For this Friday afternoon I thought I'd rehash a previous post from denialism.com 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?
See, the thing is about 5 years ago, there were a bunch of papers about adult stem cells, some neural, some hematopoietic, some derived in other ways, and their varying ability to transdifferentiate. That means to change from one cell type into another. Stem cells can of course differentiate into the progenitor cells that they are identified as replenishing in the body and this has been known for decades. A single hematopoietic or blood stem cell can, for instance, replenish the body's entire blood supply, this is known and has been involved in treatments for decades. However transdifferentiation is when those stem cells get tricked into making a cell they wouldn't ordinarily make based on the idea that stem cells are generally plastic. These papers were very cool, there were even some in our field in which they purported to show that up to 70% of smooth muscle cells in lesions generated in blood vessels induced by various methods were blood stem cells that had transdifferentiated into a smooth muscle phenotype. It was one of those moments in science when an idea was hot and lots of people were rushing to publish on it.
Now, this is why I wish everyone would watch the lecture from Ioannidis on how scientific publication often goes through swings of exaggerated findings that are eventually brought down to Earth. It happened in this case, Nature published two papers on stem cell fusion, quite unapologetically I might add, that seemed to indicate that many of the findings (some of which had been published in their own journal) might not have been real. Instead the cells only appeared to have transdifferentiated but in reality had only fused, or essentially stuck, to another cell giving the appearance of differentiation when there really was none.
Ouch. Suddenly everyone is attuned to adult stem cell fusion, lots of papers are being looked at more carefully, and many results, when subjected to higher resolution methods, were far more modest or (including that one in our field) simply fell apart. All those old papers are still part of the literature, and only someone who's been watching the story unfold will understand that, taken out of context, the literature gives a completely different picture of the so-called plasticity of adult stem cells.
Then enter a political problem. George Bush doesn't want human embryonic stem cells studied. Human ES cells, are taken from the inner cell mass of a pre-implantation embryo that's little more than a ball of a hundred or so cells. These cells were isolated in mice in 1980, but it took another 18 years before the same feat could be replicated in humans (this time difference becomes important). It also can not be emphasized enough, ES cells are the real deal. By definition, they are capable of differentiating into every cell in the body (I work with they mousey-type), and you don't even need to work really hard to make them differentiate, all you have to do is aggregate them or remove the chemical signals that you use (a chemical called LIF in combination with a feeder layer of embryonic fibroblasts - although new methods are in place) to keep the cells from spontaneously differentiating. They make everything. This means they have enormous potential for tissue engineering as well as for in vitro study of development and differentiation.
Take for example this little video I made of a cardiac "beater" in one of my embryoid body differentiation cultures.
That's spontaneous cardiac contraction from cells derived from ES cells. These cardiac foci are a good example of the power of ES cells, cardiac stem cell populations are small and difficult to isolate and adult stem cells isolated from fat or marrow probably won't form myocytes, or only at very low frequency (if at all probably through fusion). In fact the stem cell injection protocols for treatment of myocardial infarction might not be benefiting from differentiation so much as formation of fibroblasts, secreted factors, etc.
Well, you can see that for those who don't want these cells used their ability to spontaneously make cells from all tissue types is a disaster. Clearly there must be an alternative! Enter, adult stem cell hype. One of the reasons I include this as denialist crankery is because of some of the perpetrators. Wesley Smith a co-founder of the DI is constantly harping on how adult stem cells are hitting the market while ES cells? Nothing. Never mind actually reading what kind of treatment that was, essentially a piece of total quackery in which they include the magic adult stem cells in a fat-transfer breast augmentation. Not exactly the kind of result one should try to hang their hat on to prove their point but Smith has such a poor understanding of science he's perfectly happy to describe propranolol as "Soma". All-purpose crank Michael Fumento loves writing about it too, with articles essentially saying ES cell research is a scam (Hwang Woo Suk is apparently proof every scientist in the field is a liar), and adult stem cells can do everything. Sites like Do no harm publish lists of adult stem cell successes, which basically represents a pubmed search and a cut-and-paste of anything that even mentions an adult stem cell, and most references on closer inspection are a joke in terms of demonstrating adult stem cell plasticity. You hear arguments that ES cells haven't resulted in treatments even though they were discovered 30 years ago! Because they weren't, they were discovered in humans less than 10 years ago. Even Anne Coulter cribbed a list of "adult stem cell cures" for her latest book. And every time there is a new result in which adult stem cells are used they go nuts. The latest from Wesley Smith hyping adult stem cells is this Jama article, "Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in Newly Diagnosed Type 1 Diabetes Mellitus". An anon in my comments also asked what I thought about this as, I guess, proof of adult stem cell therapies. My response is that this is not even relevant to the discussion. This is the problem with the hyper, they don't care about the meaning of the science. This paper is not about transdifferentiation potential of adult stem cells, which has largely been discredited. That's not to say there hasn't been some wonderful progress, in particular in reprogramming adult stem cells and in spermatogonial stem cells which both act very ES-cell like, but have yet to be fully characterized.
But that's not enough for a crank. There is real progress in these fields but a crank can't just be satisfied with modest progress and some signs of advances. They have to make every adult stem cell paper out to be a godsend, and all ES cell research, and the researchers, demonic liars who are perpetuating some kind of hoax. Creeps like Krauthammer (creep or crank? probably both), suggest stem cell research is so fundamentally corrupting it makes scientists evil while hyping their modest advances.
This most recent paper is a good example. One, this is not a "cure" for type I diabetes. The follow up is only a mean of 18 months, not all the patients were able to go insulin free, and frankly if this were my kid I wouldn't give them this treatment, it's extremely dangerous - I'll explain at the end. Further, the real distraction here, is that this has little or nothing to do with transdifferentiation which is the real dispute between the adult stem cell and ES cell advocates. These cells aren't transdifferentiating in some special way, they're doing what hematopoietic cells always have done, make blood. This is not a stem cell breakthrough, this is a immune-system reprogramming breakthrough.
What this paper is really showing is that if you whack an emerging diabetic's immune system with a hammer, and then re-establish it with hematopoietic stem cells from the same patient (that you saved in the freezer from before you started), you have some ability to short-circuit the body's attack on the insulin-producing beta cells of the pancreas without permanently destroying the patient's immune system. Very interesting stuff. Nothing to do with adult stem cells vs ES cells, but hey, they're cranks, they don't really care about science.
The debate is about which cell type can transdifferentiate into cells of any kind. There is limited evidence of the potential of adult stem cells to transdifferentiate. Everybody knows a hematopoietic stem cell can differentiate into blood, so this JAMA study doesn't say what they think it says. The cells aren't transdifferentiating and making islet cells which is the implication from the hyper, they're making blood cells, and this treatment would only work for diabetics who are just beginning to become insulin dependent, not those who have already lost their islet cells. Embryonic stem cells, by definition, differentiate into every single cell type in the body, it's just what they do. They make islet cells, albeit at low frequencies, but that's a technical problem, and real science moves pretty slowly.
As a post script I'd say, this is also a treatment in its infancy. The study is also missing a valid control group (it probably would have been unethical), and is not some minor intervention. This would be a very dangerous treatment to undergo, and would have to be done at major medical centers since it involves temporary destruction of the patient's ability to fight off illnesses. Such a treatment could take a kid and make him insulin independent for 18 months, but it could easily kill the patient who would otherwise have lived a normal, if insulin-dependent, life. Further, I will mock, endlessly, magic-bullet type ES cell treatments which are also based on bad science and have the potential to really damage the field.
Thanks for this.
Do that again Mike and I delete and ban.
That is not the discussion at hand. And we do not argue with cranks here.
Speaking as someone who has been trying to replicate trnasdifferentiation of marrow stromal cells into neural precursors for MONTHS with no success, I have to agree wholeheartedly.
We tried working with some adult stem cell sources too. Pretty much all we found they could make was fibroblast-type cells. I think adult stem cells make their pre-ordained derivatives pretty well, but not much else.
All those early papers have really performed poorly in terms of replication, there's been a big stink over MAPCs and lots and lots of revised findings in terms of HSC contribution to various pathologies.
I'd avoid adult stem cells for the most part, they seem to me to be a great way to never graduate.
Hahaha. Good advice.
A problem I've run into often is that the culture methods outlined in some of these papers effect morphological changes in the cells which make them appear like the cells of interest, but analysis suggests they are phenotypically unchanged.
An understandable mistake (if this is the case) for a scientist to make, and also easy for a crank to add to their arsenal.
Cool video, incidentally.
Great post! I'm a layman in this field, but I think I understood what the differences are between ES and AS cells. You stated regarding the ES-based cardiac cells you grew that cardiac AS cells are hard to isolate. Is the transdifferentiation plasticity of ES important only to overcome the isolation problems of AS cells or are there other advantages inherent in ES cell lines?
I agree that this debate is all nonsense, from a scientific point of view I also think it helps to understand why sme fundamentalists try to make it into an argument.
In some religious ethical frameworks, it would be acceptable to use embryonic stem cells if and only if two conditions are met. First it would have to lead to some very significant benefit. Second, it would have to be the case that there is no other way to accomplish the same good.
So far, so good, but then the argument gets strange. Since they have already decided that use of embryonic stem cells would be bad, they have to show that the same good could be accomplished with adult stem cells, in order to complete rule out the possibility of using embryonic stem cells.
Of course, anytime you decide ahead of time what the conclusion of the argument has to be, the argument gets pretty muddled in the middle.
You know, Mark, I would be satisfied if medical mistakes didn't kill 200.000 people a year.
You know, if doctors spent less time blogging and passing out pamplets they might have more time with patients.
Of course, I assume you will be going into research and not getting your hands dirty.
I mean, if the doctors my family had met had just GIVEN A SHIT we wouldn't have felt so bad about the malpractice.
Wow, someone's got some doctor-hate. But what does that have to do with anything that's written here?
Medcial mistakes kill 200,000 people a year.
They killed my dad.
I wish the doctors had spent more time with patients and less arguing about evolution here in Kansas.
I'm sorry to hear that, but this is what's known as concern trolling. It's irrelevant and kind of rude.
Medical mistakes, further, do not kill 200,000 people a year. This is simply not a factual claim. The actual figure is 90k deaths that are thought to have some contribution from medical decisions. That doesn't mean doctors actively are killing people, but may make mistakes which merely hastened an inevitable death.
And what is your suggestion? That we should kill all the doctors? Not use medicine any more? I don't understand the point of these comments. Is it just concern trolling? Should people that go into medicine have no hobbies, no outside interests? Should we just be sitting in front of books 24 hours a day and not be allowed to do something as simple as try to inform public debate about science? Is your implication that my blogging kills patients? That would be strange since I'm currently in the PhD phase and don't see any patients, I do research in cardiovascular disease.
These comments generally castigating medical doctors as a whole because of unfortunate experiences within the healthcare system have nothing to do with a discussion of adult stem cells. I'm sorry you have had negative outcomes from medical care, but I'm not going to live in a cave with a copy of Harrison's and stop blogging because of it.
Wait, did you get typekey working?
Mark, the figure is AT LEAST 200,000. Beside medical negligence, there are mistakes in hospitals, etc.
These are the stats from the medical establishment. If they admit that, then you know its higher.
And where did I say doctors are actively killing people? I clearly said MISTAKES. You are simply trying to poison the well.
But what is most nauseating is your implication that its not so bad, its 90,000, not 200,000.
90,000! Thats more EVERY YEAR than were killed in the Vietnam War.
What should happen is that doctors should be held legally responsible in the same way someone who accidentally kills someone with a car is. They should bear full CIVIL and CRIMINAL legal responsibility. As it is, malpractice laws protect them.
And you say you are "sorry" about my dad but call me a troll,
Q.E.D and KMA
By the way, Mark, for your review:
The doctors should be more hands on. Of course, that would sap profits, wouldn't it?
I really do find it unfortunate that you've had a death in the family from a medical mistake. I am sincere in this regard.
However, that doesn't excuse trollish behavior. You are a troll for two reasons. For one, this is a thread hijack, and second, your doing what is called "concern trolling".
Both are bad forms of internet etiquette.
Finally, if you actually read the report rather than getting things filtered through a malpractice news website you see the language is more nuanced. This report does not say what you think it says. What it's doing is correlating deaths to "patient safety incidents" which are complications from hospitalizations and surgery. They aren't alleging that these complications caused deaths or were even unavoidable. After all, the hospitals which they regard as distinguished still had significant rates of these incidents and if you read the list of what they include these are the classic complications of hospitalization and surgery (ranging from simple decubitus ulcers to post-operative ARDS). They simply happen a great deal of the time in ICUs because people there are extraordinarily sick. It doesn't mean that the patient would have been doing cartwheels out of the ICU if the patient safety incident had not occurred.
Finally, it doesn't make sense to hate me simply for studying medicine. People who want to be doctors want to help people, and when I am on the wards I'm going to do my best. Modern medicine allows people to live decades longer than they ever have before, and medical scientists are constantly looking ways to extend the quantity and quality of life.
I'm sorry that this incident with your father has made you so hateful towards us. But it has nothing to do with this discussion.
... Krauthammer (creep or crank? probably both)...
Krauthammer is evidence that the two conditions can overlap.
I want to say two things:
1. To the folks that have lost family members through medical malpractice, you need to look at the meaning of the word. Malpractice means that the doctor made a bona fide mistake. For whatever reason. That means that they did not deliver medical care at the proper accepted standard. The test is whether the majority of doctors would agree that the given treatment was irresponsible, not whether the outcome is bad. I lost both my grandfathers due to malpractice, in one case it was medical (choosing a treatment he was allergic to -> not reading the chart properly), and in the other case it was a hospital accident (nurse left the room when he/she shouldn't have). While these are both extremely horrible and unfortunate incidents, I do not think the medical establishment is horrible in any way, although there are some poor doctors out there.
And one of the reasons doctors aren't more hands on is to pay their malpractice insurance, which is being driven up by the number of fraudulent/nonsense claims - a very vicious cycle for all involved.
Sorry...didn't mean to go on so long about #1.
2. Mark, thank you for this post. It's a very interesting look at the research field and how results are often misreported by the media. I am not in molecular biology or medicine, but am in bioengineering (clinical/theoretical stuff), and my limited exposure to these types of experiments was plenty of background to understand your point. I found the link to the Nature commentary very informative as well.
Personally, I feel that ES cell and other stem cell therapies have a lot of potential, but won't become reasonable for at least a decade or two (or more). The Edmonton protocol still seems to be the best "cure" for Type I diabetes, also, as good/bad as it is. Maybe using NSC for Parkinson's would be another good step that's also far away.
Thanks for getting us back on track Adam.
And honest man would look at the 200,000 thousand dead...probably 90,000 DIRECTLY due to negligence...and say, SHIT! WE GOTTA COCENTRATE ON FIXING THIS!
A weasel, like you Mark, would make excuses.
Actually I explained why the paper that was cited doesn't really say what the doctor-hate crowd think it does. If you look at the way they are counting deaths about 90k deaths occur a year that are associated with a "medical" mistake - not necessarily a "doctor's" mistake by the way. Read page 21 of the report to see a breakdown of the numbers. Also remember this is in hospitalizations, not all medical care.
The first thing you notice is that this is essentially all ICU/inpatient-based stuff. These are things that tend to happen to the sickest of the sick, a very difficult patient population to say the least and this does not reflect mistakes that you'd get say, in an orthopedics or trauma service. The second thing you notice is the biggest field is what is called "failure to rescue" which represents about 70% of the tabulated deaths. This is an interesting metric, and is usually associated with quality of nursing care rather than a metric describing the efficacy of doctors. Further, I suspect they're not giving the nurses a fair shake because it sounds like to me that they're conflating determinations of medical futility with inattentive nursing.
The most concerning field is on the previous page with is "death in low mortality DRGs" and that's a metric that describes instances in which death occurred in people that were fairly healthy. This number was about 3-4k a year and probably represents the most egregious medical errors. Many of the other patient safety incidents aren't mistakes so much as known complications of procedures.
Finally for those that are confused about this. I'm not a doctor. I'm a graduate student who does basic research. It is unlikely I'll practice medicine except maybe as a specialist, but I'm mostly interested in science - hence the scienceblog. All this concern trolling and thread hijacking about what I should be doing to save the world from evil doctors is tiresome and I'm just going to delete it from now on.
I'll write a thread soon where doctor-hate will be appropriate, how about that?
Thanks for clearing this up. I have just started getting into gynecology , and the other article had me a little bit confused. You have really helped me understand this better. Thanks!