Loring Open Letter to CIRM: Continuing Shared Labs Will Keep California’s Stem Cell Edge

Jeanne LoringBy Jeanne Loring

As the California Institute for Regenerative Medicine (CIRM) celebrates its successes on its 10th anniversary, there is coincidentally a less happy CIRM-related event. One of CIRM’s first investments in stem cell research was a network of dedicated stem cell laboratories throughout California. This program, called “shared labs” has been cancelled.

The shared lab idea originated as a means for California researchers to work on human embryonic stem cells without compromising their funding from the NIH. CIRM invested a million dollars for each of 17 institutions to purchase equipment for a laboratory that would have the sole purpose of supporting human stem cell research, development, and training. They provided a modest stipend for support staff and instructors.

As with every bold idea, there were unexpected consequences. In this case, CIRM did not anticipate that the shared labs would have such an enormous impact beyond their original intention. Over the last 6 years they have existed, the labs have provided the infrastructure upon which California’s reputation as the center of the stem cell universe was built.

Unwittingly, CIRM’s shared lab program jump-started human stem cell research in California, sending it on a trajectory that has led to stem cell clinical trials in just 6 years. Far beyond being havens for embryonic stem cell research, the labs became the places where new technologies were developed and shared, where clinical projects were born, and where scientists carried out the necessary lab work for bringing a stem cell therapy to the clinic.

CIRM did not expect that there would be interaction among the labs that would make the whole greater than the sum of the parts. The network of shared labs became our means to communicate and share ideas. It sparked new partnerships between institutions throughout the state, and became a conduit for trainees to move from CIRM’s Bridges internships to graduate school. One scientist described the shared labs as “the beating heart of California’s stem cell program”.

Why would CIRM discontinue such a remarkably successful program with so many unexpected benefits?

The decision was made in 2013, and predates “CIRM 2.0″, the optimistic restructuring that recently breathed new life into the institute. It is being implemented by Randy Mills, who became CIRM’s president just a few months ago.

A year ago, CIRM’s future looked bleak. In December 2013, Alan Trounson was CIRM’s president, and he expected that CIRM would run out of money by 2017, if not sooner. At that month’s meeting of CIRM’s governing committee, called the ICOC (Independent Citizens Oversight Committee), all of the discussion was focused on the end game- how they would spend the last hundreds of millions left in their coffers.

Anticipating an attack on the shared lab program, scientists from 11 of the dedicated CIRM-supported stem cell labs traveled to that ICOC meeting in LA to plead the case for continued support of stem cell infrastructure. We were asking for a chance to reapply for stipend funds for the labs, which would cost CIRM about $350,000 per year for each lab. The transcript of that ICOC meeting is here (jump to page 205) and the blog I wrote about the meeting is here.

Some of the ICOC members found the scientists’ requests compelling, and understood the scientists’ concern that loss of the infrastructure would have negative impact on all aspects of CIRM’s mission, from training young scientists to supporting development of clinical applications for stem cells.

But, money was the main concern, and the decision came down to this: did CIRM want to retain the laboratory infrastructure or did it want to dismantle it and disperse the money to other projects?

The answer was clear to the researchers in the audience and the fact that we were all there was living proof that the shared laboratories had made us into a cohesive group throughout California. In addition, CIRM had already invested nearly $20 million just in the equipment for the labs, and millions more in training the personnel who run them.

One irony is that the NIH now funds a broader range of human embryonic stem cell research, so the original purpose of the labs no longer applies. But the NIH and other funders don’t pay for maintaining labs like these. That idea belongs to CIRM, which remains the only agency that fortuitously created a network of stem cell scientists.

A second irony is that having existing stem cell labs has been a boon for California. Institutions were able to attract an estimated $240 million from granting agencies and philanthropy for research based on the existence of the dedicated stem cell labs. This represents a tenfold return on CIRM’s investment.

In spite of our testimony, we lost. Alan Trounson didn’t pay attention to anything we said, and instead told us that the labs were a luxury that CIRM couldn’t afford, and that we should find other sources of money to pay our staff, perhaps turning the labs into for-profit service centers. We explained that we all had been trying to raise alternative funds for our laboratories for years, but there is concrete evidence that facilities like these just don’t exist in the US without subsidies from a granting agency.

Because of potential conflicts of interest, only 6 members of the 29-member ICOC could vote. Two of them (Art Torres and Diane Winoker) abstained; the other 4 voted to close the program.

What will happen now? One or two labs will be able to support their staff with other grant money and be able to keep their labs, although they will no longer be shared. Some will lose everything: the lab space, the highly trained personnel, and CIRM’s equipment.

The third irony in this story is that the ICOC voted in October 2014 to continue the Bridges internship program for another year, unaware, apparently, that closing the shared labs means there will be no labs in which to teach the interns and no trained personnel to teach them.

I know I speak for the majority of my colleagues when I say that the dedicated stem cell laboratory program was the key to establishing the rapid pace of stem cell research in California. Loss of the labs and their trained personnel will lose us the edge that made California uniquely qualified for stem cell success.

What can we do? We have a very specific request. We ask that CIRM consider one of the ideas raised by an ICOC member at the fateful December meeting: open a new request for applications to allow the shared lab directors to reapply for a competitive award. Since CIRM has already paid for the equipment, we need only to pay for upkeep and for our personnel who run the labs and teach courses to Bridges interns.

I’ve shared this letter with other lab directors; those listed below express their support for this letter.

Dennis Clegg

Peter Donovan

Susan Fisher

Linda Giudice

Arnold Kriegstein

Andrew McMahon

David Schaffer

Evan Snyder

Alice Tarantal

David Warburton

Karl Willert

The nonsensical list of stem cell journals

Stem Cell EnquirerThe list of stem cell journals seems to grow longer every day.

In fact, the list is so long and some of the names kind of funny that it inspires coming up with a slew of satirical and nonsensical stem cell journals.

I’m betting that some of these (the ones listed first) may be thought up independently by people to try to turn into real journals.

Some of these pseudo-journals have popped unjust  in 2014, which are shown in green.

 

The Nonsensical Stem Cell Journals List

  • Could be real someday?
  • PLoS Stem Cells
  • Stem Cell Sports Medicine
  • Stem Cells Digest
  • IPSC
  • Stem Cell Cosmetics (or Stem Cell Cosmetic Surgery)
  • De-Extinction
  • Steminess
  • Pluripotency
  • Potency
  • Stemomics
  • The Stem Cell
  • Super Silly
  • The Closed Journal of Stem Cells (by invitation only)
  • Stem Cell Fortune
  • Stem Cell Retractions (published weekly)
  • Stem Cell Practice of Medicine (no experiments or research here!)
  • Consumer Stem Cell Reports
  • Stem Cells Illustrated
  • Law and Order: SVF
  • Better Homes and Stem Cells
  • The Journal of Stem Cell Journals
  • The Journal of Stem Cell Duplicated Images
  • Stem Sells
  • Stem Cell High Impact Journal
  • Stem Cels (stem cells in animation)
  • Stem Cell Irreproducible Results
  • Costempolitan (focusing on hottest stem cell treatments of the famous)
  • Good Stem Cell Keeping (stem cell protocols that actually work)
  • Dancing with the Stem Cells
  • Stem Cell Shades of Grey (the sex lives of those ‘enhanced’ by stem cells)
  • Nature Stem Cells
  • Glamour Journal of Stem Cells
  • Cell Cell Cell
  • Stem Cell Data Already Published Elsewhere
  • The Beverly Hills Journal of Stem Cells
  • The Hot Journal of Stem Cells
  • Taste of Stem Cells (journal on stem cell-produced food recipes like burgers)
  • Stem Cells in the Hood
  • Sexy Stem Cells
  • Stem Cell Assays, Therapies, Reports, Studies, Reviews, and Essays
  • Self-Renewal (caution: the journal subscription always renews automatically)
  • Stem Cells Breaking Bad (the effects of drugs on stem cells)
  • American Journal of Stem Cells & Bioethics
  • Stem Cell Media & Medium (how to both grow stem cells and predict the future)
  • Cellular Deprogramming (from cultures to cults)
  • Stem Cell Irreproducible Protocols (reprints of published methods that won’t work)
  • iStem (only available on iPhone with proprietary Apple cable required)
  • Stem Cell Protocols and Recipes
  • Stem Cell Star
  • Stem Cells & Daughter Cells
  • Stem Cell Stem Cell
  • Stem Cellar (vintage collection of fine stem cell stories)
  • Stem Cells & Sons
  • Vatican Journal of Stem Cells
  • The Immortal Journal of Stem Cells
  • The New Immortal Journal of Stem Cells
  • Journal of Stem Cell Clinics
  • As the Stem Cell World Turns
  • People’s Journal of Stem Cells
  • Cloning Encounters of the Good Kind
  • Stem Cell Enquirer

Response from Drs. Braude & Lovell-Badge to My Letter on Mitochondrial Transfer/3-Parent Technology

The following is a response to my Open Letter to the UK Parliament on mitochondrial transfer/3-parent technology from Drs. Peter Braude and Robin Lovell-Badge.

Dear Professor Knoepfler,

We read your open letter to the UK Parliament and the Science and Technology Committee with interest and concern. We are two scientists, like you, with particular interests in genetics, stem cell and developmental biology and preimplantation genetic diagnosis, who were appointed amongst others to form a Panel of independent advisors to the HFEA and the UK Government on the subject of mitochondrial donation. You will no doubt be aware of the three main reports in the public domain, and the recent addendum to the third one, that have been published by this Panel[1]. Those reports are detailed examinations of the current available evidence on the possible use of mitochondrial donation procedures, and their safety and efficacy for severe mitochondrial disease. Unlike the FDA we did not consider the use of cytoplasmic transfer proposed for protracted infertility, nor did we consider the ethics, a task undertaken here by the Nuffield Council on Bioethics: Novel techniques for the prevention of mitochondrial DNA disorders: an ethical review[2].

Whilst we take no role in lobbying Parliament, we believe it behoves us to defend the findings as presented in our reports, and the advice that our Panel unanimously agreed should be put forward. In this regard we would like to take the opportunity to correct some of the misunderstanding about the processes in the UK, and to bring to your readers’ attention some of the information we considered in forming our opinions.

First, it is important to appreciate that the regulatory process in the UK by the HFEA is different from that in the USA as demonstrated in the FDA hearing. In contrast to the USA where there is no federal regulation of IVF technology, in the UK we have specific legislation that deals with the use of gametes and human embryos in vitro (HFE Act 1990)[3] wherein, after thorough debate during the 2008 amendments to this legislation, specific provision was made that could allow in prescribed circumstances, processes to be applied to an egg or embryo designed to prevent the transmission of serious mitochondrial disease (Section 3ZA(5)). This clause would come into force if allowed by Parliamentary regulations, which are soon to be the subject of the vote you comment upon in your blog. However, even if passed, these Parliamentary regulations would not allow any trial to take place in the UK until the regulator (the HFEA) felt that there was sufficient safety and efficacy information to do so; this is in contrast to the FDA’s Cellular Tissue and Gene Therapies Advisory committee hearing which addressed deliberations on permitting a clinical trial. Thus these Parliamentary regulations are in essence ‘enabling legislation’ which would simply take the UK onto the same footing as the current situation in the USA, where safety and efficacy data determine whether clinical application should be allowed. We are therefore not rushing ahead of the USA, and the same issues that concern you and the FDA committee are those that exercised us in our deliberations.

Second, the main difference with the UK approach so far is that rather than spending a day and a half of public presentation and debate to include genetic disease, infertility and ethics, we have spent over three and a half years examining in detail published and also as yet unpublished evidence[4], interviewing those involved with basic and clinical mitochondrial science (including Evan Snyder whom you quote), and holding round table discussions with those ‘at the coal face’ of mitochondrial replacement techniques; we allowed opponents of the technology the opportunity to present their cases in person and included them in our discussions. We have thoroughly examined the ‘more specific risky elements to the proposed experiments’ as suggested by Burgstaller, Dowling, Reinhardt, Morrow and others, and have produced detailed comment in our 2014 report, and have published a rebuttal [5] of the New Scientist article warning about three-parent IVF that you quote. In our 2014 report, we suggested that, where practical, the use of haplotype matching could overcome some concerns, and have taken a view in balancing the theoretical risk of harm against the inevitable inheritance of a serious genetic mutation whose effects and expression are variable and unpredictable, including death, or lifelong disability and the inevitability of transmission along the female line.

We are also concerned in the mistaken general belief that PGD is a panacea for couples with mtDNA mutations – although you yourself acknowledge it is not suitable for all. Although it can help those with mitochondrial disorders of nuclear origin, for those with mtDNA mutations, there are some who have such high levels of heteroplasmy (or homoplasmy) that the likelihood of finding an embryo for transfer with an acceptable mutation level is very low if not impossible. Moreover, it is clear that in many cases of PGD for mtDNA disorders, embryos selected for replacement have a significant heteroplasmy for the mutant gene, much in excess of that being expected for mitochondrial replacement. In these cases, all the concerns being levelled at the risks of carryover of mutant DNA apply here too, but are not mentioned in the arguments put forward against mitochondrial replacement.

We are of the view, and have expressed such to the Select Committee, that most concerns about mitochondrial replacement are based on expecting a near zero tolerance for risk, especially where alternatives might exist. For couples with mtDNA mutations, there are no alternatives that allow the couple to have genetically related children free of mitochondrial disease. No medical first-in-man technique is ever without risk, whether this be heart or kidney transplants, or the first IVF or the first embryo biopsy for preimplantation genetic diagnosis. The risk of treatment must be balanced against the certainty of adverse outcome without.

Yours,

Peter Braude PhD FRCOG FMedSci

Robin Lovell-Badge PhD FMedSci FRS

 

[1] http://www.hfea.gov.uk/8807.html

[2] http://nuffieldbioethics.org/project/mitochondrial-dna-disorders

[3] http://www.legislation.gov.uk/ukpga/2008/22/contents

[4] All the non-confidential evidence we received is available on the HFEA website1.

[5] Mitochondrial replacement: no need for a rethinkhttp://www.newscientist.com/article/dn26400-mitochondrial-replacement-no-need-for-a-rethink.html?cmpid=RSS|NSNS|2012-GLOBAL|health#.VGNYVL7gZj4

Weigh in on Shirtgate with Poll

A male scientist, Dr. Matt Taylor, who is a leader of the Rosetta comet space mission team wore a shirt covered with cartoon depictions of scantily clad women (you can click on picture of Taylor to see a larger version of the image) during a TV interview.Rosetta Matt Taylor T-shirt

Some people found the wearing of the shirt to be very negative, while others found the reaction to the wearing of the shirt to be the problem instead. Some people’s feelings fall in between.

There has been intense discussion ever since and taken together this all has been termed “Shirtgate” and “Shirtstorm”.

How do you feel about this turn of events?

Take our poll below. Please also weigh in in the comments section.

 

Summaries of WAFSF super stem cell vision talks: Hinton, Tsukamoto, Klassen, Takahashi

Recently I was at the World Alliance Forum in San Francisco (WAFSF), a great meeting on stem cells and regenerative medicine. WAFSF had some excellent talks and I saw one session on the use of stem cells to treat vision impairment that was particularly striking.

This session’s all-star lineup included Drs. David Hinton, Ann Tsukamoto, Henry Klassen, and Masayo Takahashi. I’m going to summarize the talks below with permission of all speakers. Note that these summaries are based on rapidly scrawled notes. Together these talks show just how far the translational stem cell vision field has come in the last few years and the very real promise for the coming years in this area for major clinical impact.

David HintonThe session began with Hinton (pictured at left in USC photo) from the Project to Cure Blindness at USC, who spoke about research on treating geographic atrophy using retinal pigmented epithelial cells (RPEs). Hinton’s stem cell device is a polarized RPE monolayer. The team places 100,000 RPEs made from human embryonic stem cells (hESC) on a parylene membrane. My impression was that they are using H9 hESC for the preclinical studies, but I’m not 100% sure.

He indicated that because of the membrane there is no significant cellular migration, but there is PEDF and VEGF secretion and the RPEs appear resistant to stress. Are the RPEs functional? It seems so as there is rhodopsin phagocytosis.

For the studies he discussed, they used the RCS rat model of retinal degeneration of which there was a partial rescue by hESC-RPEs and encouragingly from a safety perspective, no teratomas.

Surprisingly, control parylene alone without cells has some rescue function, but with RPE there was substantially better organization and electrical function. One kind of cool thing from a techno perspective is that they invented a special delivery tool that gently folds the RPE sheet for insertion into the eye upon which it unfolds. It looked like it worked like a charm based on a video shown.

What does the future hold for this project?
They hope to file an IND within a few months and the target for starting a clinical trial is 2015. There was a question from audience on IP navigation. They have a license deal with WARF and they are aware of the ACT patents (now known as Ocata Therapeutics), which presumably will need to be addressed in some fashion such as licensing. Another question was on residual undifferentiated ESC. Shouldn’t be a problem, he said, because the special media that they use causes ESC death.

 

The next talk was from Ann Tsukamoto of StemCells, Inc.

They are studying the use of human CNS stem cells for treating dry eye AMD. These cells are called HuCNS-SC. After transplantation in mice the cells engraft and migrate. In RCS rats there is loss of RPEs and then 2ndary loss of photo receptors. HuCNS-SC transplanted at P21 migrate well (there’s no matrix). With transplant of HuCNS-SC they see maintenance of photoreceptors and visual acuity. What is the mechanism?

Ann Tsukamoto
One is suggested by the observation that the cells have phagocytosis function and debris is absent. They hypothesize that as a result there is preservation of synaptic connections. They have a combined phase I/II trial going, which includes a 3-month immunosuppression regimen. They have done 6-12-month follow up on 7 patients and found encouragingly no cell-related safety concerns. Best corrected visual acuity (BCVA) improved in 2 study eyes, but also in 1 control eye. They found that 6/7 treated eyes had 70% reduced geographic atrophy. I’m curious to see how this work goes as it continues to develop. HuCNS-SC may have utility to treat other diseases as well.
Henry Klassen                                                   Henry Klassen from the Gavin Herbert Eye Institute at UC Irvine spoke next (photo from UCI). Klassen’s team is studying the use of fetal retinal progenitor cells (RPC) for treating retinitis pigments (RP).
In RP there is loss of photoreceptors and loss of cones by bystander effect, Klassen said. Because of the importance of cones, the goal is to try to rescue them. This team produced their stem cell-based product here at UC Davis in the GMP facility. The RPCs, which are not immunogenic, are injected into the vitreous. They used the same RCS rat model as the first two speakers. They transplant the RPC as a single cell suspension but cells aggregate after transplant into neurospheres that float around in the vitreous and secrete cytokines. It’s like a floating pharmacy (my analogy). They observed that the RPCs rescue rods and cones in rat.
 jcyte
Their goal is to have an IND before the end of the year. They have done the work in part with funding from CIRM and interestingly have founded a company called jCyte. One pretty neat additional point was that this therapy has the potential for treating AMD too and would be complimentary with other types of therapies such as those mentioned by the first two speakers. I didn’t have a have chance, but I had hoped to ask Klassen if they thought that patients would be able to see (or not) the neurospheres like little floaters in the eye.

 

Masayo TakahashiThe final speaker of the session was Stem Cell Person of the Year, Masayo Takahashi, from RIKEN. She spoke about using RPEs made from human induced pluripotent stem cells (IPSC). She discussed treating wet AMD with the RPEs. I understood that to make IPSC they used the episomal vector approach.

They started with 24 IPSC lines, then picked the top 6 and then 3 of those lines were used to make the RPEs using a 4-month differentiation period. Of the original 6, it was notable that despite using an episomal vector, in one there was a plasmid remnant. So for all you folks out there using “transient”, “non-genetic” methods, one lesson here is to be sure to do the needed testing and validation of human IPSC lines.

They then pick pigmented clones and made sheets. It’s a lengthy and expensive process with one of the biggest expenses being the facility itself, which costs ~$500K/year just to run.

For safety testing and validation, they did their Lin28 PCR assay for residual IPSC as well as whole genome sequencing. In addition, no tumors were observed.

The RPE product, a 1.3 x 3 mm wide device, was just transplanted recently into the first human AMD patient. I think everyone is on the edge of their seat in this field to see how this clinical study progresses.

Looking to the future, Takahashi mentioned that allogeneic transplantation is an option and teams are moving in that direction. An IPSC cell bank with a variety of HLA types could be helpful to many patients in an allogeneic manner.

She also discussed the regulatory situation in Japan including the novel concept of adaptive licensing (see below the overview of the current regulatory system in Japan).

Japan stem cell regulatory system

She mentioned that it is a fast system, but acknowledged that it has risks too. She also said they are planning photoreceptor transplantation in 5 years for RP.

Overall these four talks were very encouraging for the future of treating various forms of vision impairment using stem cells.