Highlights of ISSCR2017 – A Biomedical Engineer’s Perspective

By Agnes SoosAgnes Soos

Amid the hustle and bustle of downtown Boston, nearly four thousand researchers and exhibitors gathered for the 15th Annual ISSCR Meeting. With presentations from over thirty plenary lectures, and dozens of others featured in concurrent sessions and the daily Innovation Showcases, there definitely was no shortage of exciting research to discover and discuss. There was a record number of exhibitors this year with over 150 companies set up in Exhibit Hall. Added to this, the always-busy Meet-Up Hubs, the job boards peppered with posted offerings, and the popular Meet-the-Experts luncheons and Junior Investigator Career Panel (both with full wait-lists) offered an array of networking opportunities that definitely did not disappoint!ISSCR2017-book&badge,closeup

Though the program broadly covered stem cells in development, disease, and their applications to human health, iPSC-related work featured prominently throughout the Meeting. Central to this focus on iPSC research – and quite popular among the attendees – was the plenary talk by Shinya Yamanaka. His lecture discussed the two major medical applications of iPSCs: cell therapy and disease model/drug development. Under the cell therapy topic, he relayed the high costs associated with autologous treatments and outlined the research that has gone into identifying HLA homozygous “super” donors to overcome the prohibitive nature of allogeneic therapies. Though a first transplant was successfully performed in March of this year, this work still faces some challenges. Namely, facility-dependent handling practices appear to impact the occurrence of mutations within cancer-driving genes of the iPSC clones, necessitating further study and perhaps tighter control of how these cultures are handled. On the topic of disease modeling and drug development, Yamanaka outlined early successes in using iPSCs to gain a better understanding of Fibrodysplasia Ossificans Progressiva and the effective use of patient-derived cultures to conduct in vitro drug screening.

Organoids and organogenesis was a hot topic at this year’s Meeting with dedicated plenary and concurrent sessions offering an array of excellent talks. Juergen Knoblich’s plenary lecture presented the advantages offered by 3D organoid cultures – namely, their ability to recapitulate features of brain development and disease which cannot be easily studied using animal model systems. For example, cerebral organoids have been developed using patient-specific iPSCs to model microcephaly. Knoblich also discussed some of the advantages of introducing bioengineered matrices to manipulate organoids, demonstrating improved organoid generation with specific scaffold materials. Although organoid ‘mini-brains’ to study neural development and disease were the topic of several talks, other areas of organoid research included intestinal epithelium (‘mini guts’), pancreas, kidney, liver, and lung.ISSCR2017-Overlooking (part of) Exhibit Hall

Other highlights included talks from the recipients of the McEwen Award for Innovation, Elaine Fuchs, and the Dr. Susan Lim Award for Outstanding Young Investigator, Jayaraj Rajagopal. Fuchs expertly summarized four decades of research on skin stem cells in a mere 20 minutes, covering the current understanding of stem cell activity and function in normal tissue, with aging, and in cancer, using the skin as a model system, with focus on cells within the hair follicle niche. Rajagopal lectured on the topic of airway epithelium and the interactions of three constituent cell types – a stem cell, progenitor cell, and post-mitotic differentiated cell. He presented the value of this model in studying regeneration and outlined the complexity of cellular interactions in this relatively simple cellular ensemble. Both of these talks were presented as part of the plenary session on Tissue Regeneration and Homeostasis.

Unsurprisingly, lectures in all sessions presented some very exciting science. Topics covered in the other plenary talks included: Chromatin and RNA Biology in Stem Cells, Stem Cells and Cancer, Stem Cells and Stress, Senescence, and Aging, and the Frontiers of Cell Therapy.

In addition to the above, perhaps the most memorable talk of the Meeting was the address by Sanford Greenberg on his quest to end blindness. Greenberg discussed his own experiences, relaying the struggles he faced when he become blind at 19 years of age. He outlined the goals of the Greenberg Prize, a $3 million award (in gold), which has the intent of rallying the international research community to focus efforts towards ending blindness by year 2020.

Developing effective treatments – or perhaps even cures – through clinical applications of some of the research presented at the Meeting does appear promising. This was exemplified by the work presented in the final plenary session by Masayo Takahashi on the successful use of iPSC for retinal cell therapy. However, although the results of this work are cause for excitement, Takahashi emphasized the importance of being cautious in our optimism. Though there may be progress, she is often faced with the challenge of being unable to accommodate all patients seeking treatment. Thus, she emphasized, although we must promote our successes, we should avoid placing too much emphasis on champion cases and avoid hype, so that together we may see healthy progress within the stem cell field.

US Stem Cell bid for FDA RMAT rejected?

Can a stem cell clinic business get FDA RMAT designation? At least one announced it was trying, but now seems to have given up.

Stem cell clinic business US Stem Cell, Inc. has reportedly announced that it is at least temporarily abandoning its efforts at getting Regenerative Medicine Advanced Therapy (RMAT) designation from the FDA. The company’s penny stock $USRM has been gyrating for months and I had earlier wondered if could be some fake news about it. The USRM news now seems real and not good on the RMAT front. Shares plummeted earlier this week (see earlier stock graph above).

US Stem Cell Inc.As to plans, here’s something from an apparent company PR:

“Until then, U.S. Stem Cell will focus on opening new clinics around the country to better serve patients in need. In addition to the original Sunrise clinic (that has successfully treated hundreds of patients and generated over $2m in revenues in the past 12 months alone), recent clinic openings include Miami and Palm Beach, Florida. Upcoming openings include Dallas, Texas (thanks in part to the early adoption of patient rights by the State of Texas), Chicago, Atlanta, and Denver – as well as other clinics in the northeast and the west coast.”

Opening more clinics…selling non-FDA approved offerings?

This may be what the company sees as a good business move, but in my opinion it puts more patients at potential risk and takes their money for “stem cell treatments” that are not conclusively proven to be safe or effective. I have not seen RCT data from USRM to support their commercial stem cell efforts.

What happened with the US Stem Cell, Inc. RMAT application? We may never know for sure, but rejection by the FDA is one possibility. Over at the RAPS site, a new piece on CBER has this to say (“Marks” refers to CBER Director Peter Marks):

“Thanks to the 21st Century Cures Act, FDA now has a new designation for regenerative medicines, known as the regenerative medicine advanced therapy (RMAT) designation. As of last week, Marks said there have been 19 requests for RMAT designations, 18 of which CBER has acted on, and four of which have been granted…’

Unless US Stem Cell, Inc. is the 1 out of the 19 applications on which the FDA has not acted, then it’s not looking promising for their RMAT just based on the odds. Another possibility is the FDA did not reject it, but asked US Stem Cell for a lot more data and that constitutes “acted on”.

It’s worth a reminder that this business was linked to the blinding of three patients in a presentation at a 2016 FDA meeting and in a NEJM publication. The company has had patient lawsuits too, which seem to have been settled out of court.

More broadly in the oversight arena, to my knowledge the FDA and CBER specifically have not issued any warning letters to or taken other actions (at least in the public domain) on stem cell clinics in ages despite hundreds of such businesses marketing unproven stem cell offerings without FDA approval. And whatever happened to those four key FDA draft guidances? Does CBER have enough funding and staff to tackle the burgeoning stem cell business arena? It remains unclear how the FDA and CBER will handle key challenges under the new Trump administration and with new FDA Commissioner Scott Gottlieb.

Hunting for computational approaches for stem cells at ISSCR2017

Cátia Bandeiras

Me @ ISSCR2017, resting from the sessions and with my MSCs pin.

By Cátia Bandeiras, PhD Student at University of Lisbon, Portugal and Massachusetts Institute of Technology. See tweets from the conference using #ISSCR2017 @apulgarita

I just wrapped up my stay at the Annual Meeting of ISSCR 2017, which happened in Boston. I decided to take advantage of the fact that I am living in Boston at the moment and go to the largest stem cell research conference to present my work. As a matter of fact, I am not the usual PhD student in stem cell research. I don’t do lab work at all, my working hours are spent coding a simulation model for stem cell manufacturing. Given my background as a programmer, I went there with the very specific mission of finding the hottest trends in computational research for stem cells.

I was present in a varied mix of plenary and concurrent sessions. My focus was related to expansion and differentiation of induced pluripotent stem cells (iPSCs), in particular into endodermal lineages, mesenchymal stem cells (MSCs), clinical trials and research translation and ethical considerations in stem cell research, which are all topics aligned with my project. While most of the talks were interesting, to me there were two from the ones I saw that stood out:

  • Shinya Yamanaka from the Center for iPS Cell Research and Application (it’s not every day I could say I was witnessing a Nobel Prize awardee talk) gave a compelling lecture on the methodologies for allogeneic therapies produced from iPSCs, focusing on the recently initiated clinical trial with allogeneic iPSCs-derived retinal pigment epithelium cells. The need for allogeneic pluripotent stem cell derived therapies is driven by the prohibitive costs of autologous manufacturing for these therapies, reaching costs of over $1 million per patient, as mentioned by Hardy Kagimoto from Healios K.K.
  • George Daley from the Boston Children’s Hospital (and awardee with this ISSCR edition Public Service Award) focused on the “brave new world” of emerging biomedical technologies. He mentioned how gene editing of animal embryos looked like science fiction until some years ago, with the advent of CRISPR/Cas9 technology, and how human embryos will be able to be edited. Daley discussed the ethical considerations behind human gene editing, as well as mitochondrial DNA replacement in case of mitochondrial diseases and how it can only be done in male embryos, and the very recent growth of goat fetuses in an extrauterine system. He mentioned the new ISSCR guidelines for stem cell research, released in 2016, and how technology is always ahead of the guidelines.

In none of the talks I watched much attention was paid to computational methodologies for research of result analysis, even from a bioinformatics point of view, which is the most common use to evaluate the up or down regulation of gene expression during culture events. Therefore, I decided to take a closer look into the poster sessions and to look carefully into the list of abstracts for computational approaches. While most of the posters that included computational methodologies were focused on computational biology and gene clustering, I found some other interesting projects. I learned about the SyMBioSys consortium, an initiative led by Sakis Mantalaris from University College of London focused on building kinetic models to explain functional behavior from varying concentrations in cell components, through a metabolic model reconstruction of umbilical cord blood mesenchymal stem cell during osteogenic differentiation. I also learned how the migration of implanted neural stem cells (NSCs) is made along the white matter of the brain and how the directions and velocity of migration can be modeled through imaging and fluid dynamics modeling with researchers from the City of Hope National Cancer Center. Finally, I was captivated by the Stem Cell Commons open source bioinformatics platform created by researchers from the Harvard Stem Cell Institute, aiming to help wet lab scientists to process, share and visualize data in stem cell research. I talked with some of the poster presenters and there were two groups: one, where the presenters are experimental researchers and have to devote the limited amount of time available to computational analysis, and another where there are specialized computational biologists or mathematicians to analyze the experimental work of their group colleagues. I am in the latter group, and I generally tend to think that this is a more productive approach to research. From the feedback I got from my poster, there seems to be a lot of interest for new computational methods that are ready to use, open source, and user-friendly for experimental scientists. It is upon us to develop these tools with reliability and reproducibility to help advance stem cell research even further.

I was very pleased with my first experience at ISSCR and hope to be able to present in the future. This was only a very quick overview of my experience, focused on my research field, but I was impressed with the amount of innovation and recent successes with pre-clinical and clinical trials presented there. As Sally Temple, president of ISSCR said in the opening session, “This is our Century”. I hope for our community that we can keep on working on bringing safe and effective stem cell therapies to the clinic, as well as better disease models and drug screening platforms, with the collaboration of professionals with many different expertises.

Sally Temple ISSCR

Sally Temple during her opening remarks at ISSCR 2017. Photo copyrights by ISSCR

3 CIRM challenges: search for new prez, funding, & clinical POW!

The idea of CIRM as a dedicated state stem cell agency was one of the things that got me excited about starting my time as a professor doing research on stem cells in California way back in 2005-2006 on the job hunt. Fast forwarding to today now 11 years later, CIRM is still on the cutting edge, but some major things have changed for California’s stem cell agency and as it looks to its future, the questions and challenges are different too.CIRM 2.0

By analogy, the original CIRM was at first like a stem cell itself navigating its differentiation branches as it went. The new CIRM of 2017, what some call CIRM 2.0, is in contrast more like a developing tissue. It has matured and has a history to build upon as it continues. Today CIRM and its staff aren’t newbies. They were newbies by necessity when I came to California in 2006 because they were literally inventing themselves with no past example to use as a model. Now they are stem cell veterans and CIRM is trying to sort out its fresh path ahead relative to its current path rather than strike a path from scratch.

Three key areas need tackling to navigate the new path for maximum positive impact.

Funding. Does CIRM 2.0 and its backers go for a “Prop 71 2.0” to get another round of California state funding? If so, how much and how to approach the voters? If not (or if “yes”, but the effort isn’t successful), where does CIRM get its funding to continue? Of course, in theory a third option is that CIRM simply ends when its current funding runs out, but to me that’s not a real option. CIRM cannot end because it has so much more to do and it is in some ways just getting to the most exciting part: the bedside part of the bench-to-bedside path. Update: over at California Stem Cell Report, David Jensen has the scoop on an industry-centric stem cell bond proposal idea.

New Prez. CIRM 2.0 President and CEO Randy Mills announced the surprising news recently that he’s moving on from CIRM after a relatively short, but impactful tenure. Who will be the new CIRM President? It’s anybody’s guess at this point, but I’d say that CIRM needs to achieve two things at once here: move very quickly to get a new leader and make that leader be a fantastic choice for CIRM. What exactly do I mean by the latter? The new CIRM President ideally should have impeccable stem cell credentials and also big picture clinical vision as well as strong leadership skills. I asked CIRM where things stand on the President search today and CIRM Sr. Director Public Communications & Patient Advocate Outreach, Kevin McCormack, provided this quote:

“the Presidential Search subcommittee is going to be meeting on July 17th to evaluate the options regarding appointing a permanent President and CEO to replace Randy. They’ll then make their recommendations to the full Board.”

I’m planning a future post to throw some names out on the table for discussion of people who might be considered for the position by CIRM.

Clinical POW! CIRM’s mission is focused on having transformative clinical impact so the agency needs some snap, crackle, and POW! on that front moving forward. It already has provided key support for a number of ongoing clinical trials and the goal moving forward is final approved products that are proven safe and effective. I would call that some stem cell POW! Not everything is going to be a success, but I predict that some will.

I believe that CIRM has the potential to achieve all this. That doesn’t mean it’ll be easy, but what great things have ever been easy?

Top 20 2017 stem cell predictions: score card at 1/2-way point

In December of each year I make a list of stem cell predictions for the coming year, and I made 20 such predictions for 2017 so I’m wondering how I’m doing so far on these now that it’s June. Below is my work-in-progress scorecard for these so far.

  1. Positive news from Asterias on trial for stem cell-based therapy for spinal cord injury. Status: Correct, trial looking encouraging.
  2. Upbeat news from ViaCyte on stem cell-based therapy trial for diabetes. Status: Correct, raising $10M and things looking promising.
  3. More positive news from the old Ocata now under Astellas umbrella on trial use of stem cell-derived RPE for Macular Degeneration. Status: Not Yet.
  4. Good news on the adult stem cell front on trials for one or more major diseases. At least one and probably more positive developments here. Status: Correct, lots of good news. The potential for stem cell generated blood is just one example.
  5. Fake news hits stem cell arena. Stem cell clinics use fake news. For instance, this might be a media mouthpiece for one or more stem cell clinics actively using fake news-like approaches to promote them. Status: Correct, unfortunately.
  6. More clarity on clinics: data. More academic publications on the practices and outcomes of stem cell clinics are published, bringing greater clarity to what is going on with actual data. Status: Not Yet.
  7. More lawsuits against stem cell clinics. There has been a lot of buzz on this behind the scenes already and cases popping up in 2016. This is going to grow in 2017. Status: Not Yet.
  8. Concrete clinic harms. We learn more about additional examples of patient who feel they’ve been harmed by American stem cell clinics including in particular alleged clinic-caused blindness. Status: Not Yet.
  9. Some other federal agency besides the FDA makes news on stem cells. This may not be until 2018, but we’ll see. Status: Not Yet.
  10. At least one FDA guidance is finalized. The FDA finalizes at least one of its four recent stem cell-related guidances, but probably not all four. Status: Not Yet.
  11. More than one warning letter. The FDA issues more than one warning letter to stem cell clinics in this year. Will it still be a drop in the bucket or some kind of decisive action? The FDA may have more difficulty taking action within the Trump context and much will depend on who is the new Commissioner.  Status: None Yet.
  12. Japan IPSC trial starts. Great news as at least one IPSC trial begins in Japan. Maybe two. Status: Correct.
  13. Cures yields regen med IND. The FDA takes at least one accelerated stem cell-related IND action traceable to the Cures Act related to a promising new stem cell/regenerative medicine therapy. Hopefully no direct to consumer businesses try to tap in. Status: Looking correct based on many RMATs granted.
  14. Athersys, Cytori, and Mesoblast have some ups & downs amongst them. Status: Correct.
  15. Prop 71 2.0. CIRM and/or Prop 71 supporters start more openly talking about a new round of CIRM funding. This may include mention of Trump as problematic for the stem cell field and the continuing need for California to take the lead. . Status: Correct. Will they pull the trigger though this year?
  16. Trump somewhat, but not entirely limits ES cell funding. The Trump administration probably does not outright ban federal funding of embryonic stem cell research, but there may be some effort to limit it in some way such as not supporting generation of new lines perhaps à la Bush.  Status: Not yet.
  17. Fetal tissue research restriction effort. The Trump administration and/or the GOP attempt to restrict human fetal tissue research.  Status: Not yet.
  18. CRISPR of human embryos is blocked or limited in some way in the U.S. (e.g. FDA is not permitted to review applications related to this area as was the case with the rider on spending bill for 2016).  Status: Not yet.
  19. Trump creates something like Bush’s President’s Council on Bioethics. It’s packed with conservatives including someone tied to the Witherspoon Institute. Deja vu all over again.  Status: Not yet.
  20. Florida acts on clinics. The state of Florida takes some action on stem cell clinics, which are out of control there. Things are a mess clinic wise here in California too, but I’m not so sure the state will do anything helpful to deal with it.  Status: Not yet.

Overall, I’m doing OK so far, but much is up in the air for the final 6 months of the year.