Mini-bios on some top finalists for Stem Cell Person of the Year

Heather_MainBy Heather Main

I was a little ashamed of myself that I didn’t know who half of the finalists were in Paul Knoepfler’s Stem Cell Person of the Year Award. I decided to look into it and find out what (or who) I have missed…..Interestingly, 3 of the 7 listed here are not scientists but instead are patients and/or patient advocates, showing the major impact these groups have on progression of our field. I have listed my write-ups of the finalists here alphabetically.

Bill Moss – FSHD sufferer, FSHD global foundation founder and chairman

Bill was diagnosed with FSHD (the most common form of muscular dystrophy) at 28 years old. The youngest child of a gardener, Bill became a masterful businessman and spent 23 years as a senior executive and Executive Director of a pre-eminent Australian investment bank before leaving at 52 years of age to pursue philanthropic initiatives. He has self-funded programs for industry development in Australian aboriginal communities, advocated for disability rights and established the FSHD Global Research Foundation. This foundation funded derivation of the first FSHD affected hESC and successful highthroughput modeling of the disease through development of an efficient protocol to differentiated them to skeletal muscle. 

Jeanne Loring – Academic researcher

Personally I think PluriTest (the bioinformatic test for assessing pluripotent status) alone earns Jeanne a spot in this ‘hall of fame’. Her lab also leads fields including the ‘Frozen Zoo’ (iPSCs from the endangered species), translational projects in arthritis, Alzheimer disease, Parkinson’s disease, autism, and addiction as well as creating collections of iPSC lines for disease modeling and ethnically diverse toxicity testing. Jeanne is also recognized for her public work in ethics, legal issues, clinical use, cell generation and clinical use, the legal implications of patents and stem cell tourism. In December she will be awarded the 2015 World Stem Cell Summit ‘Stem Cell Action Award for advocacy’.

Judy Roberson – Huntington’s Disease patient advocate

Judy is a registered nurse, who now works as a full time volunteer patient advocate for Huntington’s disease. This includes supporting the UC Davis Huntington’s Disease Clinic, the UC Davis Institute for Regenerative Cures, and CIRM (California’s Stem Cell Agency), including legislative advocacy. She was appointed as the first voting patient representative to the FDA Huntington’s Disease Advisory Committee and is past president of the northern California chapter of the Huntington’s Disease Society of America. Judy advocates for the role patient advocates play in driving stem cell sciences towards making the goals a reality.

Michele de Luca and Graziella Pellegrini – academic researchers/clinicians

Professor De Luca, and his principal collaborator Graziella Pellegrini, have worked together over 20 years, towards the use of human epidermal stem cell cultures for life saving burns treatments as well as treatment of repigmentation and piebaldism. The team has also established human limbal stem cell culture for sight restoring corneal regeneration. Michele De Luca is coordinating the first (successful) gene therapy clinical trial for junctional epidermolysis bullosa and studies the stem cell behaviours of epithelial stem cells. Professor Graziella Pellegrini is based at the Centre for Regenerative Medicine “Stefano Ferrari” at the University of Modena and Reggio Emilia and one of the principal scientists on the corneal repair system Holoclar ®.  Together they have achieved Europe’s first approved advanced therapy medicinal product (ATMP) to be integrated into health services for patients across Europe in the future. 

Robert Lanza – ‘child science star’, CSO of Ocata Therapeutics

Reading about Robert Lanza is like reading about a rock star. In TIME magazine’s 2014 100 most influential, in FORTUNE magazine and even suggested to be played by Ben Affleck if his work leads to restoring eyesight to millions. Son of a professional gambler and growing up in Boston, Massachusetts, the weirdest find is that at the age of 14 (1969), he partially induced melanin synthesis in chicken to change the colour of its feathers for a science fair project. While it is hard to find the details of this first study, at the age of 19, with the assistance of Stephen Kuffler and Joshua Sanes at Harvard Medical School, Robert published a complete change in pigmentation in Nature using nucleoprotein from the Harco chicken and a standard cross between the Barred Plymouth Rock hen and the Rhode Island Red rooster. Since this early fascination of genetics, Robert developed methods for deriving hESC lines from single blastomeres in an attempt to avert the ethical discussions of the destruction of human embryos and is now running clinical trials for macular degeneration with hESC derived retinal cells.  Robert is currently Chief Scientific Officer at Ocata Therapeutics (formerly Advanced Cell Technology).

Shoukhrat Mitalipov – academic researcher

Shoukhrat was the first to derive hESC through somatic cell nuclear transfer, publishing in Nature 2013. He is also the ‘father’ of 3-parent IVF where by ‘spindle transfer’ the genetic material of a donor oocyte is swapped out for the DNA of a mother who carries a mitochondrial disorder. This creates a new egg with ‘normal mitochondria’ and nuclear genetic information from the mother, which is then fertilised with the sperm of the father. The technique is successful in rhesus macaques but has not yet been tested in humans. Shoukhrat’s company Mitogenome Therapeutics appears to be pursuing 3-parent IVF in China, because it is not currently allowed by the FDA in the US.

Ted Harada – ALS sufferer and unproven stem cell treatment recipient

Another patient advocate, Ted has received two doses of fetal neural cells in his spinal cord from Emory University in Atlanta as an experimental treatment to slow progression of his ALS. While Ted showed improvement in limb movement, strength and dexterity from the first transplantation his abilities have slowly been regressing, leading to this second treatment. Ted is a strong advocate for “Right To Try” that patients’ choice to receive experimental treatments should be respected and will speed up innovation.  He challenges the idea that patients who are out of options may need to settle for ‘silver standards’ with novel FDA approved treatments taking 10 – 15 years and sometimes nearly a billion dollars. He feels that these patients do not have that time to wait. Refreshingly, he is not a fan of stem cell tourism and the Right-To-Try movement stipulates the treatment has to have completed an FDA phase I portion of a trial and been approved for phase II.

Do Patients Have a Fundamental Right to Choice?

What is the “proper” amount of freedom of choice for patients in medicine?

What if the treatments in question are experimental and come with their own baggage of associated risks, personal costs, and potential costs to society?

More broadly, do patients have a fundamental right to medical choice?

These questions seem particularly appropriate today on a number of fronts including Right To Try laws and vaccines as well as emerging stem cell and other biomedical technologies. The recent measles outbreaks including the one sparked at Disneyland are warning signs of what harm is awaiting us if the choice to opt out of vaccinations continues to be available to the general public. The California Senate today passed the mandatory vaccination bill. Assembly lawmakers are now weighing the bill.right to choice in medicine

As we discussed at our recent UCD Stem Cell Ethics Symposium, that phrase “a fundamental right” is very powerful. A potential benefit of medical freedom would be the power to make choices that may benefit oneself or one’s loved ones that otherwise would not be available if solely decided on a collective, governmental level.

For example, there may be a new experimental drug that a doctor and patient together decide is worth the risk to try, but the FDA has not approved it or even given the green light for a clinical trial on it. In principle, that drug might help the patient or it might hurt or even kill the patient. Advocates of medical freedom believe patients should broadly be allowed to evaluate and take such risks with their own personal physician if they so choose. They see the FDA as an obstacle to their freedom.

As someone who has faced a very serious form of prostate cancer, I get the sense that being in a serious medical situation can change one’s views. Everything feels different when you are faced with a potentially lethal medical diagnosis yourself or for a loved one. Sometimes it’s not that simple though.

As individuals our freedom and desire for choices can conflict with a greater good. For example, as a biomedical scientist and parent I do not believe that childhood vaccination should be optional. While there is no compelling evidence that vaccination is harmful beyond for that tiniest fraction of those who have severe reactions or pre-existing immune diseases, there is profound evidence–I would go so far as to say proof–of powerful benefits to both individuals and society as a whole of vaccination.

Some parents feel that the best choice is not to have their kids vaccinated. Should they be allowed that choice? I don’t think so in the sense of the unvaccinated kids still being allowed to go to school where they can interact with and potentially harm other children via infectious diseases. Not being vaccinated also poses risks as an adult for other workers in the workplace.

While some might say that mandatory vaccination is “anti-freedom” and that there are costs to such governmental mandates, from my view the benefits dramatically outweigh those risks. But some argue a libertarian view that there is a price for that in loss of free choice.

Another example of a hotly debated area today that shares some of the same issues is emerging stem cell technology. Some say that patients should be free to entirely make their own choices as to whether to get an experimental, potentially risky stem cell intervention. The argument is also in conjunction often made that patients are in the best position with their doctors to make such decisions. “Get the government out of my doctor’s office”, might be the clarion call for those folks.

These kinds of “freedom-based medical decisions”, as we might call them, have possible societal costs even if they do not involve highly contagious infectious diseases. If companies sell unapproved stem cell treatments, then patients buying those treatments are at the same time as they think they are trying to help themselves, also are undermining the authority of the FDA more generally and in that way indirectly putting future potential patients at risk. As much as I think the community that reads this blog can agree that the FDA is imperfect and could benefit from reforms, the FDA performs a very difficult, complex and crucial mission, without which we’d face medical chaos leading to great harm.

It seems appropriate at this point to also point out that many stem cell clinics also sell these interventions to children. As such, if you believe that people should be allowed to get any stem cell therapy they want, keep in mind that there are possible broader consequences to you making that choice beyond undermining the FDA mission. One might say, for instance, that you are supporting a sketchy company that is putting other people at risk. Some of those other potential patients may not be in the same position as you to make decisions about risks. They may be kids or they may be less educated than you. By giving this stem cell business your money you are enabling them to put others into risky situations.

As much as some people might advocate for specific stem cell clinics selling unapproved stem cell treatments, I’d say that within this community most of us also can point to some clinics and doctors (and fake doctors) that are truly frightening and dangerous. Even if reasonable people can disagree on broader issues regarding the appropriate level of governmental regulation and freedom of choice, relentlessly attacking the FDA for the cause of near universal freedom of medical choice for investigational stem cell treatments poses the risk of giving the wildly dangerous clinics a freer hand. Sometimes what we believe is best for ourselves cannot be viewed only in a bubble.

The bottom line is that freedom of medical choice for an individual is far more complicated than it might seem and it is easy to oversimplify it. The reality is that our medical freedom and decisions have impact on others. I don’t see that we in the America, for example, have a fundamental right to medical choice based on The Constitution. Our medical rights and ability to make health-care related choices change over time too.

Should there be a constitutional amendment for a right to freedom of medical choice?What’s the best goal for these rights (or lack thereof) even if not a constitutional right for the immediate future? How much freedom in this area is best in the longer term?

New Interview with FDA on Key Stem Cell Regulatory Issues & Its Own Research

FDAIt’s been a seemingly rather quiet year on the regulatory front in the US when it comes to direct-to-consumer stem cell interventions even as the number of dubious stem cell clinics continues to skyrocket.

I requested an interview with the FDA to cover the key pressing issues in this arena. I want to thank the FDA for taking the time to do this interview.

Below are their answers covering regulation of SVF, homologous use, FDA action/inaction on dubious stem cell clinics, Right To Try Laws, and the FDA’s own research on stem cells.

Paul: One of the hot topics in the stem cell arena is the production and use of stem cells from adipose tissue with the most common product being called stromal vascular fraction (SVF). A current debate is whether CBER views SVF as a biological drug product. Could you please comment on SVF and whether it is a 351 or 361 product? is it more than minimally manipulated? If such a definition/guidance is on a case-by-case basis, can you cite any examples of where SVF has been defined simply as 361? The field could really benefit from some clarity on this issue.

FDA:  FDA recognizes the importance of this issue and the necessity for clear communication regarding minimal-manipulation, SVF, and other stem cell-based products.  It is understandable that the field is eager for clarification on the categorization of SVF and other stem cell-based products and FDA develops guidance on these topics as the specific regulatory approaches are sufficiently mature.

The Agency recently issued or is actively engaged in developing draft guidance on these topics:

CBER’s 2014 Guidance Agenda is available here:

http://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/ucm338498.pdf

Paul: Another area where some additional clarity would be helpful is on non-homologous use. Is it correct to say that even if a biological product is defined as not more than minimally manipulated but it is used in a non-homologous manner (e.g. adipose used for a neurological disorder) does that product still require approval as a 351?

FDA:  In order to be regulated solely under section 361 of the PHS Act, a HCT/P must meet all of the criteria in CFR 1271.10(a), including the requirement for homologous use.

CFR 1271.10 can be accessed here: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=1271.10.

Paul: A number of stem cell researchers have noted a lack of apparent FDA/CBER action in 2014 with regards to stem cell clinics selling interventions based on SVF or other unapproved stem cell products and/or apparent non-homologous use coupled to broad claims by clinics (e.g. “our stem cell treatments can treat 20 different conditions”), etc. Without commenting on specific cases of course, could you comment on why the FDA/CBER appear to be relatively less active in regulating stem cell clinics in 2014? For example, in 2012-2013 there were numerous Warning Letters issued, but none in 2014 related to stem cells to my knowledge. It certainly seems that the problem of stem cell clinics is not going away so that’s not the explanation so less FDA action. If anything there are dramatically more of such clinics in the US now than in past years. Why is CBER not taking action?

FDA:  As discussed above, CBER is actively working to develop guidance on the issues relating to SVF and other unapproved stem cell-based products. These guidances will offer necessary clarification with regard to HCT/P regulations.

As you know, FDA cannot comment on any potential actions or open investigations.

Paul: Right To Try (RTT) laws have been passed in several states and the current trend seems to be for more states to pass such laws. What is CBER’s view of RTT? How do these state laws interface with the federal laws that authorize the FDA to regulate investigational drugs?

FDA:  State laws, such as the Right to Try laws, do not supersede federal laws. Please keep in mind that through FDA Expanded Access or “compassionate use”, investigational products often can be made available for a patient with a serious or immediately life-threatening disease who does not respond to current approved treatments for a variety of reasons.

Additionally, Right to Try Laws share similar aspects to the use of an investigational product under FDA’s expanded access. In both cases, a treating physician must recommend the experimental product and be able and willing to use it to treat the patient.  Additionally, the drug manufacturer must be willing to provide the experimental product. States cannot force drug manufacturers to provide their products, nor can they force physicians to recommend an experimental product or use such a product to treat a patient.

Paul: Many members of the stem cell community find it notable that CBER conducts its own stem cell research including on MSCs. Could you please tell us more about this research program and its goals? What has it achieved so far and what do you foresee for its future?

FDA:  The MSC Consortium, which started work in mid-2010, was established to facilitate the development of products and therapies that utilize mesenchymal stem cells (MSCs). Through research, the  Consortium aims to answer the complex scientific questions that face the development of stem cell-based products. The research of the Consortium is meant to contribute to the understanding of the underlying science regarding MSCs and the goal is that increasing understanding of MSCs will facilitate development of safe and effective MSC-based products.

The Consortium is studying eight unique cell lines from eight distinct adult donors, who donated stem cells from their bone marrow.  The cells were purchased from commercial sources.

The type of cell into which MSCs will differentiate depends on the conditions under which they are grown.  Similarly, factors such as the age or gender of the MSC donor may affect the quality and performance of these cells. The Consortium’s research is looking at how the biological functions of MSCs may be impacted by factors such as growth environment or donor characteristics.

Additionally, the Consortium has identified the need for further characterization of MSC-based products in order to better understand the diversity amongst subpopulations of these cells. FDA researchers are working on ways to better characterize MSCs, such as through development of assays and screening for MSC molecular markers or other characteristics that correlate with biological properties of MSCs.  By identifying these correlative characteristics, researchers hope to develop ways to characterize MSCs with measurements that more reliably predict the biological functions of MSC-based products.

Specifically, the Consortium has performed research contributing to understanding the differences between samples from different donors and  the effects of cell passaging on the differentiation capacity, gene expression, and function of MSCs (Lo Surdo & Bauer, 2012; Lo Surdo, Millis, & Bauer, 2013; Bellayr et al. 2014).

The Consortium conducted an extensive membrane proteome analysis of human bone marrow MSCs (Mindaye et al., 2013a) and proteomic analysis of culture-expanded MSCs (Mindaye et al., 2013b), resulting in datasets which can serve as a basis for further research and understanding of MSCs.

The Consortium has also developed a novel immune inhibition assay in order to investigate the immunosuppressive functions of MSCs, with the goal of improving understanding of the immune-inhibitory activity of MSCs from different donors, at different passages, or grown under different conditions (Nazarov, C., Lo Surdo, J., Bauer, S. R., Wei., C-H. 2013).

In the future, the Consortium will continue to develop and refine quantitative methods to assess the biological characteristics of MSCs and to identify molecular and other characteristics of MSCs that correlate with biological functions of MSCs.

  • References
  • Bellayr, I. H., Catalano, J.G., Lababidi, S., Yang, A. X., Lo Surdo, J. L., Bauer, S. R., and Puri, R. K. (2014)
  • Gene markers of cellular aging in human multipotent stromal cells in culture. Stem Cell Research & Therapy. 5:59. doi:10.1186/scrt448.
  • Lo Surdo, J. L., & Bauer, S. R. (2012). Quantitative Approaches to Detect Donor and Passage Differences
  • in Adipogenic Potential and Clonogenicity in Human Bone Marrow‐Derived Mesenchymal Stem Cells.  Tissue EngineeringPart C, Methods, 18(11): 877‐889. doi:  10.1089/ten.tec.2011.0736
  • Lo Surdo, J. L., Millis, B. and Bauer, S.R. (2013) Automated Microscopy as a Quantitative Method to
  • Measure Differences in Adipogenic Differentiation in Preparations of Human Mesenchymal Stem Cells. Cytotherapy, 15 (12): 1527-40. DOI: 10.1016/j.jcyt.2013.04.010
  • Mindaye, S. T., Ra, M., Lo Surdo, J. L., Bauer, S. R.,  Alterman, M. A. (2013a). Improved proteomic profiling of the cell surface of culture‐expanded human bone marrow multipotent stromal cells. Journal of Proteomics, 78: 1‐14. DOI: 10.1016/j.jprot.2012.10.028
  • Mindaye, S. T., Ra, M., Lo Surdo, J. L., Bauer, S. R., and Alterman, M. A. (2013b).Global proteomic signature of undifferentiated human bone marrow 6 stromal cells: Evidence for donor‐to‐donor proteome heterogeneity. Stem Cell Research 11(2): 793-805. DOI: 10.1016/j.scr.2013.05.006
  • Nazarov, C., Lo Surdo, J.L., Bauer, S.R., Wei, C-H. (2013). Assessment of immunosuppressive activity of human mesenchymal stem cells using murine antigen specific CD4 and CD8 T cells in vitro. Stem Cell Research & Therapy 4:128. doi:10.1186/scrt339.

Interview with Neuralstem CEO Richard Garr

Richard GarrI invited Neuralstem CEO, Richard Garr, to do a Q&A interview and he kindly accepted. The interview provides some novel insights into this major biotech in the stem cell sector.
1. How is Neuralstem doing today? What programs are underway that you find particularly exciting? 
Garr: Neuralstem is moving on all cylinders these days on both our cell therapy and small molecule clinical programs.  We have just completed all the transplantations of our phase two ALS patients, with the data lock coming early in January, and hopefully the phase2/3 starting early next year; and in September we expect to transplant our first SCI patient at UCSD (chronic thoracic ASI-a patients).  We continue to dose phase 1 patients in our stroke trial in China.  On the small molecule side, the MGH group presented our 1b data in MDD patients at ASCP this past june and it was frankly, stunning; showing clinically meaningful improvement in all the patients who took the medicine as well as reaching statistical significance in treatment of depression measures, as well as cognitive improvement.  It is a first in class neurogenic drug, and we we will be going into a phase two we believe sometime near the end of the first quarter next year.
2. How are the financials?
Garr: The financials are stronger than they have ever been, and the last Q showed roughly $30 million in cash and equivalents.  Our burn rate continues to be a fraction of the industry norm thanks to our near virtual model, and generous funding of our ALS trial by the NIH and ALSA.
3. Where do you see the company in 5 years? 10 years?
Garr: We expect to commercialize the cell therapeutics ourselves, certainly in the U.S. With partners world wide in selective markets.  We expect to take the small molecule drug through, at least phase two, but ultimately to partner it out.  We have a wholly owned subsidiary in China, and a partner with an option on markets in Korea, Vietnam, Malaysia, Indonesia and Singapore, so we see a great deal of our growth also coming in Asia in the long term in cell therapy.
4. What makes Neuralstem  unique as a stem cell biotech company?
Garr: I don’t know that we are unique, but we are built differently than most.  We were built to move our technology forward, in every therapeutic area to which it might apply; we don’t look for other technologies for a particular disease, and we don’t look to expand beyond what we own.  So we, from that point of view, we are perhaps more focused than other companies on a particular way of treating diseases.  On the cell therapy side, we only have looked at incurable disease from the start; we believe that that is what our technology is capable of, and that has been our goal from the beginning.  That is now and has always been the ethos of our company.
5. How important is patient involvement in the stem cell biotech arena? Building on that, what is your view of Right To Try laws?
Garr: We have always been a much more “patient centric” company than most.  And we have always had an intimate relationship with various patient advocacy groups.  It is part and parcel of our make up.  And yes, that is why I got involved with the RTT movement.  There are roughly 30,000 ALS patients, 5,000 newly diagnosed each year;  and there is literally nothing our there for them to significantly improve their quality of life or their life span.  We believe our ALS therapy is doing both; our trials have not yet been powered to demonstrate that to the level that it meets various existing FDA early access programs, and I think that with the right safeguards RTT can provide a structure to build such programs around.  My view of RTT is that it is dependent on, and must work with the FDA.  It is built so that it relies on FDA diligence on safety; and I can tell you from our own experience that when you develop treatments for terminal diseases (and the law only applies to terminal diseases) you have spent (at least) tens of millions of dollars before you ever get into a phase one human trial, and you have a great deal of safety data before and after such trials.  The law also requires that you be actively engaged in at least a second FDA trial, so these eligible treatments are under the constant villigance of the FDA in order to be eligible.  I understand that there are many issues to be worked out in terms of liability and payments to mention just a few; but these are the types of issues this industry deals with every day, this is not peace in the middle east we are trying to solve here.  And so when critics of RTT bring up issues with the implementation, to me that is a separate issue from whether or not RTT is the right thing to do; and while those are serious issues, they are “second level” issues.   Also, it is a transitory program; that is, it’s only meant to provide access until the drugs are either approved by the FDA and available, or shown not to work.  As Ted says, it’s a right to try, not a right to cure.  Everyone involved understands that.
6. What is the IP portfolio like for Neuralstem? I understand there has been a conflict with StemCells, Inc. and Greg Schiffman commented on that in my interview with StemCells, Inc. leadership. Can you please let us know the Neuralstem perspective on this?
Garr: I won’t comment on the ongoing litigation other than to say this; the end will speak clearly for itself.  With respect to our IP position, it should be understood that NONE of our patents are being challenged in this litigation, only STEM’s patents are being challenged in this litigation.  We have patents issued worldwide which cover both our cell therapy and small molecule platforms.
7. How important is social media in this day and age for biotechs? As both a scientist and blogger myself, I note your blog as being unique and valuable to patients, investors, and the larger community. What prompted you to do a blog? What has your experience been like with it so far?
Garr: I think that social media is an essential part of communication today, with all the stakeholders in a company.  I started the blog because of the intense interest in what we are doing from the patient and caregiver communities, and as it has evolved, that has become the main focus.  It is complicated by the fact that we are a public company which brings in an entirely new and different set of rules and regulations that inform what you can and can’t say (about ongoing trial data for instance) but those are simply rules that one lives with.  Social media is changing the way patients communicate with each other.  That’s a genie you can’t put back in the bottle.  We see patients in trials blogging about their progress (or lack thereof).  They are not like juries where you can quarantine them until they reach a decision. It’s all about community, and patients and their support groups are always looking for more community in these stressful situations, it is a human instinct, and I believe a good one.  We reach out to comfort each other, that is what is behind the exponential growth here.  The industry is going to have to figure out a way to accommodate the new reality of social media and clinical trials, just like every other industry has had to learn how to adapt to the internet age.