Holding Institutions Responsible for Research Misconduct: the recent case of a death of stem cell scientist

Zubin MasterBy Zubin Master

Scientist Yoshiki Sasai, age 52, committed suicide and was found dead on August 5, 2014. Sasai was deputy director of the Center for Developmental Biology (CDB) at RIKEN in Kobe, Japan, and coauthor on two recently retracted Nature papers about a reportedly easier way to make induced pluripotent stem cells. The papers were retracted due to duplication and manipulation of images done by the main researcher and lead author on the two papers – Haruko Obokata. Although cleared of any direct involvement, Sasai was under immense pressure and heavily scrutinized by the media, public and peers. This involved speculation about Sasai’s alleged intentions to orchestrate a media frenzy, and for being overly ambitious and motivated to win future grants overlooking the integrity of the science.

According to colleagues at RIKEN, Sasai was receiving counseling since the scandal broke headlines and he was also hospitalized for about a month in March (1). He was ultimately found hanging in a stairwell of a neighboring building close to the CDB and beside him were three letters addressed to CDB management, his laboratory, and Obokata. On August 12, Kazuhiro Nakamura, the family lawyer explained the contents of Sasai’s suicide note left for the family. Sasai was “worn out by the unjust bashing in the mass media and the responsibility he felt towards RIKEN and his laboratory” (2). But unsubstantiated claims in the media were not the only source of stress for Sasai. The speculation in tabloids might have also influenced how RIKEN and other colleagues behaved towards Sasai. In June, a report released by an independent RIKEN reform committee criticized CDB leaders for hyping the science and did not interview Sasai about such accusations. Their final recommendation was to dismantle CDB. According to the family lawyer, this was a tremendous shock for Sasai (2).

In this blog, I want to discuss the responsibilities research institutions have over research integrity and misconduct. Zimbardo’s Stanford prison experiments (3) and other social psychology research has taught us that ethical behavior is not only shaped by dispositional attribution (an internal moral character), but it is also influenced by many situational (environmental) features. Similarly, our understanding about the causes of research misconduct is shifting from the idea of a few “bad apples” to the realization that the immense pressure to publish and translate research findings, and poor institutional support are factors that influence research misconduct. This is not to excuse misbehavior by researchers; rather, it is about moral responsibility, and research institutions are also accountable in cases of research misconduct. While scholars on research integrity are aware of the responsibility of research institutions, the institutions themselves have taken few measures to promote research integrity and prevent misconduct; they remain virtually blameless in high profile cases of research misconduct (4). The tragic death of Dr. Yoshiki Sasai should cause us to consider the role of institutions. How well do research institutions handle investigations? Do they take measures to protect researchers and others involved in the case? How do institutions promote research integrity and prevent misconduct? I think the short answer to these questions is that institutions still do the minimum to promote the responsible conduct of research and likely react punitively to individual researchers by removing the supposed bad apples and then taking minimal corrective measures. This institutional myopic view of research misconduct needs to change, and institutions need to be held morally accountable along with scientists who commit misconduct.

The Case

There has been no shortage of news surrounding misconduct in stem cell research even beyond the STAP situation. I have given lectures to science trainees in stem cell research (5) and blogged about several relatively recent scandals (6; 7). The pattern of misconduct seen in stem cell research might be due to the heightened attention it receives in the media and interest by the public. Moreover, ways to detect misconduct are becoming relatively more widely used by journals and other scientists, and publishing in top-tier journals like Science and Nature certainly draws attention.

In January of this year, Haruko Obokata in the CDB, RIKEN reported that she was able to convert mouse cells to a pluripotent state simply by exposing cells to stress, the procedure called stimulus triggered acquisition of pluripotency (STAP). Soon after its publication, allegations of plagiarism, and figure manipulation and duplication were reported. Additionally, other researchers were unable to reproduce the STAP experiments. In April, an investigative committee at RIKEN found Obokata had committed research misconduct. While she admitted to being sloppy, Obokata continued to defend the results. The investigative report also concluded that while Sasai was not directly involved in misconduct, he bore “heavy responsibility” (8). A reform committee, chaired by a University of Tokyo emeritus professor Teruo Kishi, faults Sasai and a former CDB researcher, now at another university, for accepting Obokata’s data without question or further examination (9). The reform committee found that inadequate oversight extended to the highest leadership of CDB due to the desire for a major breakthrough and the committee recommended that CDB be completely reformed.

It is evident that Yoshiki Sasai, a leader in the scientific community and at CDB, was under massive pressure. I will neither speculate on the toll this incident had on Sasai or whether the investigation was handled well and the recommendations sound. Instead, I want to shift focus to look more at the research environment scientists work in more generally and consider what research institutions do (or can do) to promote research integrity.

Shifting the Culture of Science.

The espoused norms of science we learn in the past seem incongruent with current practices today. The ideals of science – openly sharing materials/methods, being motivated by discovery and not personal gain, judging one’s own work and others rigorously through strict standards – are being replaced with secrecy, self-promotion, and fierce competition (10, 11, 12). Competition in science creates a pressure to publish, and perhaps more recently to translate and commercialize research (13, 14). A recent survey by New Scientist reported that of 111 stem cell scientists who responded, 56% felt stem cell research was put under more intense scrutiny than other areas of biomedical science, and of those that replied positively, 56% said that this affects their work (15). Moreover, almost 17% of the stem cell researchers reported that they felt pressure to submit a paper for publication they believed was incomplete or needed verification. Combining the pressure to produce results in a hyper competitive and a bleak job market creates a stressful environment for anyone. It remains empirically unclear however, whether such a competitive environment is a recipe for research misconduct. Given the culture of science today, what are institutions doing to create a healthier environment?

Globally, several research institutions promote research integrity but differ in their approach. Some have robust policies, training, and provide resources while I suspect many only have a suite of policies and a non-transparent mechanism to address allegations of misconduct. I believe research institutions can do several things to promote research integrity and help prevent misconduct.

For starters, institutions can raise awareness and help promote a culture of research integrity by educating trainees, faculty, and research administrators and staff. Education can provide scientists with the tools they need to deal with ethical issues in a constructive manner when they arise. Michael Kalichman explains that the primary goal of education should be to “foster a research culture in which conversations about the responsible conduct of research are expected and acceptable” (16). Efforts to restore and rehabilitate researchers found to engage in misbehavior is likely going to incorporate education as part of the program. Education about the responsible conduct of research needs to be more than a minimum requirement scientists have to undertake and institutions are obligated to offer.

In addition to fostering a culture of integrity, some scholars advocate that research institutions can perform random or for-cause (when misconduct is suspected) data audits (17). However, it seems scientists have little appetite for such audits because they fear it would inhibit scientific freedom, and be burdensome and costly. While there is virtually no evidence to demonstrate whether such a policy decreases research misbehavior within an institution, it does not have to be a taxing effort on scientists or research administration (17).

Institutions should further make transparent a mechanism of how allegations should be handled, but also to provide resources like an ombudsperson as trusted broker for researchers to confidentially discuss potential problems amicably prior to raising a formal allegation requiring investigation. And if a formal investigation is needed, institutions must make serious efforts to ensure there are no reprisals against the complainant, witnesses, investigators, or the accused. In cases where scientists are under tremendous duress during an investigation, appropriate accommodations for researchers should be made.

UC San Diego is one example of an institution that has made significant efforts to promote the responsible conduct of research by having several research ethics policies, a hotline to report research fraud, a transparent mechanism to address potential allegations, and providing courses, seminars and resources to faculty and students (18). The tools are available – university and college administrators need to seek them out and implement them at their respective institutions.

Empirical research on institutional integrity climates is beginning to be performed (19). While journals, funding agencies, integrity scholars, scientific societies and other players can all do their part to promote a culture of research integrity, research institutes are well poised to promote integrity not only within their organization, but also to the larger institution of science. Research institutions should do more than simply remove the “bad apples” as they too bear some moral responsibility over research misconduct.

Acknowledgements: I would like to thank Dr. Paul Knoepfler, Ms. Lisa Willemse, and Ms. Tina Muratovic for helpful feedback.

This piece was also co-posted at the AMC blog and on the Signals blog.

Guest Post was written by Dr. Zubin Master, Assistant Professor at the Alden March Bioethics Institute, Albany Medical College and Research Associate at the University of Alberta’s Health Law Institute.

Web Links

1. http://www.japantimes.co.jp/news/2014/08/05/national/embattled-stap-study-co-author-dies-after-apparent-suicide-bid/#.VADIBE10ymQ

2. http://www.nature.com/news/stem-cell-pioneer-blamed-media-bashing-in-suicide-note-1.15715?WT.ec_id=NEWS-20140819

3. http://www.prisonexp.org/

4. http://mitpress.mit.edu/books/research-misconduct-policy-biomedicine

5. http://ori.hhs.gov/images/ddblock/march_vol22_no2.pdf

6. http://www.signalsblog.ca/rush-to-publish-and-the-repercussions-of-carelessness-in-science/

7. http://www.amc.edu/BioethicsBlog/post.cfm/not-another-stem-cell-scam-alleged-fabrication-false-affiliation-plagiarism-and-poor-publication-ethics-all-in-a-single-shot

8. http://www.nature.com/news/research-integrity-cell-induced-stress-1.15507

9. http://news.sciencemag.org/asiapacific/2014/06/japanese-stem-cell-debacle-could-bring-down-center

10. http://jama.jamanetwork.com/article.aspx?articleid=194592

11. http://www.ncbi.nlm.nih.gov/pubmed/12712166

12. http://www.jstor.org/discover/10.1525/jer.2007.2.4.3?uid=2129&uid=2&uid=70&uid=4&sid=21104081253391

13. http://genomemedicine.com/content/1/2/22

14. http://genomemedicine.com/content/4/2/17

15. http://www.newscientist.com/data/doc/article/dn25281/stemcellsurveypdf1.pdf

16. http://www.ncbi.nlm.nih.gov/pubmed/24073608

17. http://www.tandfonline.com/doi/abs/10.1080/08989621.2013.822259?journalCode=gacr20#preview

18. http://blink.ucsd.edu/research/policies-compliance-ethics/responsible-conduct.html

19. http://link.springer.com/article/10.1007%2Fs11948-012-9409-0

Given a do-over, would you still go to grad school again? Take our polls

Science is a wonderful field to be in, but there are many challenges too and in some ways things have gotten more complicated and difficult.

Below are four polls for people already with M.S.s or Ph.D.s in science.

Knowing what you know now, would you still go to grad school if you could do it over again?

If so, why?

if not, why not?

Also please let us know your current job position. Update: Note that I should have included “postdoc” as a separate category, but I messed up and the poll is already well underway. I imagine most “other” votes are postdocs.

StemCells Inc. leadership interview: Pipeline, Financials, IP Conflict with Neuralstem, CIRM, & more

GregSchiffmanStemCells, Inc. is a top biotech company developing stem cell-based therapies. They have a deep pipeline that includes already ongoing trials for a variety of diseases. I invited company leadership to do an interview and they graciously accepted.

Below is the interview with CFO Greg Schiffman (picture at left from LinkedIn) including what I thought were some tough questions from me and very detailed answers from Shiffman. Thank you, Greg.

1. Where does the company stand today in terms of product development, capitalization, and such? What are its strengths? What are potential areas for improvement or development?

We currently have three active programs underway two clinical and one pre-clinical.  The two clinical programs are in the spine, spinal cord injury (SCI), and in the eye, dry age related macular degeneration (AMD), and the pre-clinical program is in the brain focused on Alzheimer’s disease.  Both clinical programs have completed enrollment of the Phase I/II clinical trials and we have plans to initiate controlled proof of concept Phase II studies in both indications in the second half of this year.  Both indications have large unmet medical needs.  We have released interim results for both of the Phase I/II programs.  We have not seen any safety issues associated with the cells.  In addition, we have seen preliminary signs of efficacy in both programs.  Our pre-clinical efforts are focused on filing an IND for Alzheimer’s disease in 2016 following which we could move this program into the clinic.stemcellsinc-logo

We just completed a $20 million gross equity financing.  If you include the proceeds from the equity financing and warrant exercises that occurred in the month of July, the company had approximately $37.8 million dollars of cash and marketable securities at the end of June.  This provides us with a strong balance sheet to move our programs forward.

We believe that we have a unique platform utilizing our proprietary HuCNS-SC® human neural stem cells that have the potential to address numerous indications affecting the CNS.  This would include white matter brain disorders such as leukodystrophies, multiple sclerosis, cerebral palsy and transverse myelitis.  Other potential indications could include Alzheimer’s, spinal cord injury, dry age-related macular degeneration and centrally mediated lysosomal storage disorders.  We have performed pre-clinical work in many of these indications and we have selected one indication, where there is a large unmet medical need, in each major organ of the CNS the brain, eye and spine to pursue clinically.  The cells have shown a very favorable safety profile and all of the pre-clinical and clinical findings have shown signs of efficacy.  This is a very exciting time for the Company as we are now rapidly generating a significant amount of clinical data which will help to provide much greater insight into the potential clinical benefit we can bring to patients.

2. What unique challenges does the stem cell/cell therapy/regenerative medicine biotech sector face overall say compared to a pharma company producing a chemical-based drug and how is StemCells, Inc. approaching those hurdles?

Anytime you are pursuing a new therapeutic paradigm you encounter additional regulatory hurdles and scientific scrutiny.  StemCells, Inc. has very methodically pursued the science.  We have published all of our work so that others can critique the findings.  It has taken a significant amount of time and resources pursuing the science to understand the potential of the platform we are building.  However, it enabled us to move forward with our clinical programs on a very strong scientific foundation.  In addition, given the nature of our cells which engraft into the host, replicate, migrate within the host and differentiate into the cell types associated with the CNS, our early clinical trials faced significant safety hurdles as this was the first time that these cells would be transplanted in humans.  The first indications had to be fatal diseases and the subjects were in the most advanced stage of the disease.  In addition, we were limited to one surgeon and a single site for patient recruitment.  We would treat a patient following which safety data was generated and submitted to the FDA for review.  After review we were able to begin looking for the next patient to be transplanted with the cells.  The clinical trials moved forward very slowly given these hurdles.  However, given the favorable safety profile we have shown in both the spine and eye, as well as the favorable safety profile demonstrated in our previous clinical work in the brain for both Batten disease and Pelizaeus-Merzbacher disease (PMD), we are now able to proceed forward at a much more rapid pace, consistent with other biologic clinical trials, with our Phase II studies.  In 2015 we plan to have between 10-15 sites enrolling patients for each of our clinical programs and expect to be able to complete the enrollment in about one year.  As we continue to move forward with the clinical efforts, and hopefully to an approved therapeutic, we expect that there will be additional hurdles to overcome including physician and patient education on this new platform of stem cells.  This is an exciting opportunity; and we are comfortable in our role as pioneers breaking new ground.

3. How important has CIRM funding been for StemCells, Inc.?

StemCells, Inc. has spent over a quarter of a billion dollars pursuing our science.  This includes pre-clinical and clinical work as well as building out our manufacturing capabilities.  We have completed two Phase I/II clinical trials in fatal childhood brain disorders, PMD and Batten’s disease, have two active Phase I/II clinical trials ongoing in SCI and AMD, and are about to initiate two Phase II controlled studies in each of those indications.  All of this has been funded by the Company.  We are also working to file an IND in Alzheimer’s disease.  This would enable the company to begin clinical trials in this indication.  CIRM is funding half of the expected costs for filing the IND in Alzheimer’s in the form of a forgivable loan.  The total funding from CIRM for this effort is up to $19.3 million dollars.  This investment was important for the Company to be able to pursue this activity in parallel with the other clinical programs we have underway.  As a small biotech we need to prioritize investments and without this funding this program would be on hold while we pursued our other clinical programs in spinal cord injury and dry age related macular degeneration.  CIRM’s decision to fund half of the costs of the IND is allowing us to pursue this activity today.  This accelerates the timeline for a potential therapy for this disease that affects so many people.  Should the program be successful, CIRM will see a significant financial return on the investment.  However, if you look at the investment that has been made in our platform technology and the ongoing clinical investments we are making, the $19.3 million from CIRM, which is to be disbursed over the next four years, to help fund half of the costs of filing the IND in Alzheimer’s disease is very important to the timing of our Alzheimer’s disease clinical program but not to the overall clinical agenda StemCells is pursuing.

4. Which of your products/programs are closest in the pipeline to getting to patients? What excites you the most?

Our two most advanced programs are the SCI and AMD programs.  We are very excited about both of these programs and the potential they may bring to dramatically affect patients afflicted by each indication.  We believe that the AMD program is probably the program that will move forward the fastest given the number of people affected by the disease and the nature of the treatment.  The interim results we presented at the International Society for Stem Cell Research (ISSCR) showed very promising early signs of clinical benefit.  We showed a 70% reduction in the rate of geographic atrophy.  Geographic atrophy is the progressive loss of two important retinal tissue layers, the photoreceptors and the retinal pigmented epithelium.  Degeneration of the macula is the cause of vision loss in dry AMD.  We also saw an improvement in visual acuity in 4 of the 7 patients as evidenced by their ability to detect differences in light and dark referred to as ‘contrast sensitivity.’ These results exceeded our expectations.  We will have final results from this study next year and, based upon the strength of both the safety and efficacy findings, we are initiating a Phase II controlled study in AMD later this year.

We are also encouraged by or SCI program.  We have seen clinical benefit in our Phase I/II trail where patients are seeing multi-segmental gains and a return of function in the cord in half of the patients. This indicates that something that was not working in the spinal cord, now appears to be working following transplantation. This is even more significant because of the time that has elapsed from the date of injury, which ranges from 4 months to 24 months across the subjects with sensory gains.  Our next study in SCI will occur in the cervical or neck region.  This is the section of the cord that controls motor function of the upper extremities.  The cervical cord directly controls motor function of the upper extremities.  Thus, these patients may represent a population in which regaining, or enhancing, upper extremity motor function may be more readily anticipated.  Even a gain of one to two motor segments in the cervical spinal cord could allow for additional function in the upper extremities. No one has been able to run a study using stem cells in this patient population previously.  Given the safety profile of our cells in the previous SCI study where we recruited patients with thoracic injuries, the FDA is now permitting StemCells to enroll patients with cervical spinal cord injuries.  This has the potential to significantly improve the quality of life for victims of SCI and at the same time reduce the overall cost to the healthcare system.

5. Besides HuCNS-SC, do you have other cell products in the works? Does the company have interest in reprogramming and iPS cells? ES cells? Adult stem cells such as MSCs?

All of our current clinical efforts are leveraging our HuCNS-SC human neural stem cells platform.  We have performed pre-clinical work using a proprietary platform of human liver stem cells, however, in order to focus our efforts we are not actively pursuing this technology at this point in time.  We think our HuCNS-SC cellular platform has tremendous potential and we want to move or AMD and SCI clinical programs forward as rapidly as possible.  Nevertheless, we are constantly evaluating new technologies that we think have potential as this remains a constantly evolving field.

6. There has been quite a bit of discussion in the media and on social media about former CIRM President Alan Trounson joining the board of StemCells, Inc. shortly after departing from CIRM. Can you comment on this situation and perhaps clarify the realities of this situation as there has been a fair amount of speculation about this?

We are not prepared to provide any additional information beyond the public comments the Company has already made, except to say Dr. Trounson is a very accomplished leader in the stem cell field and we are delighted to have him join us as a director.

7. A former employee of StemCells, Inc. has filed suit against the company and made certain allegations. I am not going to ask you about that suit specifically (unless it is something you want to discuss), but I wanted to give you an opportunity to talk about the  steps the company takes for handling its cells and products, quality assurance, GMP practices, and such. Can you please tell us some of the ways by which the company maintains standards for its products? How confident are you in your products?

We are very focused on the processes we use to manufacture our products.  You should know, the elements of manufacturing practices that concerned Mr. Williams were immediately and carefully reviewed by the Company.  The Company’s primary concern has always been, and will continue to be, the safety and tolerability of stem cell transplantation in its clinical trials. Over the years, we have consulted with multiple experts in the field and we believe our processes, procedures and controls, as fully described in our regulatory filings, are appropriate for a company at our early stage of clinical development and comport with applicable guidelines and regulations.

8. Can you tell us some about the IP portfolio of the company? Are there elements that you are particularly excited about? What is the situation with Neuralstem in a nutshell on the IP front?

We have established a strong base of intellectual property surrounding human neural stem cells.  In addition, in 2013 we further strengthened our patent portfolio with the outright acquisition of previously licensed patents from Neurospheres Holdings in addition to the acquisition of a number of patents from NsGene which complement our portfolio.  The patent portfolio from Neurospheres, which was based upon the groundbreaking research by Samuel Weiss and Brent Reynolds at the University of Calgary, has repeatedly been recognized as the seminal intellectual property pertaining to purified populations of human neural stem cells.  Today, we believe we have the broadest and deepest IP portfolio of any company in the neural stem cell space.

StemCells has been engaged in a long-standing patent infringement suit against Neuralstem, Richard Garr and Karl Johe.  Our suit alleges infringement of six patents, owned by StemCells, claiming populations of human neural stem cells, their proliferation and their use, inventions arising from the groundbreaking work of Drs. Samuel Weiss and Brent Reynolds while at the University of Calgary.

We are pleased that recently the judge in the case denied Neuralstem’s motion for summary judgment and moved us one step closer to a final resolution in the case by scheduling the first part of the trial to begin this December.  It is certainly welcome news that our case will finally have its “day in court.”  In light of the judge’s rulings, we can anticipate trial on the merits next year and, I sincerely hope, a speedy and final resolution of our various patent and business tort claims against Neuralstem.

It is important to understand why we filed this lawsuit in the first place.  Over the years, StemCells has made a considerable investment in its patent portfolio, which now consists of dozens of issued patents worldwide.  Both the Company’s Reynolds and Weiss patents and its other patents, whether owned or exclusively licensed by StemCells, have been licensed out, on a non-exclusive basis, to several companies for sizeable licensing revenues in return for freedom to operate.  Our SEC filings describe these patents and our licensing activities in detail.  The Company’s proprietary cells, the HuCNS-SC cells, are protected by multiple patent families held by the Company. This lawsuit is not about StemCells’ freedom to operate, there are no claims of infringement against STEM; but it is challenging Neuralstem’s freedom to operate and we seek injunctive relief and substantial damages from them.  We contend that Neuralstem has willfully infringed our intellectual property and we owe it to our shareholders to do everything in our power to protect the investments we have made, on their behalf, in this groundbreaking neural stem cell technology.  We look forward to the prospect of presenting our evidence and our arguments to the judge and jury.

9. The stock has had a bit of tough month in terms of PPS. What would you say to the average shareholder out there?

There is always a lot of noise when you are pioneering breakthrough new technologies.  We think that there are areas investors should look at carefully to help guide their investment decisions. First, StemCells has attracted a world-class team of professionals, with the experience and expertise needed to drive success.  Second, our clinical trials have attracted partnerships with world-leading researchers, hospitals and institutions.  Third, StemCells holds a wealth of valid patents that protect our technology.  Fourth, we are rapidly accruing clinical data that validates the findings of our preclinical models. Two of our clinical programs addressing major medical conditions (SCI and AMD) are rapidly advancing towards controlled Phase II trials. Risk decreases with each regulatory milestone reached.  Fifth, StemCells has a sound balance sheet and a strong cash position.  Sixth, our diversified clinical program addresses multiple major medical conditions affecting large populations, two of which (AMD and Alzheimer’s), target aging populations that are rapidly increasing around the world.  There is short term volatility in micro-cap stocks, often associated with noise unrelated to clinical progress and clinical outcomes.  We believe that we are well positioned and have a very exciting platform technology that has the potential to address many conditions of the CNS that have not been able to be addressed by traditional approaches.  Should we be successful in moving one or more of these programs forward, we believe that there is significant value creation potential for our shareholders.

10. What’s your outlook on the future for the company? Are you optimistic? Where do you see StemCells, Inc. in say 5 and 10 years?

I am very optimistic about the potential for StemCells, Inc.  We have spent over 15 years pursuing the science and early stage clinical trials.  This has been done very methodically, which was important to establish a strong foundation for our late stage clinical work.  We are now at a stage where we will quickly generate significant amounts of clinical data providing much greater insight into the potential of our platform technology.  Over the next five years we would expect to have final results from our ongoing Phase I/II studies in SCI and AMD as well as final results from the Phase II studies we plan to initiate later this year.  In addition, if we continue to see results consistent with our interim clinical findings,  we should be well underway with our pivotal Phase III registration studies.  This is truly an exciting and transformative period for the Company.  If the technology is successful in the Phase III studies, in 10 years we could have multiple approved clinical products on the market.  The Company would actively be pursuing additional clinical programs, using our HuCNS-SC platform, to address other unmet medical needs in the CNS.  It would also be pursuing some of the other exciting technologies that we are investigating today.

Slowly Removing the Mask of the Phantom of the Stem Cell Opera: BioGatekeeper

BioGatekeeperThe technology to change just about any human cell into a super powerful kind of stem cell called induced pluripotent stem cells (iPS cells or iPSC) has great potential not only to help millions of patients, but also to make companies millions or even billions of dollars.

Many scientists have been on the trail of cellular reprogramming, as this process of making powerful stem cells is called, but it was Dr. Shinya Yamanaka who finally got it to work first and the predominant intellectual property in this area so far has been the so-called “Yamanaka Patent”.

A mysterious organization called BioGatekeeper, Inc. has filed a legal challenge to the Yamanaka Patent seeking to cancel it (for more on this see here and here).

Who is BioGatekeeper?

So far the stem cell field does not know, but I’m convinced the truth will come out.

Another question is why BioGatekeeper would want to hide. The seemingly obvious answer is they want to avoid potential negative PR. However, another perhaps complimentary notion is that BioGatekeeper wants to avoid being identified because it is really a team effort, there are several parties behind it, and frankly some of this group do not want to publicly be associated with the others.

One of the most fascinating things for me as I’ve been following this story is the large number of different possible people and companies that have been suggested to me by people in the know as being behind BioGatekeeper.

Even if none of these are behind BioGatekeeper (whether alone or collectively) it is intriguing that there are so many companies who might want a slice of the iPS cell pie and so might be very happy to see the Yamanaka Patent nullified.

I suppose it is also possible that BioGatekeeper chose that name not only to put on the appearance of a do-gooder, but also using some kind of reverse psychology they wanted to attract attention and get publicity via this mystery. If the latter is the case, then I guess I’ve fallen for their trick.

Whatever their motivations, it’s also interesting how quite a few of these potential BioGatekeepers can one way or another be linked to the same law firm(s) that seem to be involved.

The cell reprogramming intellectual property arena has many players, is interconnected, and brings into play some of the say attorneys over and over.

The best current prediction is that behind the mask of BioGatekeeper, behind that temporary curtain of anonymity, are several different parties who each have a financial interest in nullifying the Yamanaka Patent. As the clues continue to pour in, the stem cell field will determine who they are and what they are up to soon enough.

Interview with Jane Lebkowski on Asterias FDA-approved Stem Cell Trial

Jane LebkowskiThe BioTime subsidiary, Asterias, has received FDA approval for a combined Phase I/IIa clinical trial of OPC1 for treating spinal cord injury.

BioTime (BTX) and Asterias (ASTY) have picked up the portfolio of the former Geron clinical trial using oligodendrocyte precursor cells (OPC). Asterias also acquired a second element from Geron in the form of a lung cancer treatment based on stem cells that sounds quite intriguing.

To learn more about this exciting news I interviewed Jane Lebkowski, President of Research and Development at Asterias.

1. What are the most important things for the stem cell community to know about Asterias getting the FDA approval to move forward with this Phase 1/2a trial?

Asterias BioTimeLebkowski: There are a couple of very interesting points.

In the first clinical trial by Geron, safety was established in patients with thoracic spinal cord injury. Now, with this current FDA clearance and the new clinical protocol, we will test AST-OPC1 in a different patient population, those patients with complete cervical spinal cord injuries. We think this population will be the first target for registration trials for AST-OPC1. Patients with cervical injuries have more extensive paralysis involving both the lower and upper limbs. Because of both the anatomy of spinal cord in the cervical spinal cord region and superior ways to assess restoration of upper body movement, we believe testing of AST-OPC1 in this patient population will provide a better opportunity to assess potential clinical benefit of the cells.

Another important point of the new trial is that will test escalating doses of AST-OPC1. The first clinical trial performed by Geron tested a single low dose of the cells. In the new Phase 1/2a trial, we will escalate doses into the range where we feel we can see potential clinical activity.

2. What are the doses in the new trial versus the original one?

Lebkowski:  The dose used in the Geron trial was 2 million cells. The new trial will start with a dose of 2 million cells in the first cohort and then escalate to doses of 10 and 20 million cells in cohorts 2 and 3.

3. The patients that originally received OPC1 when Geron was starting things have now been followed for a relatively long time. How are they doing?

Lebkowski:   There have been no safety problems observed in these patients that were associated with the cells, injection of the cells, or immunosuppression used in the first clinical trial. We haven’t seen measurable neurological improvements in the patients, however these patients were administered only a low dose of cells. Importantly, there were no immune responses observed which targeted the cells. By MRI, there were indications of tissue sparing effects (reduced cavitation) in four out of the five patients in the original trial.

The device and procedure used to administer the cells in cervical spinal cord injury patients are essentially the same as those used in the first trial in thoracic injury patients.

When the product was owned by Geron, it was referred to as “GRNOPC1”.  It is now called “AST-OPC1” to reflect its new owner, Asterias Biotherapeutics.

4. What does the involvement of CIRM mean for the whole process?

Lebkowski:  CIRM will be helping to co-fund this new clinical trial. This funding can now be activated with the FDA clearance.

5. What will the time course be like for this trial? 

Lebkowski:  We plan to start the trial in early 2015 with data becoming available as the trial progresses through the cohorts. 

6. In a broad sense, what does this clearance and the trial mean?

Lebkowski:  Although the first trial was small, a good safety profile was established enabling more advanced testing of AST-OPC1 in clinical trials where both safety and efficacy can be potentially measured. The clearance also shows more broadly that human embryonic stem cell based therapies are progressing in their development. The field is advancing beyond the feasibility stage now.

8. Can you tell us briefly about Asterias’ lung cancer program?

Lebkowski:  A second Asterias product is AST-VAC2, which are human embryonic stem cell derived dendritic cells. These cells are modified to express telomerase, a protein typically expressed in cancer cells. The aim is to use these telomerase expressing dendritic cells to stimulate immune responses against cancer cells. We are now preparing for clinical trials with this product.