Adult stem cell lies – everything old is new again

It’s come time to lie about science again – this time about the reality of embryonic stem cell pluripotency – and some of the old lies are coming back out of the storage shed. For instance, Andrew Breitbart on Real Time last night, and in a video from (liar for Jesus) Tony Perkins of the Family Research Council, I’ve heard about how adult stem cells have cured or treated 72 diseases. Oh and embryonic stem cells, they’ve cured none. It’s been a while since we’ve seen this adult stem cell nonsense.

I had to jog my memory for a minute, I knew this was a lie, but it had been so long since I heard it, that I really had to think about where I had heard it from. Oh yeah, this nonsense list that was famously cribbed by Ann Coulter from a right-to-life group.

To understand the problem with this list and why these citations don’t say what they think they say, we have to learn a little bit about adult stem cells and a big scary word – transdifferentiation. Adult stem cells, which exist in many tissues throughout your body, have specific jobs to perform for the human body to continue to function. Hematopoietic (blood) stem cells make all the red blood cells, white blood cells, and platelets you need to as they are continuously lost or degenerating as part of their natural life span. Stem cells in your gut continuously replace the lining of your intestines as it wears down from the harsh process of breaking down food. There are stem cells that have been isolated from most tissues that function as a repair and maintenance pool of cells to keep our organs functional. Not all organs have a ready pool of stem cells, and most stem cell populations, with the notable exception of blood stem cells, are hard to harvest without risking injury to the host.

However, while these cells are great at doing their job, the issue with adult stem cell research is, can they do another stem cell’s job? That is, instead of making just blood, could a hematopoietic stem cell make, say, an insulin secreting pancreatic cell? The answer, despite some initial promising results around 2001, is no. While hematopoietic stem cells may be able to make some other mesenchyme or connective tissue cells from the mesodermal germ layer, it doesn’t appear that we can make such adult stem cells transdifferentiate – or make a type of cell from another embryonic germ layer. This ability is what is meant by totipotency. The ability to differentiate not just into one of the three major tissue types (mesoderm, ectoderm and endoderm), but all three of them.

So, what is up with this list then? They have 72 treatments using adult stem cells!

No they don’t. This is a lie. They really only are describing one treatment in most of these list items. That is, hematopoietic stem cell replacement of marrow being used in the course of treatment of many diseases. The hematopoietic stem cells are not treating these illnesses, they’re letting us use chemo, or irradiation, and then replenishing the patient’s blood supply. In other words, they’re doing what a good blood stem cell does, replace blood. They’re not treating the disease at all.

Let’s take a look at some of these references.

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Lifting the stem cell ban – was there any point?

President Obama has lifted the ban on embryonic stem cell research enacted by Bush, but I’m left feeling that this intervention came many years too late.

Pledging that his administration will “make scientific decisions based on facts, not ideology,” President Obama on Monday lifted the Bush administration’s strict limits on human embryonic stem cell research.

But Mr. Obama went on to say that the majority of Americans “have come to a consensus that we should pursue this research; that the potential it offers is great, and with proper guidelines and strict oversight the perils can be avoided.”

In making his announcement, Mr. Obama drew a strict line against human cloning, an issue that over the years has become entangled with the debate over human embryonic stem cell research.

As someone who works with stem cells I find this largely an empty, symbolic act, but one that needed to be done anyway. The reality is the damage was done by Bush already, and we’re fortunate that it was only a temporary delay in some of the most important research humans have developed to date.

What a lot of people don’t realize is that in 2006 a revolutionary result was discovered by Japanese scientists led by Shinya Yamanaka at Kyoto University. What they found was the reset button for mammalian cells, the genes that need to be expressed for a cell to revert to a pluripotent state. We wrote extensively about what results in these cells – induced Pluripotent Stem Cells or iPSC – mean for stem cell research and regenerative medicine overall. Basically, the ability to reprogram the cells of any individual to a totipotent state – one in which the cells may make any cell-type or tissue in the human body. Before some fool suggests this was due to Bush remember it was a Japanese group, the research started long before Bush, and it never would have been possible without ES cells from which they culled the critical genes for the transformation.

So why does it matter that Obama has reversed this policy? Not only are ES cells inferior compared to iPSC for human therapies, but wouldn’t it be easier not to upset the fundamentalists that would equate the value of our lives to that of a ball of undifferentiated cells?

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Tumors in a (quack) human stem cell therapy

It’s almost like a bad Yakov Smirnoff joke, “In America you test therapies in animals before giving them to humans, in Russia…” All I can do is wonder, what were they thinking? Injecting stem cells into a kid’s spinal fluid to correct a genetic disorder? Are they insane?

Stem cells, in particular embryonic and fetal stem cells, are useful because they represent cells that are less differentiated than the cells that are working at specific functions throughout your body. Another result of being stem cells is that they are able to divide and proliferate without differentiating or undergoing apoptosis and as cells differentiate towards their final fate they tend to divide less and ultimately commit cellular suicide if they are signaled to begin dividing again – a protection against cancerous growth. The downside of this is that stem cells act, in their normal state, a bit like cancerous cells. In fact one of the assays to demonstrate the pluripotency of a cell (the ability of a stem cell to make many kinds of other tissues) is to inject them into an animal where they will make tumors called teratomas which are (usually) benign growths of cells that represent endoderm, mesoderm, and ectoderm – the three germ layers than give rise to all tissues in the body during development.

As a scientist who works with stem cells, both in culture and in vivo I could have told you this therapy was a bad idea. A year ago Jake explained why this was a bad idea. If you had described this therapy to us, we would have told you exactly what would happen based on scientific knowledge of how these cells act in vivo. The therapies offered to stem cell tourists are frank quackery. They are unproven, untested, unstudied, and unmonitored. And to you anti-FDA libertarians out there, this is what you get when you don’t have regulatory oversight of human therapies. You get stupid quackery. The fact that this kid’s cancer was detected is probably just luck – there are likely many more people who have tried these therapies of desperation who suffered side effects, and possibly even death, but we just haven’t heard about it yet.

Ethical human trials require many things. At the very least, the therapy should have been tested extensively for safety in animals and ideally for efficacy in animal models of the disease. The patients should be selected carefully, should have a reasonable expectation of therapeutic benefit, and after the treatment follow-up should be extensive. Further, in the case of such a novel therapy, the bar should have been set higher before attempts in humans were made. In this case we have a child with a rare genetic neurodegenerative disorder that was experimented on without proper oversight, or a reasonable expectation that this therapy should do anything. Ataxia Telangiectasia is an autosomal recessive disorder in which every cell in the child’s body lacks the appropriate gene which is involved in cell cycle regulation and DNA repair. By what mechanism did they think neural stem cells would have an effect on such a disorder? Would the cells replace the child’s entire central nervous system? Would they miraculously repair the genetic defect? Or manage to insert themselves in just the right places to fix symptoms caused by a universal defect in the the hosts genome? This is magical thinking, not scientific thinking, and further I believe it is grossly unethical and stupid.

It is of no surprise that the careless injection of fetal stem cells into a child would result in tumors. This was a mind-bogglingly stupid act. What’s worse, as we hear more about the damaging quackery being offered in countries without proper regulation and oversight of human therapy we will likely hear more stories like this one.

In the rush to find some dramatic cure for a disease using stem cells it is likely efforts like these will damage the success of legitimate and careful studies in regenerative medicine and stem cell therapies. Injury and deaths from careless stupid quacks using these cells will create and association in people’s minds between stem cell therapies and cancer. We know the obstacles to using these cells in humans. The major one – immune compatibility – may have been solved already. The major remaining obstacles towards implementation of some fairly crude stem cell therapies are going to be (1) differentiating the cells into the appropriate tissues, (2) purifying the cells so that undifferentiated cells aren’t accidentally transplanted into humans, (3) preventing tumorous growth in the transplanted cells (possibly including a lethal gene to reverse the therapy if necessary), and (4) proper anatomic delivery of the cells so they perform a useful function and survive in the host. We know what the problems are. Careful study must include addressing each of these issues and ensuring they are resolved before shoving them into someone’s spinal fluid.

This quackery is not only going to prove harmful to individual human patients, but will likely harm the burgeoning field of regenerative medicine as a whole. For the sake of the patients, and for all future patients that might benefit from well-studied therapies, this quackery must be stopped.

Reprogramming adult cells into pluripotent stem cells – what do these new results mean

Blogging on Peer-Reviewed ResearchYou guys might have noticed I’ve been quiet lately, that’s because I’ve scheduled a thesis defense and am under deadlines. However, I couldn’t let these two (1) papers(2) on reprogramming of human adult cells into stem cells slip by without some comment (NYT piece here)

These reports are a follow-up on landmark animal studies that we discussed previously that showed that expressing 4 genes in cells obtained from adult animals you could induce them to form embryonic stem cell (ESC) like cells that researchers dubbed induced pluripotent stem cells (iPS cells). At the time we noted several obstacles to the practicability of this technology, and these papers represent success in overcoming the first – transferring the technique into human cells.

I admit I’m surprised they were able to do so so quickly. But this turned out to be a nice example of the discovery of common exploitable pathways between humans and other animals.

Below the fold I’ll go over the differences between these studies and the previous animal studies, the evidence of the pluripotent nature of these cells, unresolved problems with this technology and why this isn’t a victory for the anti-ES cell crusaders.

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Saletan on the Ethics of Stem Cells

William Saletan takes the position that progressives have no real bioethical position on stem cells in his most recent column in Slate. I’m a bit disappointed with Saletan over this one, because in his never ending quest to be thoughtful about everything, he’s usually much more fair to people – even those he disagrees with. But listen to his characterization of “progressive bioethics”.

I have problems with liberals. A lot of them talk about religion as though it’s a communicable disease. Some are amazingly obtuse to other people’s qualms. They show no more interest in an embryo than in a skin cell. It’s like I’m picking up a radio signal and they’re not. I’d think I was crazy, except that a few billion other people seem to be picking up the same signal. At most liberal bioethics conferences, the main question in dispute, in one form or another, is whether to be more afraid of capitalism or religion.

Lately, “progressives” have taken to issuing talking points. Every time a peer-reviewed science journal reports some new way of deriving embryonic stem cells without having to kill embryos, I can count on receiving a “progressive bioethics” e-mail that warns me not to be distracted by such fantasies. Bioethics has become politics by another name.

To fend off the bullies, the nerds have seized on stem cells. Some of them think embryonic stem-cell cures are just around the corner. Others know better but believe in the research anyway. What unites them is awareness that stem cells score very well in polls, much better than anything else on their agenda. Of 32 commentaries posted on the Web page of the “Progressive Bioethics Initiative,” 26 focus on stem cells. Some don’t even address ethics; they just lay out the polls. Stem cells are a chance for liberal bioethicists to beat the living daylights out of their opponents.

So I went to talk to them last night. I bitched about the atheism, the talking points, and the word progressive. I made a pitch for my version of liberalism. The freedom to strip-mine embryos, have a baby at 60, or kill yourself can’t be the end of the story. Not everything that’s legal is moral. The most interesting moral questions aren’t the ones you can settle with simple rules. They’re the subtle ones you find in literature and real life.

Conservative bioethicists think that when we recoil at something in this gray area, our repugnance signals a moral problem. Liberal bioethicists dismiss this argument as “fuzzy intuitionism” based on an illogical “yuck factor.” The liberals are making a big mistake. Fuzz and yuck are very real. They’re a lot more real to most people than bioethics is. You can’t just ignore them or wish them away. You have to help people sort them out and honor their concerns in a way that doesn’t require prohibition. An embryo may be less than a person, but it’s more than a tissue source. The government can’t stop you from having a baby at 60, but don’t be so reckless.

Is this a fair characterization of the ethics of using stem cells for research and maybe one day, tissue-engineering and cures? It may be what he took from the meeting, but I hope that isn’t the extent of progressive or liberal bioethics on stem cells, a desire to use a hot-button issue to beat conservatives at the polls. As someone who thinks this research important, I’ll try and do Saletan a favor and create a positive argument for embryonic stem cell research.
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Reprogramming adult cells into embryonic stem cells

Blogging on Peer-Reviewed Research

As promised, I’m going through the three papers from last week about the re-programming of adult cells into an embryonic-like phenotype. Since it is three papers I’ll go through first what’s common to all three, and then what each group did special.

First of all, let’s summarize the method one more time.
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The death of a wedge issue

I hope this time I’m finally right about this. I’ve been hopeful that some strategy of developing stem cells would allow us to bypass the absurd ethical restrictions from those who think one type of destruction of an embryo is worse than another. Particularly promising were spermatogonial stem cells, but they could only be made from men (and the procedure might have been unpopular), and placental/amniotic stem cells, which were limited by the ability to passage them without differentiation, and supply (not everybody freezes back their placentas).

The ideal stem cell would have the following properties.
1. It would be immortal until differentiated – meaning that you could make as many as you want from a single cell
2. It would be totipotent – that means it could make any cell in the body – this can be tested by injection into blastocysts to make chimeric animals or by in vitro differentiation in EBS
3. It would be genetically matched to an individual – that would allow tissues derived from the stem cell to be compatible with a recipient.

Adult stem cells just never were able to meet all three of these requirements. Usually, they would excellent ability to differentiate into what they ordinarily make, but they couldn’t transdifferentiate – that is make a cell it wouldn’t ordinarily make in the body. Blood stem cells could make endless amounts of blood, but it was unclear if they could effectively make anything else. Mesenchymal stem cells could make things like cartilage and bone really well, but appeared limited in making non-mesenchymal cells, like neurons. And many tissues don’t appear to have an adult stem cell population, or, their isolation would not be possible without killing or injuring the donor.

Several news reports from today have been discussing this new advance (Alex Palazzo was hinting about this last week in his coverage of this paper). Here is the new paper (subscription not required) here, and here’s Nature’s coverage:

Last year, Yamanaka introduced a system that uses mouse fibroblasts, a common cell type that can easily be harvested from skin, instead of eggs4. Four genes, which code for four specific proteins known as transcription factors, are transferred into the cells using retroviruses. The proteins trigger the expression of other genes that lead the cells to become pluripotent, meaning that they could potentially become any of the body’s cells. Yamanaka calls them induced pluripotent stem cells (iPS cells). “It’s easy. There’s no trick, no magic,” says Yamanaka.

The results were met with amazement, along with a good dose of scepticism. Four factors seemed too simple. And although the cells had some characteristics of embryonic cells — they formed colonies, could propagate continuously and could form cancerous growths called teratomas — they lacked others. Introduction of iPS cells into a developing embryo, for example, did not produce a ‘chimaera’ — a mouse carrying a mix of DNA from both the original embryo and the iPS cells throughout its body. “I was not comfortable with the term ‘pluripotent’ last year,” says Hans Schöler, a stem-cell specialist at the Max Planck Institute for Molecular Biomedicine in Münster who is not involved with any of the three articles.

This week, Yamanaka presents a second generation of iPS cells1, which pass all these tests. In addition, a group led by Rudolf Jaenisch2 at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and a collaborative effort3 between Konrad Hochedlinger of the Harvard Stem Cell Institute and Kathrin Plath of the University of California, Los Angeles, used the same four factors and got strikingly similar results.

The improvement over last year’s results was simple. The four transcription factors used by Yamanaka reprogramme cells inconsistently and inefficiently, so that less than 0.1% of the million cells in a simple skin biopsy will be fully reprogrammed. The difficulty is isolating those in which reprogramming has been successful. Researchers do this by inserting a gene for antibiotic resistance that is activated only when proteins characteristic of stem cells are expressed. The cells can then be doused with antibiotics, killing off the failures.

The protein Yamanaka used as a marker for stem cells last year was not terribly good at identifying reprogrammed cells. This time, all three groups used two other protein markers — Nanog and Oct4 — to great effect. All three groups were able to produce chimaeric mice using iPS cells isolated in this way; and the mice passed iPS DNA on to their offspring.

Jaenisch also used a special embryo to produce fetuses whose cells were derived entirely from iPS cells. “Only the best embryonic stem cells can do this,” he says.

Adult stem cell hypers shouldn’t claim victory yet. These have major promise but they haven’t killed the wedge issue yet (something I really am hoping for). For one, they haven’t been able to jump from mice to humans:

But applying the method to human cells has yet to be successful. “We are working very hard — day and night,” says Yamanaka. It will probably require more transcription factors, he adds.

If it works, researchers could produce iPS cells from patients with conditions such as Parkinson’s disease or diabetes and observe the molecular changes in the cells as they develop. This ‘disease in a dish’ would offer the chance to see how different environmental factors contribute to the condition, and to test the ability of drugs to check disease progression.

The second major problem is that two cancer risks are created by these cells. The first is that the retroviruses used to transform the adult cells into ES cells randomly inserts into the genome, causing a cancer risk. The second is that in order to get these genes to be expressed inappropriately, you have to use constitutive promoters to drive expression – in other words, the genes keep on getting expressed even after the cells are re-differentiating – which may be causing cancerous transformations in these cells.

But the iPS cells aren’t perfect, and could not be used safely to make genetically matched cells for transplant in, for example, spinal-cord injuries. Yamanaka found that one of the factors seems to contribute to cancer in 20% of his chimaeric mice. He thinks this can be fixed, but the retroviruses used may themselves also cause mutations and cancer. “This is really dangerous. We would never transplant these into a patient,” says Jaenisch. In his view, research into embryonic stem cells made by cloning remains “absolutely essential”.

So this is not a total victory for ES stem cell research, but it’s very hopeful. Ideally they would be able to create this transformation in adult cells by just injecting the proteins these genes make – but the critical issue then is identifying the rare cells that gets transformed.

Alternately, the promoters could be changed from constitutive to drug-activated, so only with administration of tetracycline the genes will get expressed. That way, once they’re differentiating, the genes can be shut off, avoiding the cancer transformation.

They also will need to deal with the problem of random retroviral insertion into the genome as retroviruses can cause cancer all on their own. This could be bypassed with an integrase system (which may work ideally) that allows for insertion into a distinct and safe chromosomal location, or possibly a different viral system could be used – like adenovirus – that doesn’t lead to genomic insertion.

I’ll need to make time to fully read the paper and I’ll post again with a full review of this article. I’ll also have some fun going through the adult stem cell hypers who will inevitably start taking credit for something they had nothing to do with (and is still far from replacing embryo-derived ES cells).

Promising Embryonic Stem Cell News

Blogging on Peer-Reviewed Research

This new paper from Stem Cells is a wonderful example of the potential of human embryonic stem cells (hESC) to treat diseases like Type I diabetes.

The reason type I diabetes is such an obvious target for hESC therapy get a little complicated, but I’ll walk you guys through this paper, and recent results in islet cell transplantation to give you an idea why this result is very promising.
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Adult Stem Cell Nonsense

For this Friday afternoon I thought I’d rehash a previous post from on adult stem cells and those that hype results inappropriately to disparage embryonic stem (ES) cells. It all started with an exciting JAMA article about using autologous stem cell transplants to help treat type I diabetics who still had some capacity to produce insulin. The problem is that the adult stem cell hypers, like Wesley Smith (you guys remember him right? Senior fellow of DI etc.) will jump on any article that says “adult stem cells” and blather on and on about there are no ES cell cures – so why study them?
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