NEJM paper links 3 blinded patients to publicly-traded stem cell clinic

Do 3 blinded stem cell clinic patients with major or complete vision loss constitute a significant adverse outcome?

I would say so and a new paper details how this happened apparently at a particular publically-traded South Florida stem cell clinic business.

You can see the damaged retinas of one such patient below in an image from a new NEJM paper reporting the severe adverse outcomes. The red areas are hemorrhaging with other substantial damage to the retina as well.

How did this all happen?

stem cells eyes

Kuriyan, et al. 2017 NEJM Figure 2A

Last year the story began to break of multiple patients alleging they had been blinded by different businesses in South Florida. Dr. Thomas Albini presented on some information on this at the FDA meeting last fall, but things weren’t entirely clear. Back then there were also indications of lawsuits by patients related to alleged vision loss due to experimental stem cell offerings against various parties involved.

Now we have more details on some of the cases in this new NEJM article (Kuriyan, et al.) in which the authors attribute these patients’ experiences to a withdrawn “trial”, NCT02024269, which lists Bioheart (now known as US Stem Cell, Inc.) as the sponsor. I put “trial” in quotes because it was withdrawn and also because as best as I can tell this wasn’t a traditional FDA-approved trial of the kind normally based on pre-clinical data and an IND. US Stem Cell, Inc. is a publicly-traded company ($USRM) and its stock has been all over the place this year. I’m not aware of US Stem Cell having FDA approval for what it is doing.

The NEJM article oddly does not mention Bioheart or US Stem Cell, Inc. by name as the place where the patients were given the stem cells, but the authors do clearly link them together and other information further supports this connection. Continue reading

Stem cell news bites: microbiota, clinic doc death, Stem Cells Inc, & more

This edition of our stem cell news bites finds a number of notable stem cell news items.

A potentially cool link between gut stem cells and microbiota is reported by Tae-Hee Kim of the Ontario Institute for Regenerative Medicine. See the nifty image of the stem cells from Dr. Kim showing proliferating gut cells in green in roughly the same location where the stem cells find their home.The work mentioned relates to necrotizing enterocolitis. Note that this article mentions only mouse work so implications in humans are unclear and I could not find an associated publication so we’ll have to stay tuned to see the meaning of this development.

gut stem cells microbiota

Dr. Tae-Hee Kim research image

Will formerly near death stem cell biotech Stem Cells Inc. ($STEM) be regenerated following its acquisition by another firm? This stem cell news has generated a lot of attention including this headline: “StemCells Inc picked up by Israeli medical devices firm.” What will $STEM shareholders get out of this? What is Microbot Medical exactly?

Stem cell clinic chain Cell Surgical Network has reported in the News section of the apparent death of a doctor who formerly was a member of that network, Dr. Steven Gitt. Dr. Gitt offered stem cell interventions via Phoenix Stem Cell Treatment Center. I was not able to find an obituary for Dr. Gitt, although his practice North Valley Plastic Surgery mentions a funeral held a few weeks ago. My condolences go out to his family.

More stem cell news on a happier note, noted stem cell researcher George Daley is the new Dean of Harvard Medical School.

I need to learn more about this other merger: Ireland’s Mallinckrodt buys US regenerative medicine firm. The firm in question is Stratatech…not one I’m familiar with.

What news on stem cells caught your eye?

ISSCR Releases Flood of Stem Cell Policy Docs

A committee of the International Society for Stem Cell Research (ISSCR) did one heck of a document dump yesterday on stem cell policy, releasing a whole bunch of policy recommendations on stem cells and more.

The torrent from ISSCR included a 37-page policy statement itself as well as several papers in top journals including the Lancet, Science, and Nature.

This output was the product of the members of a special  ISSCR Task Force, whose members I have listed at the bottom of this post. Who are the members? These are knowledgable, extremely bright people who care deeply about the issues.

ISSCR Policy Guidelines 2016

The stem cell policy positions of ISSCR and those in the associated publications were wide-ranging, touching upon everything from avoiding stem cell research hype to policies on human embryos to CRISPR of human embryos to three-person IVF/mitochondrial transfer, to clinical trials generally to patient-funded trials and more.

Continue reading

New Nature papers debunk STAP cells

Today marks nearing the completion of a full circle for one of science’s biggest controversies: the STAP cell fiasco. Today STAP cells are completely refuted with the publication of two new papers in Nature and we know much more–with some notable gaps still–about what went wrong.

In January of last year, an international team of collaborators from RIKEN in Japan and Harvard/Brigham & Women’s Hospital (including the lab of Charles Vacanti where the STAP idea reportedly originated) here in the US published two Nature papers making the extraordinary claim that ordinary cells could be reprogrammed into embryonic stem cell (ESC)-like cells.

And it could be done simply, cheaply, and quickly using various forms of cellular stress including low pH. I was highly skeptical when I read the papers, but tried to keep an open mind. This sounded cool, even if also too good to be true.

I published a review of the papers here on this blog on the day they were published and I included six key open questions that would be required to assess the real impact of these papers. Over the next few weeks I posted an increasingly skeptical series of posts questioning STAP.

Others in the larger community including anonymous scientific sleuth JuuichiJigen and some on PubPeer were skeptical as well. In fact, they started noticing issues with the data and text of the papers.

RIKEN and Nature began investigations. Ultimately the papers were retracted in relatively quick fashion. While a lot of harm was done even so and tragedy would strike later, the rapid refutation of STAP attenuated the overall damage.

For more background on the key STAP events check out this comprehensive STAP history timeline. Ken Lee’s lab took the lead in scientific refutation of STAP and published their work in F1000 here after Nature rejected it under unclear circumstances.

I also started a novel, but admittedly somewhat basic attempt at crowdsourcing global efforts at STAP replication. Very quickly we came to a consensus that autofluorescence was likely a key stumbling point for the STAP papers as the authors probably misinterpreted it as real signal from a GFP pluripotency reporter.

Suspicions grew elsewhere that STAP cells might really be ESCs or some other pluripotent stem cells, possibly mixed with trophoblastic stem cells (TSC). Ultimately, STAP first author Haruko Obokata was found by RIKEN to have committed misconduct and she is no longer working at the institution. RIKEN underwent a big shakeup as a result of STAP as well. STAP co-author and highly respected biologist Yoshiki Sasai committed suicide, which was one of the most tragic and sobering events I’ve seen in science during my career. In Japan there had been a media frenzy on the STAP problems. In the US things on the STAP front were and continue to be quieter. As recently as about a year ago, Vacanti and co-author Koji Kojima publicly expressed complete confidence in STAP and put up a refined protocol on the web.

So what was the real deal with STAP?

Today Nature published two articles thoroughly refuting STAP cells and providing some further insights.

In one of the papers, STAP cells are derived from ES cells, the authors used whole genome sequencing (WGS) to examine archived STAP cell-related samples and other cells present in the laboratories where the STAP work was conducted. Using essentially a form of genomic fingerprinting, the team reports conclusive evidence that STAP cells were in actuality ESCs:

In summary, our investigations based on WGS of STAP-cell related materials reveal that all of these materials are derived from previously established ES cell lines and refute the evidence shown in the two Nature papers that cellular stress can reprogram differentiated cells into pluripotent cells.

You can see Figure 1b from this study showing the WGS comparison that the genomic characteristics of various cell lines.

STAP refutationThe matching patterns between two STAP-derived lines FLS3 and CTS1 and the supposedly unrelated FES1 ESC line are particularly striking. It now seems almost certain that a number of STAP cells are in reality FES1-related ESC lines and that the STAP cells were not created by cellular stress.

The other new paper from another team, Failure to replicate the STAP cell phenomenon, comes to similar conclusions and further clarity arises:

“In summary, our replication attempts and genetic analysis indicate that existing STAP protocols are neither robust nor reproducible. To substantiate future claims of reprogramming and alternative states of potency, we urge a rigorous application of several independent means for validating functional pluripotency and genomic profiling to confirm cell line provenance. Ultimately, the essential standard of robustness and reproducibility must be met for new claims to exert a positive and lasting influence on the research community.”

This second team led by George Daley at Brigham and Women’s spans the globe, but importantly they did some of the work actually in Vacanti’s lab, still finding no evidence that STAP is real. They wrote, “Working within the Vacanti laboratory where the concept of STAP cells originated, and assisted by a co-author of the STAP papers…”

Seven laboratories were involved in this second STAP replication effort: Daley, Deng, Hanna, Hochedlinger, Jaenisch, Pei and Wernig. This is an all-star team of stem cell research labs.

One bottom line from the paper is that this team collectively worked very hard to try to get STAP to work, but it didn’t:

“In summary, 133 replicate attempts failed to document generation of ES-cell-like cells, corroborating and extending a recent report.”

Like the other team, these scientists analyzed the STAP cells including their genomes. They found inconsistencies between their new findings and the claims in the original STAP papers:

“In the original STAP reports, the authors stated that they mixed CD451 cells from male and female mice owing to the small number of CD451 cells retrieved from individual neonatal spleens. However, our analysis indicates that CD451 cells were female, whereas the derived cells (STAP cells, STAP stem cells and FI-SCs) were all male, a clear inconsistency.”

These authors also found indications of trophoblastic stem cells (TSC) being mixed into the STAP samples. TSC may explain the reported totipotency of some derivations of supposed STAP cells.

Nature itself explained why it published these new papers (in the Brief Communications Arising or BCA format):

“Why is Nature publishing these pieces? The main reason is to update the scientific record. The wording of the STAP retraction notices left open the possibility that the phenomenon was genuine. It said: “Multiple errors impair the credibility of the study as a whole and we are unable to say without doubt whether the STAP-SC phenomenon is real.” The two BCAs clearly establish that it is not.”

We are just about, but not quite at the end of the STAP story it seems. In my opinion there is still more to be learned about what went so wrong. How did the ESCs and in some cases TSCs end up in the cell culture mix? Accidental contamination? Intentional attempt to bolster the seductive hypothesis?

We may never know, but today there is a great deal more clarity overall at least.

The publication of these two new papers is a very positive step, but it is important to stress that absent post-publication review, rapid and open team science, and social media efforts, the STAP cell myth may have continued to have been believed by many in the research world until this day when these debunking papers were published. That delay would likely have caused immeasurable damage. Thus, there were important roles both for traditional scientific correction via journals and new, transformative types of rapid post-publication review.

NAS Meeting on Human Germline Modification Taking Shape

The US National Academy of Sciences (NAS) will hold a meeting on heritable human genetic modification on December 1-3, 2015 in Washington, D.C. Invitations to the NAS meeting to individuals starting going out last week.

The upcoming NAS meeting seeks to address these issues and discuss the possibility of a moratorium on clinical use of genetic modification technology. It could play a crucial role in shaping both national and global policy on human genetic modification.NAS gene editing

The meeting was sparked in part by rising concerns over the possibility that some scientists may race ahead to clinical use of new gene editing technologies such as CRISPR-Cas9. Such clinical use of human genetic modification technology could pose serious risks to both individuals and to science. Others have the opposite view and favor allowing heritable human editing to proceed as a natural course of science delineated only by existing regulations rather than a moratorium. An international meeting would have the goal to reach consensus on prudent policy in this area, just as the 1975 Asilomar meeting did on genetic engineering.

The NAS has announced that both the Royal Society and the Chinese Academy of Sciences are partnering on the new 2015 meeting. This is a positive step as it will increase the diverse, global views on the key issues. Leaders of both the new partners indicated their enthusiasm for the meeting:

“Human gene editing offers great promise for improving human health and well-being but it also raises significant ethical and societal issues,” said Royal Society President Paul Nurse.  “It is vital that we have a well-informed international debate about the potential benefits and risks, and this summit can hopefully set the tone for that discussion.”

Chinese Academy of Sciences President Chunli Bai said, “Both Chinese scientists and the government are aware of the pros and cons of human gene editing.  CAS scientists have organized a panel discussion and coordinated with related government agencies for regulatory policies on this issue.  We would like to work together with international communities for the proper regulation and application of such technology.”

One issue, however, is whether it could be a challenge for a meeting with such a broad spectrum of views and constituents to reach a focused consensus.

Details on the meeting are starting to come out on social media too.

Bioethicist Tetsuya Ishii tweeted about his invite to the meeting.

From the NAS website here are the meeting organizers:

  • David Baltimore (chair), president emeritus and Robert Andrews Millikan Professor of Biology, California Institute of Technology, Pasadena United States
  • Françoise Baylis, professor and Canada Research Chair in Bioethics and Philosophy, Dalhousie University, Nova Scotia Canada
  • Paul Berg, Robert W. and Vivian K. Cahill Professor Emeritus and director emeritus, Beckman Center for Molecular and Genetic Medicine, Stanford University School of Medicine, Stanford, Calif. United States
  • George Q. Daley, Samuel E. Lux IV Professor of Hematology and Oncology, and director, Stem Cell Transplantation Program, Boston Children’s Hospital and Dana-Farber Cancer Institute, Boston United States
  • Jennifer A. Doudna, investigator, Howard Hughes Medical Institute; and professor, department of molecular and cell biology, Lawrence Berkeley National Laboratory, and department of chemistry, University of California, Berkeley United States
  • Eric S. Lander, president and director, The Broad Institute of Harvard and MIT, Cambridge, Mass. United States
  • Robin Lovell-Badge, group leader and head, division of stem cell biology and developmental genetics, The Francis Crick Institute, London United Kingdom
  • Pilar Ossorio, professor of law and bioethics, University of Wisconsin; and ethics scholar, Morgridge Institute for Research, Madison United States
  • Duanqing Pei, professor and director general, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou China
  • Adrian Thrasher, professor of paediatric immunology, University College London United Kingdom
  • Ernst-Ludwig Winnacker, professor emeritus and director emeritus, Gene Center, Ludwig-Maximilians University, Munich Germany
  • Qi Zhou, professor and deputy director, Institute of Zoology, Chinese Academy of Sciences, Beijing China