Elliot Lander & Mark Berman Interview Part 1: A Window into Cell Surgical Network

Elliot LanderMark BermanThe Cell Surgical Network is a large and growing group of affiliated stem cell clinics across the US.

The Network providers use stromal vascular fraction (SVF) interventions for a host of conditions on a for-profit basis. Drs. Elliot Lander and Mark Berman lead the Network.

They agreed to do a Q&A interview with me. Below is Part 1, which delves into the Network itself.

Part 2 on SVF, the FDA, and issues of homologous use can be read here.

Part 3 of this series is my reaction to the interview and to Drs. Lander and Berman’s specific answers.

Here is today’s part of the interview.

1. The Cell Surgical Network is very novel as a linked group of stem cell clinics across the US and some abroad. What is its history? How did it come into being?

Lander: In early 2008, using equipment designed by Dr. Hee Young Lee in South Korea, Dr. Mark Berman, a cosmetic surgeon and an international expert in fat transfer, began isolating concentrated fat for cosmetic uses.   With Lee’s technology and further consideration after visits in Japan with Dr. Katoro Yoshimura and others, he quickly realized the therapeutic potential of SVF for degenerative diseases based on extensive animal studies and clinical work in the US, Europe and Asia. Dr. Berman, in collaboration with Dr. Tom Grogan, a Los Angeles orthopedic surgeon, began empirically using intra-articular injections of SVF for various orthopedic uses and found that their experience matched the positive outcomes described in the literature. I became intrigued with their positive results and we began collaborating to develop research protocols to test for safety and efficacy of various methods of SVF deployment for several degenerative conditions. We formed a multispecialty team and developed protocols to treat orthopedic, urologic, cardiovascular, pulmonary, auto-immune, wound care, and several other disease entities.

It became apparent that to achieve the kind of numbers we need to establish safety and efficacy; we would need a multicenter trial performed under the auspices of an IRB. You can find our study on www.clinicaltrial.gov registered under #CSN111. We were interested in teaching our closed surgical procedure to selected physicians around the country and we created the Cell Surgical Network™ to accomplish this in a high quality and standardized fashion. We also employ a full time clinical research coordinator and support a university quality online database to collect valuable outcomes and safety data. Our Cell Surgical Network™ has treated more than 1000 patients with autologous SVF without any serious complications.

2. What is the current status of the Network today? Is it continuing to grow? How do you evaluate clinics that are interested in joining? Do you sometimes turn down applicants and if so, why? Where do you see the Network say in 3-5 years in the future?

Lander: Our network is growing organically and we do not solicit our doctors. Most of them reach out to us based on word of mouth or referral and we select physicians based on reputation and interest in regenerative therapeutics. We have a credentialing process and a standardized and thorough training program to ensure that our affiliate physicians are performing surgical techniques properly and that they are focusing on education and avoiding claims in their interface with the public. We encourage our affiliates to use their multispecialty team members to carefully evaluate applications for SVF deployment to make sure that patients receive appropriate treatment and it is routine for us to decline at least 25% of the patient applications we receive and we often offer free treatments for new diseases if we are attempting to learn more about them. Our goal is to have regenerative therapies available everywhere in the world where surgeons can use patient’s own tissues to help them contend with disease. It is our hope that our Network will play at least a minor role in that vision coming to fruition over the next few years. We certainly will be providing vast amounts of clinical data to the field of regenerative medicine as we accumulate outcomes and safety data and we hope to contribute to improvements in deployment techniques that may be helpful for both autologous and other cell based therapies globally.

3. What are the uniting elements that link the various Network clinics together? A shared philosophy? Do the clinics share methods and apparatus?  Do the clinics share an IRB? If so, what is the IRB?

Lander: Our clinics are all independently owned but share our ICMS IRB and use the same training, methods and equipment. In order to provide meaningful data, it is imperative that we are all doing the same protocols. We share the same online database and we share the same mission statements, commitment to ethical practice, and vision of advancing our field and making cell based therapy readily available.

4. An Internet search suggests you use the Lipokit by Medikan to produce stromal vascular fraction (SVF)?. Why did you pick that approach and how has it worked for you & the Network clinics?

Lander: We use the MediKan equipment – now branded as the CSN – Time Machine™ because my partner, Dr. Berman originally obtained this equipment in 2008 and then upon visiting Japan and watching Dr. Kamakura with the Cytori machine and Dr. Yoshimura with the same MediKan equipment made an obvious decision.  If it was good enough for Kotaro  Yoshimura, arguably one of the top SVF / fat specialists in the world, it was good enough for us.  We just needed a safe GMP grade enzyme – which came along in July 2010 thanks to Roche Laboratories. We just had to refine the system so that it was completely closed, sterile and provided filtered cells. This has allowed us to reliably produce excellent quality SVF and no culturing or cell manipulation is required. There is no laboratory aspect to our SVF procurement.

Stay tuned for Part 2.

Interview with Regenerative Surgeon, Dr. Allan Wu

Dr. Allan WuOver the last few weeks, I have enjoyed talking with and interviewing Dr. Allan Wu, of The Morrow Institute on stem cell cosmetic procedures. I was impressed greatly by his talk at the World Stem Cell Summit last year.

Dr. Wu is a fellowship trained Surgical Molecular Biologist with a background in Molecular Embryology and a board certified Cosmetic Surgeon actively practicing  Aesthetic Reconstructive and Regenerative Surgery.

Below is my interview him. I hope you enjoy it and find it as thought-provoking as I did.

Paul question #1: In my opinion, one big challenge for the translational stem cell  field seems to be balancing innovation with safety. What are your thoughts on the best approach to that? If where we are at today could use improvements on either side (innovation or safety or both), what are the best ways to make a course correction for the future?

Dr. Allan Wu: There will always be novel biologic entities that stretch the very limits of our regulatory systems to the point of rendering some aspects obsolete and/or cause for revision.  The trick moving forward is to have open, honest and dispassionate communication between clinicians, scientists and Federal and State authorities and professional boards and organizations.  When you look back historically on novel therapies such as transplant medicine, IVF and ICSI, a great deal of prefacing and focus group consensus building was needed to form fair and cogent regulations to monitor safety and allow the fields to move forward.  This process has been lacking in the adult mesenchymal stem cell realm and in particular adipose derived stem cells (ADSC).  Looking back it is hard to precisely determine why we are at such a challenging juncture with the FDA, though some of blame can be placed upon ADSC being so easily accessible and profusely abundant.  That too combined with immediate marketability and high patient demand created a perfect storm in which several clinicians unwittingly (and some intentionally) jumped the gun before a clear understanding could be vetted by professional organizations.

Because legal liabilities are a reality in medicine, most physicians and surgeons turn to attorneys as a primary method to resolve very serious misunderstandings or disagreements.  The recent Regenerative Sciences Inc. case is a good example of this.  Although academic colleagues may find this approach distasteful, to their credit, the attorneys involved in the case and those in the periphery commenting upon it, have actually helped educate clinicians and their understanding of 21 CFR 1271, which until a few years ago was an obscure regulation to non-transplant surgeons.  And whether intended or not, the adversarial process helped gain a greater understanding of the FDA’s concerns.  Some of us lament that it was unfortunate either side had to legally engage one another in the first place and wonder if perhaps in the coming year a different approach modeled after our colleagues in bone marrow therapy, transplant medicine and IVF could be pursued as a viable alternative.  Regulations preserving patient safety along with the sanctity of the patient-physician relationship will never be achieved in a vacuum.  The FDA, clinicians, scientists, patient advocates, bioethicists, and yes even attorneys NEED to be involved in the process.  I think the recent legal panel video excerpts from the World Summit and STEMSO meetings this year give a great synopsis of where the current regulatory climate resides.  Pending meetings April 22-23 in Palm Springs by Select Biosciences and the World Summit in fall of 2013 will also delve into these issues further.  So stay tuned and look forward to the FDA possibly giving further guidance regarding adult mesenchymal stem cell therapy at one of the major meetings.

In terms of innovation, Dr. Guoping Fan (UCLA, Dept. of Genetics) and I have been working on and off the last 5 years on ideas and projects to quantitatively or semi-quantitatively establish safety parameters for clinical stem cells using genomic tools.  We are not alone in this quest, and though I do not speak for the FDA, I do find recent activities at CBER quite telling.  On an FDA webpage entitled “Supporting the development of mesenchymal stem cells as clinical therapies” they detail their work on a limiting dilution assay, which could indicate a philosophic shift towards defining “minimal manipulation” and safety standards for stem cells on an assay based approach.

As I’m sure you are aware, the technology in genomic and personalized medicine is growing at an exponential pace.  The thought of doing rapid point-of-care analysis using genomic assays like sequencing, methylation status, RNA expression profiles and proteomics is no longer a pipe dream, but a pending reality due to tremendous strides in nanotechnology and hyperspeed computing.  Our colleagues on the personalized medicine front are essentially building a “bridge” towards regenerative medicine. As wireless and open-source infrastructures mature, all forms of regenerative medicine from iPS to MSC will benefit.  For example, our counterparts in Spain (Estreller’s lab) completed an interesting study last year looking at osteocytes derived from ADSC and compared their epigenetic signature to osteosarcoma cell lines (MG-63).  Thankfully the ADSC derived osteocyte heat maps looked nothing like the correlated tumor cell lines despite being cultured for close to a month.  This technology in its present state, however, is not tenable from a point-of-care context, but with lab-on-a-chip design and network innovations, these kind of assays will eventually become available for stem cell pre-deployment safety assurance.

Paul question #2. What are the top cosmetic procedures utilizing stem cells today?

Dr. Allan Wu: Cell assisted lipotransfer (CAL) for various forms of tissue augmentation has taken off like wild-fire in Japan and the rest of the regulatory world that does not forbid the procedure.  The procedure itself is almost a decade old, and who would have thought adding the stromal vascular fraction (which contains ADSC) would have such a tremendous impact on free fat grafting?  Dr. Kotaro Yoshimura, the inventor of the procedure, and other colleagues outside of Japan, has had tremendous results with breast, hand and facial augmentation.  Though breast augmentation seems like a frivolous application of science, the cross-translational knowledge and skill is reaping rewards for our colleagues in wound care and cancer reconstructive surgery, thus creating unanticipated novel “spinoff” therapies.  To date the world medical literature has not reported a single teratoma or cancer as a result of appropriate CAL use.

It is important to note that as other countries continue to innovate and develop CAL and related techniques, the United States could find themselves in a predicament in which novel stem cell therapies could belong to foreign countries with a different regulatory philosophy.  Ironic too since the U.S. has significantly funded basic sciences research in regenerative medicine, and a horrible shame in that (even if the regulatory climate were to change over night) we may find ourselves eventually “locked out” due to a growing international patent thicket.  In short, our government needs a coherent, consistent and pro-active policy for regenerative medicine especially if we plan on using regenerative solutions to combat the rising cost of domestic health care and also support a promising new industry that will have direct material impact upon the American economy.

So hypothetically speaking (and to address your “course correction” in question #1), if I were POTUS or the FDA, I would find a way to at least allow SVF use in the form of CAL, but require regulatory oversight.  In this way clinicians lacking a major research budget would be able to operate without a costly IND.  In exchange all clinicians would mandatorily submit close follow up data to an independent national registry to monitor the safety of the procedure in much the same way our colleagues in infertility and transplant medicine do already.  Should a negative pattern develop, the procedure can immediately be placed on hold until further study is done to determine necessary corrections in cooperation with the FDA.

I would also try to define “minimal manipulation” on an objective assay basis to give industry a clear regulatory pathway and “set the goal posts” so to speak.  This should free up the ability for startups to work on innovative, but safe and well defined forms of manipulation, which eventually could include limited tissue culture techniques.  Smart money always likes to operate in fields where it believes it can succeed.  Providing entrepreneurs more transparent and well defined grounds to operate would do much to alleviate anxiety and simultaneously foster greater venture capital interest in the field.

Paul question #3. Where do you see stem cell therapies and the field being in 5-10  years? What are you most excited about in this area looking to the future?

Dr. Allan Wu: We are quickly finding that stem cells serve dual function as direct “mechanics” in regeneration and repair, but also secretory factories pumping out relevant stimukines/factors.  One company in particular, Personal Cell Sciences, has cleverly capitalized on this concept by converting conditioned media from ADSC cultures into specialty formulated autologous skin creams.  What I find fascinating are the lesser known fractions of the media, the exosomes, nanosomes and liposomes, which are being largely ignored.  Strange too since exosome miRNA can and do exert effects on the stemness quartet of NANOG, SOX2, OCT4 and TCF3.  I would bet that the supposed “junk” that we have ignored in conditioned media will find further clinical application in cosmetic surgery and wound regeneration within the next 5-10 years.   So the excitement generated here is the real option of inducing regenerative capabilities without cells all together.  This could lead to additional forms of cure not requiring as rigid or delicate of preservation or handling.

One other major breakthrough is using stem cells as a Trojan horse for gene therapy.  There are several companies and centers focusing on mesenchymal stem cells as the ideal vehicle for correcting heritable disease traits.  Great strides have been made this year using zinc finger technology to literally “edit” or correct foul genetic code in autologous cells ex-vivo.  I joke with operating room staff and warn them someday patients will not only have beautiful skin like Suzanne Somers, but also carry the same genetic profile of skin cells with the help of “edited” autologous stem cells.  Perhaps not 5 years and possibly not even 10, but using the stem cell as a general gene therapy work horse is a likely reality and also points to the importance of building that “bridge” between regenerative and personalized medicine.

Paul- I also asked Dr. Wu to react to my in-press article in Regenerative Medicine calling for academic fellowship training programs for physicians in cellular and regenerative medicine. Such as fellowship would include a curriculum training physicians in a number of areas such as FDA compliance, GMP, ethics, cell biology and so forth.

Dr. Allan Wu: Your curriculum reminds me of a funny conversation I had with a witness to an FDA inspection five years ago.  The inspector informed a practitioner his process was not GMP compliant after which the clinician implored, “but we get our GMP from a good chemical company!”  The field officer (without loosing composure) gently explained GMP did not stand for guanine monophosphate, but actually meant Good Manufacturing Practices.  To make matters worse, the clinician responded “…well we really do a good job manufacturing the cells…”  It just goes to show you how raw some clinicians’ understanding of regulatory issues were not long ago and why the FDA might have become a bit weary of clinicians the last few years.  The story does, however, highlight the need to educate physicians, as this is a specialty in the truest sense of the word.

And I think your idea is very insightful.  Several universities have established research centers for regenerative and translational medicine, however there are no ACGME accredited training programs in clinical regenmed.   Why build new tools for clinicians if in the end they won’t even know how to use them or even know which tools are immediately or legally available to them?  (This is also why I say our government needs a coherent regenerative medicine policy!)

Nowhere in medical school is 21 CFR 1271 even covered either.  Regulatory language and subject matter material for regenerative medicine is not a requirement for medical education at this juncture.  Medical students are lucky to be exposed to it in electives or side commentary from academic professors.  So the idea of a specific and formal post-graduate clinical and basic science fellowship will address a real unfulfilled need in medicine.  The current generation of regenerative physicians and surgeons has a difficult time with the regulatory concepts and language.  Some of this is due to unfamiliarity, but some of it is also due to misinformation.  Including the medico-legal and regulatory training in your curriculum will be critical if we hope to move the field further and work with the FDA.  The basic science training in cellular molecular biology would also help clinicians distinguish true science from hype and hopefully eliminate use/adoption of some commercial products which are more “snake oil” than real science.  So providing a fellowship would do much to improve the integrity and credibility of practitioners and the industry as a whole.  I might also add here that certification of facilities and the labs are also part of the equation and would point readers to Dr. Alan Trounson’s article on his “alpha lab” concept. (note from Paul–readers, you can see that article here).