Growing Skepticism about the Stem Cell Acid Trip

In January 2014, the two papers “Stimulus-triggered fate conversion of somatic cells into pluripotency” and “Bidirectional developmental potential in reprogrammed cells with acquired pluripotency” published in the journal Nature by Haruko Obokata and colleagues took the world of stem cell research by surprise.

Since Shinya Yamanaka’s landmark discovery that adult skin cells could be reprogrammed into embryonic-like induced pluripotent stem cells (iPSCs) by introducing selected embryonic genes into adult cells, laboratories all over the world have been using modifications of the “Yamanaka method” to create their own stem cell lines. The original Yamanaka method published in 2006 used a virus which integrated into the genome of the adult cell to introduce the necessary genes. Any introduction of genetic material into a cell carries the risk of causing genetic aberrancies that could lead to complications, especially if the newly generated stem cells are intended for therapeutic usage in patients.

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Researchers have therefore tried to modify the “Yamanaka method” and reduce the risk of genetic aberrations by either using genetic tools to remove the introduced genes once the cells are fully reprogrammed to a stem cell state, introducing genes without non-integrating viruses or by using complex cocktails of chemicals and growth factors in order to generate stem cells without the introduction of any genes into the adult cells.

The papers by Obokata and colleagues at the RIKEN center in Kobe, Japan use a far more simple method to reprogram adult cells. Instead of introducing foreign genes, they suggest that one can expose adult mouse cells to a severe stress such as an acidic solution. The cells which survive acid-dipping adventure (25 minutes in a solution with pH 5.7) activate their endogenous dormant embryonic genes by an unknown mechanism. The researchers then show that these activated cells take on properties of embryonic stem cells or iPSCs if they are maintained in a stem cell culture medium and treated with the necessary growth factors. Once the cells reach the stem cell state, they can then be converted into cells of any desired tissue, both in a culture dish as well as in a developing mouse embryo. Many of the experiments in the papers were performed by starting out with adult mouse lymphocytes, but the researchers also found that mouse skin fibroblasts and other cells could also be successfully converted into an embryonic-like state using the acid stress.

My first reaction was incredulity. How could such a simple and yet noxious stress such as exposing cells to acid be sufficient to initiate a complex “stemness” program? Research labs have spent years fine-tuning the introduction of the embryonic genes, trying to figure out the optimal combination of genes and timing of when the genes are essential during the reprogramming process. These two papers propose that the whole business of introducing stem cell genes into adult cells was unnecessary – All You Need Is Acid.

 

This sounds too good to be true. The recent history in stem cell research has taught us that we need to be skeptical. Some of the most widely cited stem cell papers cannot be replicated. This problem is not unique to stem cell research, because other biomedical research areas such as cancer biology are also struggling with issues of replicability, but the high scientific impact of burgeoning stem cell research has forced its replicability issues into the limelight. Nowadays, whenever stem cell researchers hear about a ground-breaking new stem cell discovery, they often tend to respond with some degree of skepticism until multiple independent laboratories can confirm the results.

My second reaction was that I really liked the idea. Maybe we had never tried something as straightforward as an acid stress because we were too narrow-minded, always looking for complex ways to create stem cells instead of trying simple approaches. The stress-induction of stem cell behavior may also represent a regenerative mechanism that has been conserved by evolution. When our amphibian cousins regenerate limbs following an injury, adult tissue cells are also reprogrammed to a premature state by the stress of the injury before they start building a new limb.

The idea of stress-induced reprogramming of adult cells to an embryonic-like state also has a powerful poetic appeal, which inspired me to write the following haiku:

 

The old warrior

plunges into an acid lake

to emerge reborn.

 

(Read more about science-related haikus here)

Just because the idea of acid-induced reprogramming is so attractive does not mean that it is scientifically accurate or replicable.

A number of concerns about potential scientific misconduct in the context of the two papers have been raised and it appears that the RIKEN center is investigating these concerns. Specifically, anonymous bloggers have pointed out irregularities in the figures of the papers and that some of the images may be duplicated. We will have to wait for the results of the investigation, but even if image errors or duplications are found, this does not necessarily mean that this was intentional misconduct or fraud. Assembling manuscripts with so many images is no easy task and unintentional errors do occur. These errors are probably far more common than we think. High profile papers undergo much more scrutiny than the average peer-reviewed paper, and this is probably why we tend to uncover them more readily in such papers. For example, image duplication errors were discovered in the 2013 Cell paper on human cloning, but many researchers agreed that the errors in the 2013 Cell paper were likely due to sloppiness during the assembly of the submitted manuscript and did not constitute intentional fraud.

Irrespective of the investigation into the irregularities of figures in the two Nature papers, the key question that stem cell researchers have to now address is whether the core findings of the Obokata papers are replicable. Can adult cells – lymphocytes, skin fibroblasts or other cells – be converted into embryonic-like stem cells by an acid stress? If yes, then this will make stem cell generation far easier and it will open up a whole new field of inquiry, leading to many new exciting questions. Do human cells also respond to acid stress in the same manner as the mouse cells? How does acid stress reprogram the adult cells? Is there an acid-stress signal that directly acts on stem cell transcription factors or does the stress merely activate global epigenetic switches? Are other stressors equally effective? Does this kind of reprogramming occur in our bodies in response to an injury such as low oxygen or inflammation because these kinds of injuries can transiently create an acidic environment in our tissues?

Researchers all around the world are currently attempting to test the effect of acid exposure on the activation of stem cell genes. Paul Knoepfler’s stem cell blog is currently soliciting input from researchers trying to replicate the work. Paul makes it very clear that this is an informal exchange of ideas so that researchers can learn from each other on a “real-time” basis. It is an opportunity to find out about how colleagues are progressing without having to wait for 6-12 months for the next big stem cell meeting or the publication of a paper confirming or denying the replication of acid-induced reprogramming. Posting one’s summary of results on a blog is not as rigorous as publishing a peer-reviewed paper with all the necessary methodological details, but it can at least provide some clues as to whether some or all of the results in the controversial Obokata papers can be replicated.

If the preliminary findings of multiple labs posted on the blog indicate that lymphocytes or skin cells begin to activate their stem cell gene signature after acid stress, then we at least know that this is a project which merits further investigation and researchers will be more willing to invest valuable time and resources to conduct additional replication experiments. On the other hand, if nearly all the researchers post negative results on the blog, then it is probably not a good investment of resources to spend the next year or so trying to replicate the results.

It does not hurt to have one’s paradigms or ideas challenged by new scientific papers as long as we realize that paradigm-challenging papers need to be replicated. The Nature papers must have undergone rigorous peer review before their publication, but scientific peer review does not involve checking replicability of the results. Peer reviewers focus on assessing the internal logic, experimental design, novelty, significance and validity of the conclusions based on the presented data. The crucial step of replicability testing occurs in the post-publication phase. The post-publication exchange of results on scientific blogs by independent research labs is an opportunity to crowd-source replicability testing and thus accelerate the scientific authentication process. Irrespective of whether or not the attempts to replicate acid-induced reprogramming succeed, the willingness of the stem cell community to engage in a dialogue using scientific blogs and evaluate replicability is an important step forward.

 

ResearchBlogging.org
Obokata H, Wakayama T, Sasai Y, Kojima K, Vacanti MP, Niwa H, Yamato M, & Vacanti CA (2014). Stimulus-triggered fate conversion of somatic cells into pluripotency. Nature, 505 (7485), 641-7 PMID: 24476887

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The Replicability Crisis in Cancer Research

The cancer researchers Glenn Begley and Lee Ellis made a rather remarkable claim last year. In a commentary that analyzed the dearth of efficacious novel cancer therapies, they revealed that scientists at the biotechnology company Amgen were unable to replicate the vast majority of published pre-clinical research studies. Only 6 out of 53 landmark cancer studies could be replicated, a dismal success rate of 11%! The Amgen researchers had deliberately chosen highly innovative cancer research papers, hoping that these would form the scientific basis for future cancer therapies that they could develop. It should not come as a surprise that progress in developing new cancer treatments is so sluggish. New clinical treatments are often based on innovative scientific concepts derived from pre-clinical laboratory research. However, if the pre-clinical scientific experiments cannot be replicated, it would be folly to expect that clinical treatments based on these questionable scientific concepts would succeed.

Cancer-Detecting Nanoparticles. Here, when cancer cells (cell nuclei in blue) were treated with antibody-conjugated nanoparticles, the antibodies (red) and the nanoparticle cores (green) separated into different cellular compartments. Source: National Cancer Institute \ M.D. Anderson Cancer Center. Creator: Sangheon Han, Konstantin Sokolov, Tomasz Zal, Anna Zal

Reproducibility of research findings is the cornerstone of science. Peer-reviewed scientific journals generally require that scientists conduct multiple repeat experiments and report the variability of their findings before publishing them. However, it is not uncommon for researchers to successfully repeat experiments and publish a paper, only to learn that colleagues at other institutions can’t replicate the findings. This does not necessarily indicate foul play. The reasons for the lack of reproducibility include intentional fraud and misconduct, yes, but more often it’s negligence, inadvertent errors, imperfectly designed experiments and the subliminal biases of the researchers or other uncontrollable variables.

Clinical studies, of new drugs, for example, are often plagued by the biological variability found in study participants. A group of patients in a trial may exhibit different responses to a new medication compared to patients enrolled in similar trials at different locations. In addition to genetic differences between patient populations, factors like differences in socioeconomic status, diet, access to healthcare, criteria used by referring physicians, standards of data analysis by researchers or the subjective nature of certain clinical outcomes – as well as many other uncharted variables – might all contribute to different results.

The claims of low reproducibility made by Begley and Ellis, however, did not refer to clinical cancer research but to pre-clinical science. Pre-clinical scientists attempt to reduce the degree of experimental variability by using well-defined animal models and standardized outcomes such as cell division, cell death, cell signaling or tumor growth. Without the variability inherent in patient populations, pre-clinical research variables should in theory be easier to control. The lack of reproducibility in pre-clinical cancer research has a significance that reaches far beyond just cancer research. Similar or comparable molecular and cellular experimental methods are also used in other areas of biological research, such as stem cell biology, neurobiology or cardiovascular biology. If only 11% of published landmark papers in cancer research are reproducible, it raises questions about how published papers in other areas of biological research fare.

Following the publication of Begley and Ellis’ commentary, cancer researchers wanted to know more details. Could they reveal the list of the irreproducible papers? How were the experiments at Amgen conducted to assess reproducibility? What constituted a successful replication? Were certain areas of cancer research or specific journals more prone to publishing irreproducible results? What was the cause of the poor reproducibility? Unfortunately, the Amgen scientists were bound by confidentiality agreements that they had entered into with the scientists whose work they attempted to replicate. They could not reveal which papers were irreproducible or specific details regarding the experiments, thus leaving the cancer research world in a state of uncertainty. If so much published cancer research cannot be replicated, how can the field progress?

 Lee Ellis has now co-authored another paper to delve further into the question. In the study, published in the journal PLOS One, Ellis teamed up with colleagues at the renowned University of Texas MD Anderson Cancer Center to survey faculty members and trainees (PhD students and postdoctoral fellows) at the center. Only 15-17% of their colleagues responded to the anonymous survey, but the responses confirmed that reproducibility of papers in peer-reviewed scientific journals is a major problem. Two-thirds of the senior faculty respondents revealed they had been unable to replicate published findings, and the same was true for roughly half of the junior faculty members as well as trainees. Seventy-eight percent of the scientists had attempted to contact the authors of the original scientific paper to identify the problem, but only 38.5% received a helpful response. Nearly 44% of the researchers encountered difficulties when trying to publish findings that contradicted the results of previously published papers.

The list of scientific journals in which some of the irreproducible papers were published includes the the “elite” of scientific publications: The prestigious Nature tops the list with ten mentions, but one can also find Cancer Research (nine mentions), Cell (six mentions), PNAS (six mentions) and Science (three mentions).

Does this mean that these high-profile journals are the ones most likely to publish irreproducible results? Not necessarily. Researchers typically choose to replicate the work published in high-profile journals and use that as a foundation for new projects. Researchers at MD Anderson Cancer Center may not have been able to reproduce the results of ten cancer research papers published in Nature, but the survey did not provide any information regarding how many cancer research papers in Nature were successfully replicated.

The lack of data on successful replications is a major limitation of this survey. We know that more than half of all scientists responded “Yes” to the rather opaque question “Have you ever tried to reproduce a finding from a published paper and not been able to do so?”, but we do not know how often this occurred. Researchers who successfully replicated nine out of ten papers and researchers who failed to replicate four out of four published papers would have both responded “Yes.” Other limitations of this survey include that it does not list the specific irreproducible papers or clearly define what constitutes reproducibility. Published scientific papers represent years of work and can encompass five, ten or more distinct experiments. Does successful reproducibility require that every single experiment in a paper be replicated or just the major findings? What if similar trends are seen but the magnitude of effects is smaller than what was published in the original paper?

Due to these limitations, the survey cannot provide definitive answers about the magnitude of the reproducibility problem. It only confirms that lack of reproducibility is a potentially important problem in pre-clinical cancer research, and that high-impact peer-reviewed journals are not immune. While Begley and Ellis have focused on questioning the reproducibility of cancer research, it is likely that other areas of biological and medical research are also struggling with the problem of reproducibility. Some of the most highly cited papers in stem cell biology cannot be replicated , and a recent clinical trial using bone marrow cells to regenerate the heart did not succeed in improving heart function after a heart attack  despite earlier trials demonstrating benefits.

Does this mean that cancer research is facing a crisis? If only 11% of pre-clinical cancer research is reproducible, as originally proposed by Begley and Ellis, then it might be time to sound the alarm bells. But since we don’t know how exactly reproducibility was assessed, it is impossible to ascertain the extent of the problem. The word “crisis” also has a less sensationalist meaning: the time for a crucial decision. In that sense, cancer research and perhaps much of contemporary biological and medical research needs to face up to the current quality control “crisis.” Scientists need to wholeheartedly acknowledge that reproducibility is a major problem and crucial steps must be taken to track and improve the reproducibility of published scientific work.

First, scientists involved in biological and medical research need to foster a culture that encourages the evaluation of reproducibility and develop the necessary infrastructure. When scientists are unable to replicate results of published papers and contact the authors, the latter need to treat their colleagues with respect and work together to resolve the issue. Many academic psychologists have already recognized the importance of tracking reproducibility and initiated a large-scale collaborative effort to tackle the issue; the Harvard psychologists Joshua Hartshorne and Adena Schachner also recently proposed using a formal approach to track the reproducibility of research. Biological and medical scientists should consider adopting similar infrastructures for their research, because reproducibility is clearly not just a problem for psychology research.

Second, grant-funding agencies should provide adequate research funding for scientists to conduct replication studies. Currently, research grants are awarded to those who propose the most innovative experiments, but few — if any — funds are available for researchers who want to confirm or refute a published scientific paper. While innovation is obviously important, attempts to replicate published findings deserve recognition and funding because new work can only succeed if it is built on solid, reproducible scientific data.

In the U.S., it can take 1-2 years from when researchers submit a grant proposal to when they receive funding to conduct research. Funding agencies could consider an alternate approach, one that allows for rapid approval of small-budget grant proposals so that researchers can immediately start evaluating the reproducibility of recent breakthrough discoveries. Such funding for reproducibility testing could be provided to individual laboratories or teams of scientists such as the Reproducibility Initiative or the recent efforts of chemistry bloggers to document reproducibility.

The U.S.-based NIH (National Institutes of Health) is the largest source of funding for medical research in the world and is now considering the implementation of new reproducibility requirements for scientists who receive funding. However, not even the NIH has a clear plan for how reproducibility testing should be funded.

Lastly, it is also important that scientific journals address the issue of reproducibility. One of the most common and also most heavily criticized metrics for the success of a scientific journal is its “impact factor,” an indicator of how often an average article published in the journal is cited. Even irreproducible scientific papers can be cited thousands of times and boost a journal’s “impact.”

If a system tracked the reproducibility of scientific papers, one could conceivably calculate a reproducibility score for any scientific journal. That way, a journal’s reputation would not only rest on the average number of citations but also on the reliability of the papers it publishes. Scientific journals should also consider supporting reproducibility initiatives by encouraging the publication of papers that attempted to replicate previous papers — as long as the reproducibility was tested in a rigorous fashion and independent of whether or not the replication attempts were successful.

There is no need to publish the 20th replication study that merely confirms what 19 previous studies have previously found, but publication of replication attempts is sorely needed before a consensus is reached regarding a scientific discovery. The journal PLOS One has partnered up with the Reproducibility Initiative to provide a forum for the publication of replication studies, but there is no reason why other journals should not follow.

While PLOS One publishes many excellent papers, current requirements for tenure and promotion at academic centers often require that researchers publish in certain pre-specified scientific journals, including those affiliated with certain professional societies and which carry prestige in a designated field of research. If these journals also encouraged the publication of replication attempts, more researchers would conduct them and contribute to the post-publication quality control of scientific literature.

The recent questions raised about the reproducibility of biological and medical research findings is forcing scientists to embark on a soul-searching mission. It is likely that this journey will shake up many long-held beliefs. But this reappraisal will ultimately lead to a more rigorous and reliable science.

 

Note: An earlier version of this article was first published on Salon.com.

The Science Mystique

Here is an excerpt from my longform essay “The Science Mystique” for 3Quarksdaily:

Human fallibility not only affects how scientists interpret and present their data, but can also have a far-reaching impact on which scientific projects receive research funding or the publication of scientific results. When manuscripts are submitted to scientific journals or when grant proposal are submitted to funding agencies, they usually undergo a review by a panel of scientists who work in the same field and can ultimately decide whether or not a paper should be published or a grant funded. One would hope that these decisions are primarily based on the scientific merit of the manuscripts or the grant proposals, but anyone who has been involved in these forms of peer review knows that, unfortunately, personal connections or personal grudges can often be decisive factors.

 

Lack of scientific replicability, knowing about the uncertainties that come with new scientific knowledge, fraud and fudging, biases during peer review – these are all just some of the reasons why scientists rarely believe in the mystique of science. When I discuss this with acquaintances who are non-scientists, they sometimes ask me how I can love science if I have encountered these “ugly” aspects of science. My response is that I love science despite this “ugliness”, and perhaps even because of its “ugliness”. The fact that scientific knowledge is dynamic and ephemeral, the fact that we do not need to feel embarrassed about our ignorance and uncertainties, the fact that science is conducted by humans and is infused with human failings, these are all reasons to love science. When I think of science, I am reminded of the painting “Basket of Fruit” by Caravaggio, which is a still-life of a fruit bowl, but unlike other still-life paintings of fruit, Caravaggio showed discolored and decaying leaves and fruit. The beauty and ingenuity of Caravaggio’s painting lies in its ability to show fruit how it really is, not the idealized fruit baskets that other painters would so often depict.

 

You can read the complete essay at 3Quarksdaily.com.

Replicability of High-Impact Papers in Stem Cell Research

I recently used the Web of Science database to generate a list of the most highly cited papers in stem cell research. As of July 2013, the search for original research articles which use the key word “stem cells” resulted in the following list of the ten most widely cited papers to date:

Human ES cell colony – Nuclei labeled in blue, Mitochondria labeled in green- Rehman lab.1. Pittenger M et al. (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143-147

Citations: 8,157

2.  Thomson JA et al. (1998) Embryonic stem cell lines derived from human blastocysts. Science 282(5391):1145-1147

Citations: 5,565

3. Takahashi K and Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4): 663-676

Citations: 5,034

4. Takahashi K et al. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861-872

Citations: 4,061

5. Donehower LA et al  (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356(6366): 215-221

Citations: 3,279

6. Al-Hajj M et al (2003) Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences 100(7): 3983-3988

Citations: 3,183

 7. Yu J et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858): 1917-1920

Citations: 3,086

 8. Jiang YH et al (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418(6893):41-49

Citations: 2,983

9. Orlic D et al (2001) Bone marrow cells regenerate infarcted myocardium. Nature 410 (6829):701-705

Citations: 2,961

10. Lu J et al (2005) MicroRNA expression profiles classify human cancers. Nature 435(7043): 834-838

Citations: 2,917

 

Three of the articles (Donehower et al, Al-Hajj et al and Lu et al) in this “top ten list” do not focus on stem cells but are actually cancer research papers. They were probably identified by the search because the authors may have made comparisons to stem cells or used stem cells as tools.The remaining seven articles are indeed widely known in the stem cell field.

The Science paper by Pittenger and colleagues in 1999 provided a very comprehensive description of mesenchymal stem cells (MSCs), a type of adult stem cell which is found in the bone marrow alongside hematopoietic stem cells (HSCs). Despite the fact that MSCs and HSCs are both adult stem cells in the bone marrow, they have very different functions. HSCs give rise to circulating blood cells, whereas MSCs primarily form bone, fat and cartilage as was nicely demonstrated by Pittenger and colleagues.

The article by Thomson and colleagues was published in 1998 in the journal Science described the derivation of human embryonic stem cells (ESCs) and revolutionized the field of stem cell research. While adult stem cells have a very limited capacity in terms of lineages they can turn into, ESCs are derived from the early blastocyst stage of embryonic development (within the first 1-2 weeks following fertilization) and thus retain the capacity to turn into a very wide range of tissues, such as neurons, heart cells, blood vessel cells or liver cells. This paper not only identified the methods for isolating human ESCs, but also how to keep them in culture and expand them as undifferentiated stem cells.

The Cell paper by Takahashi and Yamanaka in 2006 represented another major advancement in the field of stem cell biology, because it showed for the first time that a mouse adult skin cell (fibroblast) could be reprogrammed and converted into a truly pluripotent stem cell (an induced pluripotent stem cell or iPSC) which exhibited all the major characteristics of an embryonic stem cell (ESC). It was as if the adult skin cell was traveling back in time, erasing its identity of having been a skin cell and returning to primordial, embryonic-like stem cell. Only one year later, Dr. Yamanaka’s group was able to demonstrate the same phenomena for adult human skin cells in the 2007 Cell paper (Takahashi et al), and in the same year a different group independently confirmed that adult human cells could be reprogrammed to the iPSC state (Science paper by Yu et al in 2007). The generation of iPSCs described in these three papers is probably the most remarkable discovery in stem cell biology during the past decade. It is no wonder that each of these three papers have been cited several thousand times even though they were published only six or seven years ago, and that Dr. Yamanaka was awarded the 2012 Nobel prize for this pioneering work.

All five of the above-mentioned stem cell papers have one thing in common: the results have been repeated and confirmed by numerous independent laboratories all over the world. However, this does not necessarily hold true for the other two highly cited stem cell papers on this list.

The 2002 Nature paper by Jiang and colleagues from Dr. Verfaillie’s laboratory at the University of Minnesota proposed that the bone marrow contained a rather special subset of adult MSCs which had a much broader differentiation potential than had been previously recognized. While adult MSCs were thought to primarily turn into bone, cartilage or fat when given the appropriate cues, this rare new cell type – referred to as MAPCs (multipotent adult progenitor cells) – appeared to differentiate into a much broader range of tissues. The paper even showed data from an experiment in which these adult mouse bone marrow stem cells were combined with embryonic cells and gave rise to a chimeric mouse. i.e. a mouse in which the tissues were in part derived from standard embryonic cells and in part from the newly discovered adult MAPCs. Such chimerism suggested that the MAPCs were embryonic-like, contributing to the formation of all the tissues in the mice. At the time of its publication, this paper was met with great enthusiasm because it proved that the adult body contained embryonic-like cells, hidden away in the bone marrow, and that these MAPCs could be used to regenerate ailing organs and tissues without having to use ethically problematic human embryonic stem cells.

There was just one major catch. Many laboratories around the world tried to replicate the results and were unable to identify the MAPCs, and even when they found cells that were MAPCs, they were unable to confirm the embryonic-like nature of the cells. In a remarkable example of investigative journalism, the science journalists Peter Aldhous and Eugenie Reich identified multiple irregularities in the publications involving MAPCs and documented the inability of researchers to replicate the findings by publishing the results of their investigation in the New Scientist (PDF).

The second high profile stem cell paper which was also plagued by an inability to replicate the results was the 2001 Nature paper by Orlic and colleagues. In this paper from Dr. Anversa’s laboratory, the authors suggested that adult hematopoietic (blood-forming) stem cells from the bone marrow could regenerate an infarcted heart by becoming heart cells (cardiomyocytes). It was a rather bold claim, because simply injecting these blood-forming stem cells into the heart seemed to be sufficient to redirect their fate. Instead of giving rise to red and white blood cells, these bone marrow cells were generating functional heart cells. If this were the case, then every patient could be potentially treated with their own bone marrow and grow back damaged heart tissue after a heart attack. Unfortunately, it was too good to be true. Two leading stem cell laboratories partnered up to confirm the results, but even after years of experiments, they were unable to find any evidence of adult bone marrow stem cells converting into functional heart cells. They published their findings three years later, also in the journal Nature:

Murry CE et al (2004) Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428(6983): 664-668

Citations: 1,150

Interestingly, the original paper which had made the claim that bone marrow cells can become functional heart cells has been cited nearly 3,000 times, whereas the refutation by Murry and colleagues, published in the same high-profile journal has been cited only 1,150 times. The vast majority of the nearly 3,000 citations of the 2001 paper by Orlic and colleagues occurred after it had been refuted in 2004! The 2001 Orlic et al paper has even been used to justify clinical trials in which bone marrow was obtained from heart attack patients and injected into their hearts. As expected after the refutation by Murry and colleagues, the success of these clinical trials was rather limited One of the largest bone marrow infusion trials in heart attack patients was recently published, showing no success of the therapy.

These claims of the two papers (Orlic et al and Jiang et al) were quite innovative and exciting, and they were also published in a high-profile, peer-reviewed journal, just like the other five stem cell papers. The crucial difference was the fact that their findings could not be replicated by other laboratories. Despite their lack of replicability, both papers had an enormous impact on the field of stem cell research. Senior scientists, postdocs and graduate students may have devoted a substantial amount of time and resources to developing projects that built on the findings of these two papers, only to find out that they could not be replicated. If there is a lesson to be learned, it is that we need to be rather cautious in terms of our enthusiasm for new claims in stem cell biology until they have been appropriately confirmed by other researchers. Furthermore, we need to streamline the replicability testing process so that we do not have to wait years before we find out that one of the most highly prized discoveries cannot be independently confirmed.

 

Update 7/24/2013: Peter Aldhous reminded me that the superb job of investigative journalism into the question of MAPCs was performed in partnership with the science writer Eugenie Reich, the author of a book on scientific fraud. I have updated the blog post to reflect this.