Waking up this morning with a “stunning” finding about the recent publication of a study by Stanford researchers that noted the improved outcome in stroke patients following injection of stem cells have been positively headlined in the fairly serious “Washington Post” journal.
As a neuroscientist and stroke researcher, this sounds like a very good news because there are not much good news when we discuss stroke clinical trials that show something better than placebos. But also me and others like Pr. Paul Knoepfler as he rightly wrote in his blog post to not fail into overhyping and overselling a pilot study and by the way promising the moon to patients and come back to them with a disappointing news.
I thought it would be a great idea to discuss a bit more about this paper, its observations and outcomes and current limitations.
1. What is the study that was has been cited in the Washington Post and how does it stand in terms of scientific publication?
According to the Washington Post, this study has been published in Stroke journal and authored by Gary Steinberg, MD-PhD (Stanford University) listed as leading author. Based on the information, we are likely referring to the following article. I have attached a screenshot of the abstract page from the journal website:
First thing, is to classify the authorship ranking. Dr. Gary Steinberg is what we refer as the primary author, usually the person that has performed most of the experiments and analyzed the data. On the other hand, we have Dr. Neil E. Schwartz as a senior author. It is usually the one that has the first thought process, planned the experimental design, wrote and finalized the manuscript and usually the one that have put the money on the table (the funding awardee) to run this study. Here, I would argue that we have a difference in what we consider as the lead author of the paper. I would consider Dr.Schwartz as the lead author due to the ranking, but thats some science bickering.
The paper got published in Stroke, that is the flagship journal of the American Stroke Association (a subdivision of the American Heart Association). Being published in a society journal is a good step but in case not enough to justify the overhyping. Why? Impact factor. Impact factor matters. Stroke, according to the American Heart Association, has an impact factor of 5.76. Thats good but a clinical paper can get better rating. For instance, Circulation (the highest-ranked AHA journal) is listed with an IF~15, whereas Nature Medicine (a mastodon for high-impact translational studies) has an IF of 27.
The paper is surely good, but does it qualify for the “stunning” adjective? Certainly not and the overselling of it is not justified by the publication metric.
Also note the title, this is a Phase I, IIa. So it means it is very a early stage of the clinical trial. Phase I in the first stage of clinical trial in which we test the safety of a novel treatment, Phase IIa is to try if there is any efficacy in a very small subset of patients (less than 50). Again, at this stage, it is a dangerous step to oversell something that yet to show efficacy with hundreds of patients.
2. What does the paper says?
The paper is behind paywall so I cannot publish any figures and text. The paper got one round of revision, as it was received in February 9, revised in April 1 and accepted in April 26. If we consider a 4-6 weeks turnover between the time you submit your draft and the editor respond to you with reviewer comments, we can speculate that the revision was minimal and quickly addressed by the author.
This study rely on using mesenchymal stem cells (MSCs) in a small cohortof patient. The study uses a particular type of MSC, the SB623 bone marrow MSC cell line.
MSCs are a particular type of stem cells. They have the least pluripotency because they have already been engaged inside a differentiation (to make it simple, they are programmed to give rise to blood cells such as white blood cells, red blood cells or platelets) and therefore have little opportunity to be re-wired to form neurons or cardiac cells. However, because they are already into a certain differentiation stage, these cells are considered as the safest for implantation. Other stem cells (such as embryonic or induced pluripotent stem cells) are nefariously known to wreck havoc if injected as undifferentiated (they cause what we call teratomas), safety of differentiated precursor cells (such as neural precursor cells) remains to be addressed. Thats also alleviate the issue encountered with previous stem cell therapy based studies that consisted as injecting a mixture of bone-marrow stem cells without knowing exactly which sub-population is carrying the protective effect. Interestingly, these MSCs carry a plasmid allowing the overexertion of a protein called Notch-1 intracellular domain (ICD). Notch-1 ICD is a fragment of the full Notch-1, that is cleaved by certain enzymes. Such ICD can therefore act as a messenger inside the cell and exert some biological activity.
The study used three doses of cells and were directly injected around the site of infarct (peri-infarct area). In stroke injury, we have the core or infarct area that is considered as the ground zero. We consider it as the necrotic area or the wasteland zone. Everything inside is dead and highly hostile for repopulation. However, the peri-infarct surrounding this zone is battling for days and weeks, torn between signals telling neurons to survive the injury from signals telling neurons to die. This fine balance is one target for therapies as we consider finding factors that can title neurons in favor of survival can help them recover and minimize the loss done by the stroke injury.
What is interesting is that these MSCs have been shown to only survive for one month. Thats a good point for the safety issue. In this cohort of patients (18 in total), very few side effects were noted suggesting a fairly safe method for up to 12 months. However, one caveat of this study is the lack of proper control or placebo.
3. Why this study has been overhyped and oversold by the WaPo?
All patients improved over the 12 months period compared to their initial timepoint (the day after stroke injury). Furthermore, all three doses have been pooled together, so we cannot tell if there is a better recovery with a higher number of cells. This is a serious concern that has to be mentioned: we cannot tell if these patient recovered by their own or due to the treatment.
If we had a placebo group, we could have been able to compare and contrast the gain due to the stem cell treatment. We also cannot see how each individual and each group have been recovering. It would be interesting to see how age and sex (male/female) played a role in the recovery.
This is the sin of mainstream news media: they have again sinned in overselling a study that is interesting but still lacking solid evidence to sell that case. The study and approach is interesting but the version sold in the news is a far-stretched version of where the study actual said. Selling it as “stunning” is not only wrong and inappropriate, it is also a dangerous move that will serve some for-profit stem cell clinics to make profits on patients that have been experiencing stroke and despairingly looking for a “miracle cure”.