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.

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For IPS cell mutations, some reassuring new data but validation still key

Over the years some scientists including yours truly have expressed concerns about the possibility that mutations could crop up during the reprogramming process to make induced pluripotent stem cells (IPS cells or IPSC). How concerned should we be about IPS cell mutations?

A cool new paper, Bhutani, et al, in Nature Communications from a team led by Jeanne Loring and Nicholas J. Schork presents data arguing against significant oncogenic mutations occurring during reprogramming to make IPSC.

The authors summarize their findings this way:

“Our results show a moderate number of variants in the iPSCs that were not evident in the parental fibroblasts, which may result from reprogramming. There were only small differences in the total numbers and types of variants among different reprogramming methods. Most importantly, a thorough genomic analysis showed that the variants were generally benign. We conclude that the process of reprogramming is unlikely to introduce

variants that would make the cells inappropriate for therapy.”

The paper, entitled “Whole-genome mutational burden analysis of three pluripotency induction methods” does a strong job at probing the potential genomic changes associated with reprogramming including three different reprogramming methods.

Figure 1b

I found it surprising in a good way that the retroviral approach didn’t cause more genomic issues: “Our results using retroviral vectors showed that this method caused a similar number of mutations as the other methods, but was slightly more likely to introduce mutations that are classified as deleterious.”

When mutations were found in a general sense, they tended not to be functionally associated with cancer, which is reassuring. Mutations may not be caused by reprogramming very often per se, but rather may be primarily a function of cell doublings. In this sense the situation with IPS cells is pretty similar to that with ES cells.

The derivation and culture expansion processes for stem cells over time are going to increase the chance of mutations. The bottom line is that if a team has clinical plans for human pluripotent stem cells including IPS cells they need to rigorously evaluate those cells including genetically and epigenetically, consider passage number and the possible need for post-expansion/differentiation re-validation, and focus on those lines validated to be the best.

My top takeaways from #WSCS15 so far: IPS cells, #CRISPR, CAR-T, Patients

Mahendra RaoIt’s been a great couple days so far here at the World Stem Cell Summit in Atlanta. You can follow it on Twitter using the #WSCS15 hash tag. S.

I first attended it 5 years ago in Pasadena. One of the special aspects of WSCS is it brings together diverse stakeholders in a way that just doesn’t happen elsewhere. For instance, you can have the FDA, patients, physicians, scientists, and funding agency people all in one room together.

Some strong impressions so far include the following.

IPS cells. There is a great deal of excitement here about IPS cells of course, but Mahendra Rao providing a more sobering perspective. I’m more optimistic than he is. Here are his six “realities” of IPS cells, which I interpreted as his view of the top challenges.

  • Allogeneic therapy is not going to work unless HLA matched.
  • HLA matching requires a larger number of patients.
  • There is not enough cGMP capacity to make all the lines required.
  • The cost of making a line and the time required to make one make this an expensive therapy and probably not useful for a large number of diseases.
  • Cells may not be mature enough for use even if one could solve all of the above problems.
  • No real model for true autologous therapy where manufacturing is involved (no amortization and no comparability).

CRISPR and human germline modification. I was on a panel yesterday on human germline modification that I enjoyed a great deal. I was on the panel with Aubrey de Grey and Aaron Levine, who both gave fantastic talks. The audience asked spot on probing questions as well. There was some disagreement regarding the appropriate level of urgency for developing policies and/or regulations on human germline modification, but overall my sense was that us three panelists perceive that attempts at CRISPR-based human heritable modification are almost certain to occur in the near future.

There’s real promise for CRISPR-based therapies in the future for rare genetic diseases (not to mention all the great in vitro CRISPR research on humans cells in the lab that should continue), but to get from point A where we are now to point B where we might as a field hypothetically be ready to responsibly use CRISPR in the germline for humans is a long road. Thus, irresponsible clinical attempts in the next few years would be very dangerous and could be harmful to the field and society.

Still, patients in the audience passionately pointed out that in many cases there is a profound need for helpful therapies now and in the immediate future. That “patient drive” as it was termed at the Washington DC meeting last week on human germline modification is powerful and must be part of the discussion.

Innovation in brain cancer treatment including CAR-T. We also heard earlier about transformative approaching such as stem cells loaded with toxins and CAR-T therapies for cancer. Very exciting stuff!

Patients and stem cell clinics. In a session today that I chaired, we heard much more from patients. They articulated better than anyone else could about how difficult it is to get reliable information. How does one know if a certain therapy is legit, safe, and worth getting? Where are sources of information? I’d recommend some of the websites list in the link section of this blog (scroll down the right side of the page).

Dr. Steven A. Davis, co-founder of SymBioSys, Inc. gave a great talk using the example of the Texas stem cell clinic CellTex, now operating in Mexico, as a test case and as a way to introduce the key issues that need discussion more broadly. We then spent a good 45 minutes have questions and discussions. It’s clear that there are many gray areas and difficulties in this arena.

The leader of the Mexican Stem Cell Foundation (unfortunately I didn’t catch his name, but if I find it I will add it in here later) gave some helpful context for understanding where things stand in Mexico. His sense was that the Mexican equivalent of the FDA (COFEPRIS) is not currently equipped to carefully evaluate all the stem cell clinics there (often clustered on the border and catering mainly to American patients). However, he did indicate that his perception was that things are improving.

Overall. I have to thank Bernie Siegel, who is the organizer of this amazing meeting, and his team at the Genetics Policy Institute (GPI). They do a phenomenal job every year on the WSCS.

More talks are ongoing right now including a fascinating one on cord blood and its potential use for neurological disorders….stay tuned.

Dozen Top Candidates To Be New CIRM President

CIRM 2.0Who might make a fantastic new CIRM President?

The California stem cell community is abuzz with this question.

This new President will not only lead CIRM today, but also in all likelihood will steer CIRM in its new incarnation after 2017, what I’ve called CIRM 2.0. At least that would be ideal.

CIRM has posted a position/candidate specification document here including a summary of the position that includes this statement:

The President of CIRM must be a nationally recognized leader with a vision, scientific credibility, and exceptional leadership skills, unassailable integrity, a keen appreciation of the financial and business aspects of scientific research, a sense of urgency and ability to deliver results, and a profound respect for the ethical issues involved in this project. He or she also must be comfortable operating in a very public capacity, adept at working with a board or other oversight body, have a good rapport with regulators, and sufficiently self-possessed to not be perturbed by criticism or controversy.

To summarize, this means the successful candidate must have great scientific stem cell chops, must be a proven leader (i.e. already held a high level leadership position elsewhere), ideally would have some business experience, being ethically unassailable (as much as possible at least), must already ideally have worked with the FDA, and not be easily spooked by public criticism or media storms. Almost everyone that I talked to thought that the person should be existing California stem cell scientist too for practical reasons.

The CIRM Presidential Search Committee tasked with finding people meeting these criteria, just met on Friday.

I’ve been talking behind the scenes with some folks in the know who are particularly interested in this question. They’ve thrown some names out onto the table, but of course not all of these people will necessarily be up for being considered and it’s not an all inclusive list. Update: To be clear, these names are NOT from me, but were suggested to me by others.

Candidates mentioned by stem cell community to me in alphabetical order by last name.

  • Jim Battey is Director of NIDCD at NIH, Former Chair of NIH Stem Cell Task Force, grew up in the Bay Area, went to Caltech.
  • Fred “Rusty” Gage is a Professor of Laboratory Genetics at the Salk, Past President of ISSCR, and a true pioneer in the stem cell field.
  • Larry Goldstein, Professor of Cellular and Molecular Medicine and Director of the UCSD Stem Cell Program, Scientific Director, Sanford Consortium for Regenerative Medicine, and another top international leader in the stem cell field.
  • Arnold Kriegstein is the Director of the UCSF Stem Cell Center and Professor of Neurology at UCSF.
  • Story Landis is Director of NINDS at NIH. She is a Neurobiologist, Former Chair of NIH Stem Cell Task Force in 2007, Graduate of Wellesley and PhD from Harvard.
  • Jeanne Loring is a pioneering stem cell researcher who is the Director of the Scripps Center for Regenerative Medicine.
  • Thomas Okarma is CEO of Asterias Biotherapeutics, and former President & CEO of Geron. Received his MD and PhD from Stanford plus on the faculty at Stanford from 1980-1985.
  • Mahendra Rao is Director at NIH of The Center For Regenerative Medicine and a long-time stem cell researcher. He received his Ph.D. from Caltech.
  • Brock Reeve, Director of the Harvard Stem Cell Institute. Strong commercial sector experience and graduate of Harvard Business School.
  • Clive Svendsen is Professor in Residence of Medicine and Director of the Cedars-Sinai Regenerative Medicine Institute. Former Director of University of Wisconsin Stem Cell and Regenerative Medicine Center.
  • Michael West, CEO of California-based stem cell biotech BioTime and long time leader in the stem cell field. Former leader of ACT and founder of Geron.
  • Keith Yamamoto is a Professor of Cellular and Molecular Pharmacology at UCSF. In addition, he is Vice Chancellor for Research, Executive Vice Dean of the School of Medicine, and Professor of Cellular and Molecular Pharmacology at the University of California, San Francisco, UCSF.

I’m sure there are more worthy candidates than just these, but this list seems like a good place to start.

Who’s your pick?

Guest Post on the Future of Stem Cells: World Alliance Forum Meeting

World Alliance Forum.jpgBy Johnathon Anderson

The World Alliance Forum held a really great meeting yesterday in SF about the future of stem cells. The collective brain power in the room was pretty staggering. The meeting brought together stem cell leaders from academia, industry, startup incubators and funding agencies. The purpose of the meeting was three fold: 1.) foster collaboration between US and Japanese stem cell researchers, 2.) facilitate interaction between academics and industry, and 3.) to honor Dr. Shinya Yamanaka for his grounding breaking iPSC work that won him the Nobel Prize last year (see photo from Cell Stem Cell post on Facebook).

Yamanaka gave a great keynote address that showcased his sense of humor and his continuing efforts to bring iPSC technology to the clinic (including developing needed homozygous HLA iPSC lines). When asked for his advice to ambitious young researchers, he recommended paying close attention to unexpected results in the lab. After all, he noted, the seed of his iPSC research came when he got confusing results from a potential cholesterol lowering drug that induced liver cancer in mice.

Aside from the great talks by some of the leaders in the field (Irving Wiessman, Hideyuki Okano, Deepak Srivastava, Mahendra Rao, Hiromitsu Nakauchi), there were a couple of outstanding panel discussions including one covering the future of stem cell technology that was moderated by Alan Trouson, president of CIRM. While another discussed academia and industry collaboration moderated by Regis Kelly of startup incubator QB3. One of the take home messages was that translational academics need to start engaging industry earlier on. There was also some sage advice from industry representatives indicating that academics thinking about developing startups really need to reach a significant level of maturity before spinning off in search of VC funding.

As the sun started to set over the bay and the jazz music and wine started to flow in the reception hall, it was hard not to be struck by a couple of ideas. One, we’re incredibly lucky here in California to have CIRM and strong patient advocacy organizations that help bridge the often lamented translational funding gap. Both of these groups have really been enormously helpful in bringing potential new stem cell therapeutics to the clinical trial pipeline. Second, hearing all of these great discussions really gave a taste of the zeitgeist of the field and although there is still a lot of work yet to be done, it’s hard not to be really excited about the future of stem cell technology as it draws closer and closer to the clinic.

I’d like to really thank Dr. Knoepfler for allowing me to attend this meeting and blog about it. It was incredibly informative and I was even lucky enough to expand my network a bit. I really hope there will be future meetings that bring together all of the major stake holders the way the World Alliance Forum was just able to do.

Guest Blogger-Johnathon D. Anderson,  PhD Candidate

Jan Nolta Lab

Institute for Regenerative Cures
University of California Davis Medical Center