Introducing: bayblab definitions

schmer·oid (smîr'oid', směr'-) n. : Aggregate of cells, that vaguely ressembles a sphere, resulting from mistreating your tissue culture. They are thought to have mystical powers to differentiate into anything, including brain, kidney, ipod or a rock, provided you pray to the right gods. But mostly, they are just balls of cells. If you count them, sometimes you can be rewarded with a cell paper or a microscope-induced headache.

functional definition:
-ability for self-denial
-ability to solve differential equations

see also: transit-pimping cells, commited prudo-genitals and terminally disoriented cells.

Backboner

A couple of years ago, I went to the meeting of the Society for the Study of Reproduction (SSR) where J. Tilly presented his paper on the repopulation of germ cells in the ovary by a circulating stem cell in the blood. It was the first time that I saw both a standing ovation and grumbling from skeptics at a scientific talk. It went against everything we knew about female germ cells, and raised the possibility that woman with bone marrow tranplants or blood transfusion may not be the biological mothers of their own child. I am still not 100% convinced, but the idea that the niche can dictate what a stem cell will become is becoming more and more supported by evidence. This recent report that bone marrow cells injected in the testes can give rise to sperm further substantiates that claim. So maybe females can become, biological fathers? And it is good news for my friend who's spontaneously grown ovaries after watching too much dancing with the stars...

New source of income for grad students

Grad students will do just about anything for extra cash/food. Sell blood, semen or spend 6h motionless looking at med students writing exams. Now you might even be able to sell your eggs for stem cell research at 500$ a pop, at least if you live in the UK. Doesn't seem like much of a deal to me, since apparently, if you're an Ivy Leaguer with a high IQ you can sell your sperm or eggs for reproductive purposes at close to 40 000$ a load. Scroll to see all the comments from woman who want to sell eggs : "I have a 147 I.Q., 3.9 GPA, Brown hair, brown eyes, 5'4 115 pounds, and I also am a very skilled artist."

Sharks DO get cancer

I just gave a journal club about a trio of papers out this week in Nature Genetics. They support an interesting theory that stem cell and cancer cell self renewal is controlled by Polycomb repressor complexes (PcG). They maintain tumour supressors in a repressed but still free to be activated and thus "bivalant" chromatin environment in stem cells. However with time and because of epigenetic drift these supressor complexes tend to recruit DNA methylation and the tumour supressor become irreversibly repressed, thus with a "locked-in" stem-ness. This could be regarded as the "first" hit of the two hit transformation driving a stem cell into a cancer cell. Interresting paper, although you never know these days whether to trust stem cell papers, I guess the gold rush mentality attracts fraud.
Following JC I discussed the significance of said papers with the Ken-meister, and proposed that maybe sharks do not keep stem cells around and that is why they don't develop cancer. To which Ken replied yes they do! So I must correct myself from the podcast, although the incidence rate is low compared to other fish there has been cases of tumours including Chondromas! Oh the irony, I guess shark cartilage is not going to save you, however wrestling shark while intoxicated on vodka is still ok...