Big stem cell news: dynamic duo of all-chemical direct reprogramming reports

There’s some big, positive news on the stem cell front today.

Two new innovative papers both by teams led by Sheng Ding of Gladstone Institutes with UCSF report all-chemical direct reprogramming of human somatic cells. Ding’s team took skin cells and by exposing them to cocktails of small molecules was able to turn them directly into precursors for heart muscle and neural cells. The two direct reprogramming papers were published in Science here and in Cell Stem Cell hereThe former paper is Cao, et al. and the latter is Zhang, et al. These reports together are a very big deal.

Neurons created from ciNSC

Neurons made from chemically-induced neural precursors. Credit: Mingliang Zhang, Gladstone Institutes

It’s been almost a decade since Shinya Yamanaka first reported the creation of mouse induced pluripotent stem cells (IPSC) using a cocktail of four factors and only one year later, he and others reported the creation of human IPSC.

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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.

Hannah near-perfect reprogramming voted as iPS cell paper of 2013

iPS cell poll 2013

I recently did a poll asking readers of my blog to vote on the iPS cell paper of the year for 2013.

The vote kind of seesawed at the beginning, but in the end with 100 votes cast the paper by the Hannah lab on near-perfect iPS cell production won out (see votes at left).

In second place was the Deng lab paper on all-chemical reprogramming. I suspect that just a couple years ago, this paper would have won by a landslide, which I think shows that priorities have changed.

I wonder if I had made the poll “the top reprogramming paper” of 2013, would Shoukhrat Mitalipov’s SCNT hESC paper in Cell have top the charts?

My own choice for iPS cell paper of the year? Yamanaka’s one on how to identify defective iPS cells.

Any other papers on iPS cells that you think deserve honorable mention?

Vote For Stem Cell Person of the Year 2013 to Determine Finalists

Stem Cell SymbolHappy Stem Cell Day!

I’m using this occasion to introduce today an important element of my new book, Stem Cells: An Insider’s Guide, and that is a new international stem cell symbol and logo (see at right).

More on that later this week.

Also on this day, online voting begins on a great group of nominees for the Stem Cell Person of the Year 2013.

Please vote in the poll below on your choice from the list as to who should be the semifinalists.

You can vote up to 4 times in any 24-hour period.

Voting will close in 2 weeks on Wednesday October 16 at 11:59PM PT.

The top group of 12 vote getters will move on in the process as Finalists.

You can read a bit about each nominee in alphabetical order by first name with one or two sentences about them, often taken from the nominator(s) here. 

Feel free to post comments on your favorites.

 

 

Nominees for Stem Cell Person of the Year 2013: scientists, advocates, physicians, and the Pope

Nominations for Stem Cell Person of the Year 2013 closed last night.

stem cell logo

I ended up with a remarkable list of 30 nominees.

I have included a few sentences about each one below, often taking verbiage directly from the nominator.

The online voting on these nominees will start soon. The top vote getters will move on as finalists.

Stay tuned!

Nominees in alphabetical order by first name.

Alexey Bersenev. Leading blogger, expert, and global educator about clinical applications of stem cells. Thoughtful, knowledgeable, and balanced approach to the field.

Beth Brinkmann. Deputy Assistant Attorney General of the US who led the administration’s successful case in Sherley v. Sebelius, the case challenging the legality of federal funding for embryonic stem cell research.

Chris Centeno. Physician doing stem cell treatments, founder of predecessor to ICMS, and a leader in efforts aimed at FDA reform to broaden the use of stem cells.

Don C. Reed. Tireless spinal cord injury and stem cell research advocate instrumental in the creation of CIRM and promotion of innovative stem cell research. An unsung hero. Blogger and frequent speaker at stem cell meetings.

Duane Roth (posthumous). Energetic Vice Chair of CIRM Board and leader of CONNECT, an organization promoting entrepreneurship in the San Diego area. Passed away at age 63 on August 4, 2013 from injuries sustained from a cycling accident during a fund raising event.

Elena Cattaneo. Professor of Pharmacology and Director of UniStem, the Centre for Stem Cell Research at the University of Milano, Italy. Took a courageous stand on the Stamina case and is the driving force behind UniStem Day. A “Senator for life” member of Italian Senate, meaning appointed for the rest of her life as a Senator.

George Q. Daley. Leading stem cell researcher, Professor at Harvard, Director of Stem Cell Transplantation Program HHMI/Children’s Hospital Boston, and former ISSCR President. Outstanding voice for the stem cell field.

Hideki Taniguchi. Scientist who led the team that made the first bioengineered micro-liver like structures that have functional properties with huge clinical implications for the future treatment of liver disease, an enormous growing problem in the world.

Hongkui Deng. First stem cell researcher to achieve all chemical cellular reprogramming to make iPS cells, which may lead to safer iPS cell-based therapies.

Jacob Hanna. His lab at the Weizmann Institute has reported the first essentially perfect reprogramming efficiency to make iPS cells with big clinical implications.

Jeff Sheehy. Member of CIRM Governing Board. HIV/AIDS patient advocate. Communications Director of UCSF AIDS Research Institute. Very effective, wise advocate for stem cell research.

Joanne Kurtzberg. Professor and Co-Director of Stem Cell Laboratory at Duke. Pioneering stem cell researcher in the area of clinical application of stem cell technology.

Juergen Knoblich.  Scientist who led the team that made first human “mini-brains” from stem cells, a discovery that could have far-reaching medical implications.

Lee Buckler. Global stem cell and cellular therapy expert who is also a dedicated educator and advocate for advancing the field. Makes real things happen in the stem cell field.

Leigh Turner. Bioethicist who has been leading efforts for appropriate FDA regulation of stem cell therapies. A powerful advocate for ethical stem cell research and protection of patients.

Manuel Serrano.  Scientist who led the team that conducted in vivo reprogramming to make iPS cells in living mice. This innovative work could help make in vivo reprogramming-based medicines a reality in human patients.

Marion (Joe) Riggs. Founder of Student Society for Stem Cell Research (SSSCR). Scientist and advocate who is strongly dedicated to educational outreach and inclusivity in the stem cell field.

Masayo Takahashi. Scientist leading the first ever in human iPS cell-based clinical trial. Vision researcher who may help develop new treatments for blindness and vision impairment.

Patricia Olson. Executive Director of Scientific Activities at CIRM and active in CIRM scientific leadership from day 1. A driving force in the stem cell field.

Pope Francis. Leader of Worldwide Catholic Church. Strong supporter of adult stem cell researcher.

Robert Klein. Visionary stem cell advocate. Leader of successful Prop. 71 effort that led to formation of CIRM and now Chair Emeritus of CIRM ICOC Board.

Robert Lanza. CSO of Advanced Cell Technology (ACT) and top global stem cell thought leader. The man who will make regenerative medicine a household word.

Robin Smith. CEO of NeoStem, biotech company focusing on therapies developed using adult stem cells including VSELs. Innovator and pioneer in the stem cell field.

Sabrina Cohen.  Spinal cord injury patient and stem cell research advocate for more than a decade as well as amazing educator and motivational speaker.

Shoukhrat Mitalipov. Scientist whose lab published the first successful human somatic cell nuclear transfer-based human therapeutic cloning to make human ES cells, the most important research development in stem cells of 2013. Also pursuing research into oocyte transfer-based therapies for mitochondrial disorders.

Sonia Vallabh. Incredibly brave advocate for stem cell research. Stem cell scientist at Mass General Hospital. Co-Founder of Prion Alliance and cureffi.org.

Sonia Skarlatos (posthumous). Long-time scientific leader at NIH with the National Heart, Lung, and Blood Institute where she was a tireless supporter of stem cell research. Passed away at age 59 on August 6, 2013.

Susan Solomon. Co-Founder and CEO of The New York Stem Cell Foundation (NYSCF). Remarkably effective advocate for stem cell research.

Ted Harada. Leading stem cell research advocate and very effective ALS patient advocate. Brings unmatched energy and enthusiasm to the field. Promoting intelligent reforms to the FDA process for stem cells.

Ulrich Mueller. Stem cell researcher and Chair, Dept. of Molecular and Cellular Neuroscience at Scripps.

Disclosures. Only those nominees listed above will be voted on starting this week. Some other nominations were also sent to me that I chose for various reasons not to move forward on and hence those nominees are not listed. It is also important to note that I do not endorse any specific nominee and just because someone is a nominee does not mean I support all of their specific efforts. I also do not necessarily agree with all the language used to describe the candidates.