California's Randy Mills: Flood of Demand for Stem Cell Therapies Requires New Development Pathways

The president of the $3 billion California stem cell agency today told federal regulators that patient demand is "very real" for stem cell therapies and called for "alternative" pathways for development.

Randy Mills at FDA hearing

Randy Mills said patients are "really suffering and their needs are not being met." He said the demand is like a flood of water and will find its way around any blockages that rise up.

Mills spoke during the first day of a two-day hearing by the Food and Drug Administration(FDA) into possible new regulation of the stem cell field.

The session came as the Washington Post published online a lengthy piece about unregulated stem cell therapies and the increasing scrutiny they are facing from regulators. Reporter Laurie McGinley wrote about a clinic in Beverly Hills with a self-described "Time Machine" box.

Mark Berman, who was described as the co-founder of the "biggest network of commercial stem cell clinics" in the country, processes stems cell through the box for a procedure that he says doesn't require FDA approval.

McGinley wrote,

"In mini-liposuction procedures, Berman extracts fat tissue from patients and puts it into the Time Machine box, where a centrifuge separates stem cells from fat. The cells are then injected back into the patients to supposedly treat a variety of health problems, such as arthritic knees, heart disease, amyotrophic lateral sclerosis and even autism."

The treatments run about $8,900 each. Berman said his network has treated about 5,000 persons, McGinley reported.

The Post piece said that such treatments and their regulation or lack of regulation has "ignited a fierce debate among physicians, patients, scientists and politicians about whether the (FDA) should crack down on therapies that critics deride as snake oil but that some patients swear by. And it is fueling a broader, longer-term debate over how cellular therapies should be regulated."

Stem cell researcher Paul Knoepfler of UC Davis , who is quoted in the Washington Post article, took in today's FDA hearing from his lab in California. Writing on his blog, he delivered some "take-homes" after the session concluded. Here are a few excerpts from what Knoepfler wrote.

• "Some speakers advocated for a 'middle ground' between 'nothing' in the way of regulation for instance of the dubious clinics and the perceived 'mountainous' extreme of the current FDA oversight system. The middle ground was, for example, argued for by Janet Marchibroda of the BPC and then also in the next talk by CIRM President Randy Mills. Mills, who is a very powerful speaker, argued that there is a harmful binary system now and we need a middle ground between the extremes of little-to-no regulation and the current in his view constricted pathway."
• "Several speakers invoked patient autonomy and patient rights, and argued that they are doing what they are doing as practitioners of stem cell therapies simply for the betterment of patients. There’s the pesky problem there with this argument of probably millions of dollars in profit being made from the patients by some clinics though. If it’s all about patients, I challenge the clinics to do the transplants strictly 'at cost' with no profit margin."
• "Many parties asked the FDA for more clarity and consistency on oversight. Also, a number of speakers asked for concrete, real world examples of how definitions would apply.  I’ve been pushing the FDA for increased clarity for years including lay abstract summaries of their main guidelines and statements of current thinking. I really like the idea of flowcharts."

Industry Seeks More Clarity on Proposed Federal Stem Cell Research Rules

The nation's leading industry group for regenerative medicine today called for a clearer federal pathway to help bring stem cell products to the marketplace. 

The Alliance for Regenerative Medicine (ARM), which has 240 business, academic and patient advocacy members, testified today at a Food and Drug Administration hearing into proposals for more regulation of the stem cell industry. Randy Mills, president of the California stem cell agency, is scheduled to speak later today.

In remarks prepared for delivery, Michael Werner, executive director of the group, said,

"What all manufacturers have in common...is that they seek a clear and predictable regulatory pathway to market. In general, ARM believes that while the draft guidances are a positive step forward, they still leave some questions unanswered regarding interpretation of regulations . Consequently, ARM believes that when FDA finalizes these guidances, it should take actions to provide even more clarity."

Werner went on to make specific suggestions for more explanation on  requirements for product characterization and associated claims for each type of product.

The full text of his remarks can be found here.  You can find additional information in the texts of the group's comments that were submitted in writing  on "minimal manipulation" here and and on "homologous use" here.

The two-day hearing is being broadcast live on the Internet.

Live on the Internet: Today's FDA Hearing on Stem Cell Regulation, Preview of California's Comments

The FDA's two-day hearing into stem cell treatments is underway this morning and can be seen live on the Internet, including a presentation this afternoon by the California stem cell agency, which is seeking to ease FDA regulation of stem cell clinical trials.

A likely preview of the comments from the agency popped up this morning on California Healthline in a piece by Emily Bazar. She carried the brief text of an interview with Randy Mills, president of the $3 billion California agency.

He said,

"The problem with (the FDA's current) strategy is twofold. It doesn’t address the patients, or the need side of the equation. And I don’t think it has a chance of actually working because the FDA will acknowledge that they do not have the resources to enforce these types of regulations at the clinic level.

"They would have to be essentially regulating the practice of physicians, which is well beyond their capabilities. Even if they were able to enforce it, it would just drive these patients somewhere else.

"We’re advocating for the creation of some middle pathway that would bring essentially unregulated therapies into the regulatory fold, but in a manner which could be complied with.

"I would rather know these clinics are being regulated and collecting data than have them operating under the radar screen of the FDA. I would like there to be a formal pre-market review of these therapies before they’re put on the market. I would like there to be safety and efficacy data.

"I’m going to try hard to get the FDA to see that just plugging this hole won’t make the problem go away."

Bazar's piece also contained the text of comments from Jeanne Loring, head of the stem cell research program at the Scripps Institute in La Jolla. She said,

"There’s no scientific evidence that the fat cells (unregulated) clinics are using are going to do the patient any good. And there’s no evidence that shows they are safe.

"I’m a stem cell scientist. I need scientific evidence before I will believe anything. Regulation will help determine the efficacy and safety of those fat cells.

"There are several lawsuits or potential lawsuits brewing over these stem cell treatments. People were promised they would get improvements and didn’t. And there are cases where people were actually harmed by stem cells.

"Some people truly believe they have been helped by the stem cell injections. I’m not going to argue with them. It’s a very personal and emotional response. It’s not something that can be scientifically validated. People are really desperate, especially really sick people and their families.

"That means patients are at risk. That’s what bothers me a lot. There’s nothing we can do to talk somebody out of going to a clinic if they feel that’s the only option they have. We just want to make sure nobody gets hurt. We also don’t want people to go broke. These treatments are not covered by insurance and they cost tens of thousands of dollars."

Here is a link to the actual broadcast, which is being watched by about 300 persons at this moment. An overview of the audience seems to indicate that it is being lightly attended. Mills is scheduled to speak at 4:23 p.m. EDT.

Here is a link to the agenda including a list of speakers and schedule. The broadcast also has closed caption capability.

Center for Genetics and Society Calls Trounson Affair Scandalous

The Center for Genetics and Society, a longtime critic of the California stem cell agency, yesterday described the Trounson-StemCells, Inc., affair as "scandalous" and part of an "object lesson" in how not to set up a state agency.

Writing on center's blog, Pete Shanks referred to the disclosure that Alan Trounson, former president of the $3 billion research effort, had received $443,500 in total compensation from StemCells, Inc., of Newark, Ca., for his work on the company's board over a two-year period. Trounson was appointed seven days after leaving the agency, which came as an unpleasant surprise to the stem cell agency's governing board.

StemCells, Inc., was awarded $40 million while Trounson was president of the California Institute for Regenerative Medicine (CIRM), as the agency is formally known.

Shanks, an author and consultant to the Berkeley-based center, said,

"Did Trounson or StemCells Inc. do anything illegal? Quite likely not. Was this transaction appropriate? Absolutely not! It’s scandalous, but it’s the kind of scandal that was built into CIRM from its very inception."

Shanks recounted the conflict-of-interest issues that have troubled the agency even prior to voter approval of the program. He concluded,

"CIRM is now slowly running out of the $3 billion of public funds allocated to it in 2004, and is expected to wind up in 2020. It has provided an object lesson in how not to set up and run an independent public-funded agency. These latest revelations should end any speculation about extending its charter."

Text of Irv Weissman's Comments Re Trounson Compensation

Stanford University stem cell researcher Irv Weissman has sent along the following comment in the wake of the publication of the Sept. 2, 2016, story concerning Alan Trounson's compensation from StemCells, Inc., a company co-founded by Weissman, who also served on its board of directors.

"I would like to correct some information that can be verified by CIRM officials and employees. I have known Alan Trounson for years before he came to CIRM both as a scientist and once on a fishing trip. After he got settled into his position at CIRM we met socially, and agreed to go on another fishing trip together. From that time forward he recused himself on all grants and CIRM related activities that involved either my lab or Stem Cells Inc. This was unfortunate for me, as there were times when he was the field expert and could have suggested appropriate reviewers, or mistakes in review, for grants coming from me at Stanford or Stem Cells, Inc. Although you mention the many successes we have had with CIRM grants, there were many more times when I failed to reach a funding score that was sufficient, sometimes with what I thought were inaccurate reviews,and sometimes with reviewers that I would have asked to be removed for conflicts outside of scientific expertise. I am happy to answer any questions on these issues for all grants on which I am a principal investigator, or as on the stem cell genomics grant, a participating but minor investigator who was the only person with purified stem and progenitor cells.

"I hope you dig into the actual current value of his or my stock, so that the public will know the real numbers. At least up to the wind-down of the company I believe I have never sold stock I hold, as I felt I always could have had information not generally available to the public, even when it was legal by SEC standards. In the early days of the company I contributed personal money to the company for stock so that the company could meet its payroll, and also I never sold those stocks. All of my SCI stocks are worth no more than and probably much less than 10% of that single contribution."

Alan Trounson, Former CEO of California Stem Cell Agency, Later Received $443,500 in Total Compensation from StemCells, Inc.

The Sacramento Bee this morning carried on its front page the following article about Alan Trounson and his relationship to StemCells, Inc. The piece was written by the producer of this blog. Following this item are the full texts of the comments made via email by Trounson and StemCells, Inc. (Irv Weissman of Stanford University submitted comments following the publication of this piece.) The complete text of comments from the state stem cell agency and Consumer Watchdog are contained within the article.
--------

By David Jensen
Special to The Bee

The former president of the $3 billion California stem cell agency received $443,500 in total compensation from the Bay Area stem cell company that appointed him to its board of directors only seven days after he left his state post.

The stock and cash were provided over a two-year period to Alan Trounson by Newark-based , a firm that was awarded more than $40 million in funding while Trounson headed the California Institute for Regenerative Medicine(CIRM), as the state stem cell agency is formally known.

Alan Trounson -- LATimes photo

StemCells Inc.

In 2014, when Trounson served less than six months on the StemCells, Inc.. board, his total compensation was more than double that of any other board member.

The surprise appointment of Trounson almost immediately after he left CIRM in 2014 generated allegations of conflict of interest. The size of Trounson’s total compensation, however, was not available at that time.

Conflict-of-interest allegations have dogged the agency since it was created in 2004 by California voters to use state bond proceeds to finance stem cell research.

In 2008, the respected scientific journal Nature warned about “cronyism” at the agency. In 2012, the Institute of Medicine, a division of the National Academies of Sciences, recommended in a $700,000 study commissioned by CIRM that the stem cell agency make sweeping changes to reduce the possibility of such conflicts.

Speaking about the agency’s board, Harold Shapiro, chairman of the Institute of Medicine team, told the Los Angeles Times,

“They make proposals to themselves, essentially, regarding what should be funded.”

The agency made some changes to deal with conflict questions but resisted the institute’s far-reaching proposals.

The latest news prompted John Simpson, who has followed the stem cell agency for Consumer Watchdog of Santa Monica, Ca., to say in an email,

 “Trounson’s joining the StemCells Inc. board a mere seven days after quitting as CIRM’s president at the time smacked of being a payback for a job well done on behalf of the company when he should have been looking out for the taxpayers’ money and interests. It was a blatant conflict that undermined the agency’s credibility. Now we know his price tag.”

In 2014, the stem cell agency said its “limited” investigation showed that no violation of law occurred. At the time, CIRM Chairman Jonathan Thomas described the issue as a “perception” problem.

The state’s Fair Political Practices Commission (FPPC) later investigated to determine whether Trounson “had made, participated in or influenced a governmental decision involving StemCells, Inc., after he began employment negotiations.”

A Feb. 6, 2015, letter to Trounson from the FPPC said there was “insufficient evidence to demonstrate” a legal violation.

Asked for comment, Robert Stern, the key author of the California Fair Political Practices Act and former president of the Center for Governmental Studies in Los Angeles, said in an email,

“It is an appearance problem when someone goes to work for a company that has benefited from huge contracts from the agency that he heads even if he had nothing to do with the decision to award the contract.”

The payments to Trounson were made in 2014 and 2015, according to Securities and Exchange Commission filings by StemCells, Inc. (See here and here.) The cash totaled $59,500 and the stock options totaled $384,000 for the two-year period. Trounson was appointed president of California’s stem cell agency in 2008. He was named to the StemCells, Inc., board July 7, 2014. The stock price has dropped precipitously since the award of Trounson’s stock options.

Last month, Trounson resigned from the StemCells, Inc.,  board as part of a deal in which the financially troubled firm was acquired by Microbot Medical Ltd. of Israel. StemCells Inc. said in an Aug. 15 SEC filing that the resignations of Trounson and Stanford University researcher Irv Weissman were not “the result any disagreement with the company on any matter.”

Irv Weissman, Stanford photo

Weissman was a co-founder of the company and also served on its scientific advisory board. Trounson served on the company’s strategic transactions committee.

Connections between Trounson and Weissman surfaced well before Trounson’s appointment to the StemCells, Inc., board. In 2013, a $40 million CIRM funding application round involving Weissman was postponed after it was disclosed that one of the application reviewers had a legal conflict of interest. The case involved Lee Hood of Washington state, who owns property in Montana with Weissman. Hood acknowledged the conflict of interest and resigned as a reviewer. Trounson helped to recruit Hood as a CIRM reviewer, the agency said.

In 2012, StemCells, Inc., was awarded $40 million in a single funding round, the only applicant ever to reach that level of success. One of the two $20 million awards was approved by the stem cell agency’s board despite being rejected twice by its grant reviewers. It is the only time that an application has been rejected twice by reviewers and then approved by the governing board. (See here.)

In 2013, the company declined one of the awards, which required a matching amount. In December 2014, the second $20 million award was terminated early because of poor results. That left StemCells, Inc., receiving a net of $9 million from the agency.

Trounson, a pioneering researcher in the field of in vitro fertilization, returned to his home in Australia after leaving the agency. Contacted by email, he said,

 “I was cleared by independent legal advice by CIRM and no conflict was found by a Californian government investigation. ... The share values are unknown – perhaps worth nothing. I actually pay monthly fees to hold them.”

Weissman, who has received $30.5 million from the agency, did not respond to a request for comment. (Following the publication of this piece, Weissman said in an email that some time after Trounson "got settled into his position" at the agency, "he recused himself on all grants and CIRM-related activities that involved either my lab or StemCells, Inc.")

The Trounson controversy surfaced shortly after C. Randall Mills was named to replace Trounson as president of CIRM. Mills then signed a pledge that he would not accept employment with any award recipient for at least a year after he leaves the agency. However, the agency did not set restrictions on future employment by other agency employees.

Asked for comment, Thomas, chairman of the agency since 2011, said in an email,

“Dr. Trounson’s financial involvement with StemCells Inc. occurred after his separation from CIRM in June of 2014, and we have not been in contact with him since. Two years later, CIRM is a very different and vastly improved organization – we’ve reduced the time it takes to review applications by 80 percent, recaptured $75 million from programs not meeting performance standards, and reinvested that money, doubling the number of clinical trials in our portfolio.

“In addition we are doing all this with the good governance, transparency and accountability the citizens of California deserve.”

The agency has about $800 million in uncommitted funds. It expects to run out of cash for new awards in 2020 unless it finds fresh sources of funding.

Text of Trounson Comments Re Compensation from StemCells, Inc.

Here is the text of Alan Trounson's email comments concerning the total compensation he received from StemCells, Inc., for service on its board. Trounson made the comments in response to an inquiry by the California Stem Cell Report regarding the matter and conflict of interest issues. The query did not involve reimbursement of travel expenses.

" I don't know what you think the conflict of interest is - I was cleared by independent legal advice by CIRM and no conflict was found by a Californian Government investigation. I was paid Directors fees and travel expenses to attend Board meetings. Do you expect me not to be reimbursed for travel and sitting as a Board Director? The share values are unknown - perhaps worth nothing. I actually pay monthly fees to hold them. I am no longer a Director of Stem Cells Inc and do not know what will happen to the shares. Stem Cells Inc has advised you the $ you quote for my reimbursement is inaccurate.
"Alan Trounson PhD
"Emeritus Professor"

The California Stem Cell Report followed up with an additional question regarding the matter and the state investigation. Trounson replied,

"Stem Cells Inc has told you exactly what I was paid and the state of the shareholding. You ought to do your own investigations into the Cal Government investigations and report like any reasonable journalist. The CIRM review was not 'limited' - external legal advice confirmed internal advice." 

Text of StemCells, Inc., Comments on Trounson Compensation

Here is the text of remarks from Ken Stratton, president of StemCells, Inc., concerning the $443,500 in total compensation from the company to Alan Trounson.

"As stated in our SEC filings, Dr. Trounson was paid total cash compensation of $59,550 for the years 2014 and 2015, consistent with board practice. He has also been provided stock awards which were to vest over time. Dr. Trounson currently owns fewer than 20,000 shares of our common stock and to my knowledge, he has never sold any of his shares. His unvested equity awards will not continue to vest now that he has resigned from the board in connection with the Microbot deal."

Good Safety News in Asterias California Stem Cell Trial

Jake Javier and family -- Javier family photo

For 18-year-old Jake Javier, it's a small matter of 10 million stem cells. And hope.

Javier is one of the patients in a clinical trial backed by $14.3 million from California's stem cell agency, which announced today some good news about the safety of that research.

For Javier, however, the details about "efficacy cohorts" and "AST-OPC1" were a little more personal. The former high school football player is paralyzed from the chest down as the result of a swimming pool accident in June on the eve of his high school graduation.

Today he is one of a handful of patients enrolled in the spinal cord clinical trial by Asterias Biotherapeutics of Menlo Park, Ca., which picked up the human embryonic stem cell trial after it was abandoned by Geron in 2011.

The $3 billion stem cell agency announced today that Asterias "has cleared two key safety hurdles and been given approval to expand the therapy to a larger group of patients with a much higher dose of cells."

The next step is to insert 20 million stem cells into patients, up from the 10 million that Javier received.

Javier, who played football at San Ramon Valley High School, has been the subject of widespread media attention and fund-raising, including considerable reporting by San Francisco Bay Area television station KTVU.

Writing today on the stem cell agency's blog, The Stem Cellar, Kevin McCormack, senior director for communications, said,

"For people like Jake Javier this news is not about numbers or data, it’s personal. Earlier this summer Jake broke his neck at a pool party, celebrating graduating from high school. It left him paralyzed from the chest down with extremely limited use of his arms and hands. On July 7^th Jake was enrolled in the Asterias trial, and had ten million cells transplanted into his neck.

"It could be months, even as much as one year, before we know if those cells are having any beneficial effect on Jake. But at least for now we know they don’t seem to be having any negative effects."

McCormack wrote,

“Our focus is always on the patient, so making sure a potential therapy is safe is an important first step,” says C. Randal Mills, Ph.D., the President and CEO of CIRM. “I recently met with Jake Javier, a young man who was treated in this trial, and heard first-hand what he and his family are going through in the aftermath of his injury. But I also saw a young man with remarkable courage and determination. It is because of Jake, and the others who volunteer to take part in clinical trials, that progress is possible. They are true heroes.”

For more on Javier and the research see: Facebook and the stem cell agency progress report.

Left to right, Dr. Marco Lee, a member of the transplant team, Jake Javier,
 his mother, Isabelle, and Randy Mills, president of the California Institute for
Regenerative Medicine, as the stem cell agency is formally known. 

'Unnerved' Researchers and Proliferation of Stem Cell Clinics: The Perspective from Los Angeles Times

The Los Angeles Times this past weekend picked up on the growing concern about the spread of dubious stem cell clinics triggered in many ways by a first-ever study by a UC Davis stem cell researcher. 

Pulitzer Prize-winning columnist Michael Hiltzik wrote,

"The proliferation of clinics nationwide offering stem cell therapies unnerves many researchers, who fear that unrealistic public expectations could undermine their own credibility. Patients with hard-to-treat conditions such as multiple sclerosis and Parkinson’s are easy marks who can be led to forgo established therapies in favor of unproven ones."

The headline on Hiltzik's piece said,

"These new stem cell treatments are expensive — and unproven"

Hiltzik interviewed a California lawyer who is working in the field. Hiltzik wrote,

"'Stem cell scientists include the best and the brightest doing great work, and I admire them,' says Janice Mulligan, a San Diego attorney currently assembling evidence for a potential class-action lawsuit against unnamed stem cell clinics. "At the other end of the scale, there’s snake oil.'"

Hiltzik also spoke to Paul Knoepfler, the UC Davis researcher who co-authored the study about stem cell clinics with Leigh Turner of the University of Minnesota. Hiltzik wrote,

"In an article just published in Stem Cells Translational Medicine, Knoepfler described his visit to one informational seminar sponsored by a clinic pitching a $5,999 stem cell treatment to about 30 attendees. Each was given a pack of forms to fill out, including a credit application. The spiel, he reported, featured personal anecdotes and 'questionable medical claims' — including the assertion that '90% of patients had a 50% or better improvement.'"

Odds for a Stem Cell Cure vs. Odds on Trump Winning the Election

The article explored one particular search for a cure for diabetes, but the headline was bleak.

"Will Embryonic Stem Cells Ever Cure Anything?"

The question came at the top of a piece by Aleszu Bajak in the Aug. 12, 2016, edition of the MIT Technology Review. 

Bajak quoted Doug Melton of Harvard as saying,

“The public definitely doesn’t appreciate that much of science is failure.”

Bajak, a veteran science writer and journalism instructor, continued with his own conclusion, 

"In fact, no field of biotechnology has promised more and delivered less in the way of treatments than embryonic stem cells." 

Hard, hard language that probably disturbs many in the field, including some at the California stem cell agency, which was founded on the promise of therapies from human embryonic stem cells(hESC). The agency has committed more than $2 billion to stem cell research since 2005 and is still looking for its first big score.

One can argue the fairness of the conclusion by Bajak, but it certainly seems tied to the excessive rhetoric that has surrounded the hESC field, particularly the $34 million ballot campaign that created the $3 billion state stem cell agency in 2004.

The rhetoric of the campaign came with a price. The agency is scheduled to run out of cash for new grants in 2020. Whether it can deliver on the campaign promises of 2004 will in large part determine whether it can conjure up additional funding.

The likeliest prospects for success today can be found in the list of clinical trials the agency is helping to fund and the scores of additional trials that it plans to assist in the next several years. They include efforts to deal with afflictions ranging from heart disease to diabetes.

By one widely cited measure, only one out of 10 conventional therapies entering clinical trials reaches the market place. Those are slim odds, ones that do not involve novel stem cell efforts, which are presumably more difficult. To put it another way, Donald Trump has better chances -- as of this writing -- of being elected president than of a clinical trial producing a stem cell cure.

Trump, however, is only going to have one chance. The California stem cell agency is expecting to take more than 50 shots at a therapy via its involvement in clinical trials over the next several years.

Nonetheless, it is a risky business, as venture capitalist Gregory Bonfiglio, pointed out to the California Stem Cell Report last December.  He said,

“There are risks inherent in the development of new, disruptive technology. The bigger risk is failing to deliver on their underlying promise to bring new regenerative therapies to patients…. The bigger risk is not doing anything.”

Digging into the 'Stem Cell Hard Sell:' Researcher Ventures Into 'Lion's Den'

A California stem cell researcher went "semi-undercover" recently and attended a commercial "educational seminar" that promoted stem cell treatments and handed out requests for credit information from those attending.

Paul Knoepfler -- UC Davis photo

Paul Knoepfler of UC Davis recorded his experience at the session in an article this week in the Stem Cells Translational Medicine, which was founded in 2011 with $600,000 from the California stem cell agency.

Knoepfler did not identify the stem cell clinic that conducted the session. He said he wanted instead to be able to use a "higher degree of frankness" in writing about the session. Knoepfler noted, however, that he was quickly spotted by one of the organizers, some of whom lurked around him during the session. Knoepfler wrote on his blog Monday, 

"It was an intense experience and one where I felt at risk. To some extent it is akin to  going into the lion’s den. I didn’t know what reaction I would get if I were recognized by those running the seminar, which in fact did happen. They did not seem happy at all that I was there even though I wasn’t disruptive in the least. I had hoped to ask a few questions from my place in the audience, but the format did not allow it. Still I wondered if I could be kicked out. That didn’t happen."

The clinic involved is one of at least 570 across the country. Earlier this summer, Knoepfler and Leigh Turner, a University of Minnesota bioethicist, were the first to report on the scope of what passes for the commercial stem cell clinic industry in the United States when they documented the existence of those clinics.

About 30 people attended the session Knoepfler was at, including some who obviously had "serious medical conditions." He wrote,

"The seminar team (mostly dressed in medical scrubs) handed out a clipboard to each attendee with three pieces of paper very much like those that one might be given on arriving at a new doctor's office. We were told to fill in our information and then to return the sheets back to them before we left. Notably, the top sheet was a credit application. On another page, the clinic asked for extensive personal information, including name, age, birthdate, address, e-mail and phone number. Additional questions asked about medical conditions, as well as medical tests that had already been conducted." 

Knoepfler said several medical claims were made during the meeting including that the treatments had no side effects, were safer than the normal standard of care, did not pose immune rejection problems, were federally approved and were specifically effective for arthritis and pain.

The price of the treatment was $5,999 but attendees could get $1,000 off "if you sign up today at the seminar." Attendees were told that the clinic was heavily booked already with a one to two month waiting period.

In the piece about his foray into the "lion's den," Knoepfler wrote,

“Given the growing realization that there are hundreds of stem cell clinics in the U.S. today in 2016 and the observation that many hold recruitment seminars, it is possible that thousands of members of the public each year are attending infomercial seminars that provide misleading or even outright factually incorrect information about stem cells and questionable medical claims. This could not only lead many patients to receive unnecessary, unsafe or ineffectual treatments, but it may also contribute to public confusion about stem cells and the field of stem cell clinical research. These seminars represent only one type of an assortment of recruitment methods, including Internet, radio, newspaper, and television ads for various clinics, which may also contain dubious statements. I believe that such stem cell clinic marketing poses a significant threat to public perception and understanding of the legitimate stem cell translational medicine field.”

Pigs and People: Growing Human Organs in Animals, Changes at the Federal Level

Last week's news that the federal government is moving to lift its ban on funding research involving human-animal hybrids is a bit of old hat in California.

The state's $3 billion stem agency has long been okay with such research and has well-established protocols to ensure that it is conducted ethically and safely.

Last year, the agency, formally known as California Institute for Regenerative Medicine (CIRM), reported (see below) on its activities to the National Institutes of Health, declaring,

"CIRM has reviewed twelve protocols at seven different institutions where stem cells or neural progenitor cells were introduced into vertebrate animals. CIRM found that all protocols were reviewed and approved by a SCRO(standards review) committee consistent with CIRM requirements."

The Chimera of Arezzo -- photo by Joe deSousa

The announcement that the NIH is once again likely to fund the creation of chimeras -- organisms composed of genetically different cells -- received a significant amount of attention in the media. But none of the stories noted the origin of the word in Greek mythology, where it signified a fire-breathing female monster with a lion's head, a goat's body and a serpent's tail.

Sara Reardon of Nature wrote,

"Chimeras are a growing area of research. Currently, researchers use them to study early embryonic development and to create animal models of human diseases. But one major goal is to engineer animals to grow human organs. The organs could later be harvested from the adult animal and used for transplantation into a patient."

Kevin McCormack, senior director of communications for CIRM, told the California Stem Cell Report, last April,

"On a purely theoretical level CIRM has no objection to growing replacement organs or tissues in pigs, provided it met all CIRM’s rules and regulations. We fund research that does that all the time with mice and rats. Right now none of the research we fund is being used to do that."

Shen Ding -- Gladstone photo

Lenny Bernstein wrote in the Washington Post that researcher Shen Ding at the J. David Gladstone Institutes in San Francisco and who has received $6.7 million in research funding from CIRM, sounded a note of caution.

"While he does not favor the current (NIH) moratorium, Ding said, he believes scientists in this field must move slowly because 'we don't know how to precisely control where and how [cells] might contribute' to different organs."

Bernstein noted,

"The NIH imposed its temporary ban on funding last September, citing ethical concerns. These include worries over animals whose brains might contain human brain cells and what might happen if chimeras were able — and allowed — to reproduce."

The NIH is accepting comments over the next several weeks and then is expected to move forward with its proposal, perhaps with changes.

For Hank Greely, a Stanford law professor, it's about time. Last spring, he wrote an op-ed piece in the Los Angeles Times and said, 

"Today we face the possibility of babies getting organs grown in human/nonhuman chimeras — beasts that are pigs except for a single human organ. To the uninitiated, this may sound more like the dark arts than modern medicine, but pursuing careful research and potential clinical use of these chimeras is both proper and important."

  CIRM Statement to NIH re Chimera Research by DavidJensen on Scribd

The Human Egg Business: More Media Coverage of California Cash-for-Eggs Legislation

A renewed legislative effort in California to pay women for handing over their eggs for research is attracting more attention this year, including opposition from a former state senator sometimes called the mother of the state's stem cell agency.

Deborah Ortiz, former chair of the California Senate Health Committee, wrote an op-ed piece published this week in The Sacramento Bee. She noted that the stem cell agency prohibits paying women for their eggs. Ortiz wrote,

"I oppose AB 2531 (the number of the bill) on a number of grounds: First, we have very limited information on the long-term health effects of the egg retrieval process. Second, women who undergo egg retrieval are not research subjects in the traditional sense, as proponents assert. Finally, paying for women’s eggs for research purposes contradicts well-established national recommendations and state policy."

She continued,

"This is not an issue of equity with other research subjects. Women providing eggs for research are not comparable to research subjects in clinical trials. Their role is providing raw materials for pre-clinical research, rather than participating as subjects in medical research. And they are not afforded the safeguards or follow-up of subjects in clinical trials.

"Finally, AB 2531 conflicts with national recommendations and with policies in our state constitution. The 2010 guidelines of the National Academy of Science recommend that no payments beyond reimbursement for expenses be made for donating eggs for research."

Ortiz has been called the mother of the California Institute for Regenerative Medicine (CIRM), as the agency is formally known, because of her early role in support of stem cell research and authorship of an initial measure to use bond funding to finance it.

The cash-for-eggs bill also drew attention from Michael Hiltzik, a Pulitzer prize-winning columnist at the Los Angeles Times. He said that the measure should not be approved. Hiltzik wrote,

"There is scant research on the long-term health risks of egg retrieval, and nothing in the bill that would encourage more. To paper over that fact, the measure’s advocates have engaged in a neat bit of obfuscation. Assemblywoman Autumn Burke (D-Marina del Rey), who is carrying the bill for the ASRM, labels it a 'pay equity' bill....

"But it’s not about equity or discrimination. What worries the bill’s critics is that the measure may allow women to be misled into taking uninformed health risks by the prospect of easy cash."

The legislation surfaced at Buzzfeed in a piece by Cora Lewis and Azeen Ghorayshi. They quoted Sean Tipton, a spokesman for the fertility industry group, American Society for Reproductive Medicine (ASRM), that is sponsor of the legislation.

“'It’s (the bill is) needed to correct a strange and outdated feature in California law.'...Women are paid when they donate eggs to make babies, and people are paid when they are research subjects, he noted. 'But if you combine the two, you can’t be compensated. I don’t think that makes any sense,' Tipton said."

Another piece appeared on the Undark web site. It was written by Diane Tober, an assistant professor at UC San Francisco. She wrote,

"As a researcher myself, I can sympathize with the seduction of discovery, and the lure of developing new technologies and treatments that stem cell research may offer society at large. The millions of dollars of funding available to support such research would also be enticing.

"But the history demonstrates that the burden of human experimentation has rested on the shoulders of the socially and economically disadvantaged. The focus of AB-2531 is to obtain eggs for research, but it ignores the need for research into the impacts of the myriad drugs and procedures used to coax and extract those eggs in the first place." 

Leading the drive against the measure, vetoed by Gov. Jerry Brown in 2013, is the Center for Genetics and Society in Berkeley. It is circulating a flyer aimed at California lawmakers that says,

"This bill incentivizes invasive procedures that expose women to substantial short-term and unknown long-term health risks."

Brown has given no indication that he has changed his position on the measure.

Why Does It Matter? Clues for Scientists When Dealing with Reporters

Scientists -- like Boy Scouts -- should be prepared when that call comes in from one of the ink-stained wretches of the mainstream, print media or one of the harried online reporters who hardly have time to think.

Based on decades of experience on behalf of the folks who own the presses, I can tell you that is a good admonition. It was reinforced mightily by another few years on the opposite side of the reporters' notebook, where it became readily apparently that interviewees need to think carefully about the message they want to impart.

Today, I ran across some advice to journalists who aspire to query researchers. I am passing it along to the readers of the California Stem Cell Report, 99.9 percent of whom would never see it otherwise.

It helps give our readers a frame of reference and a clue to what to expect when a mass media opportunity comes knocking. So here it is, questions for journalists to ask scientists, as prepared by Elissa Yancey of the Poynter Institute, a well-respected Florida enterprise involved in journalism training.

• "Why does this study matter?
• "Why did you want to do this study?
• "How does this study relate to your other work?
• "What was your role in the study?
• "What surprised you the most?
• "Did you change any of your or your family’s habits as a result of anything you learned from this study?
• "What are the economic stakes of the study/topic from your perspective? Your employer's or funder's perspective? (i.e., whose profits / earnings might be harmed or helped by this study? Who is invested in it?)
• "What comes next? (More studies? Different funders? Legislation?)"

NYTimes: Fresh and Major Attention to Immunotheraphy and Cancer

The New York Times personalized its look at immunotherapy -- Times graphic

The New York Times this weekend unveiled a dramatic, special report on immunotherapy to treat cancer, a field in which California's stem cell agency has invested tens of millions of dollars.

The Times' work will undoubtedly focus greater public attention on the use of immunotherapies and generate a fresh surge of interest on the part of patients who are unfamiliar with the expensive treatment, which is very much in its infancy. The Times wrote,

"Harnessing the immune system to fight cancer, a medical dream for more than a century, is becoming a reality. Terminally ill patients who had slim chances of surviving have gone into remission and patients with inoperable tumors are gaining months or years. But so far, the new treatments work for only a minority patients, and doctors are not sure why. The treatments are prohibitively expensive, and not all patients have access to them."

The Times did not deal with any of the work specifically backed by California. But as recently as March, the $3 billion California Institute for Regenerative Medicine(CIRM), as the stem cell agency is formally known, made another investment in the field with more than $10 million to two researchers, William Murphy of UC Davis and Lili Yang of UCLA. (See Tran1-08533 and Tran1-08635 here.)

In February, Alex Lash of xconomy reported that a new immunotherapy firm has sprung from handsome support by the stem cell agency. He wrote,

"Forty Seven(the firm's name), emerged Wednesday with a program already in clinical trials, a rarity for an academic spinout. Stanford researchers led by Irving Weissman, the director of the school’s Institute of Stem Cell Biology and Regenerative Medicine were able to begin testing the drug in humans thanks to $30 million in funding from California’s stem cell agency, known as CIRM."

Lash said that Forty Seven is named for the CD47 protein on tumor cells that its experimental cancer drugs target.

The agency also sponsored a webinar last year on immunotherapies with participation by the Food and Drug Administration and Kite Pharma of Santa Monica, Ca., and which covered such topics as safety and regulatory issues. The webinar is available here. Slides offered by Margo Roberts of Kite can be found here.

Here are links to the various Times stories.
Harnessing the immune system to fight cancer
What is immunotherapy
Immunotherapy offers hope to a cancer patient but no certainty

NY Times: Stem Cell Theory vs. Flourishing, Dubious Stem Cell Clinics

The New York Times this morning took a crack at coverage of the first-ever study of the wave of dubious stem cell clinics in America. The headline on the Times' prominently displayed story said,

"Stem Cell Therapies Are Still Mostly Theory, Yet Clinics Are Flourishing"

The starting point for the article by Gina Kolata was the study by UC Davis stem cell researcher Paul Knoepfler and bioethicist Leigh Turner of the University of Minnesota.  They reported on June 30 that nearly 600 dubious stem cell clinics have sprung up around the country. It is the first study to document the reach of these businesses. The report, published in the scientific journal Cell Stem Cell,  received heavy mainstream media coverage.

Kolata highlighted the tentative nature of stem cell research. She wrote,

 "In theory, stem cells might be a useful treatment for certain diseases that involve the loss of cells, like Type 1 diabetes, Parkinson’s or osteoarthritis. They are primitive cells that can develop into a range of mature cells and perhaps serve as replacements. But progress is slow. After a flurry of stem cell excitement two decades ago, almost all the research today is still in mice or petri dishes. The very few clinical trials that have begun are still in the earliest phase.

"The problem is that stem cell therapies are still mostly theory. So what is going on? How can there be clinics, even chains of clinics run by companies, offering stem cell treatment for almost any disease you can think of — sports injuries, arthritis, autism, cerebral palsy, stroke, muscular dystrophy, A.L.S., cancer?"

She said that the Knoepfler-Turner study showed "what can happen when regulations fall behind." 

And she noted the limits of federal regulation as well as the failure of state regulatory bodies to deal with the issue. 

Kolata's story was displayed online this morning on the main page of the New York Times. The media attention to the work by Knoepfler and Turner has significantly raised the visibility of the issues involving dubious stem cell "therapies."  A narrowly defined search on Google news this morning turned up nearly 11,000 citations, up from about 7,000 early this month.

The coverage certainly has increased the likelihood of some sort of additional regulatory action. However, such moves take time, and it is not realistic to expect a crackdown anytime soon. Indeed, it may require legislative changes at the federal and state levels.

As for the ethical and medical concerns raised by Knoepfler and Turner and the Times piece, one Times reader -- identified online only as Susan -- said,  

"So what? A lot of what the scientific/medical establishment tries to sell us is just theory. Studies of this and studies of that. A study will come out and 6 months later another study will come out debunking the first study. I believe the problem is that some of these science/medical 'experts' are under the delusion that 'one size fits all.' I disagree. What may kill one person may help another."

Tracking California Stem Cell Awards: Diabetes to Dialysis

The California stem cell agency, as expected, yesterday pumped $10 million into a North Carolina firm for a kidney dialysis device and upped its stake in a San Diego diabetes therapy firm to $60 million.

The awards were first reported (see here and here) by the California Stem Cell Report last week, which will have more on the subject and other awards in the next day or two. Here is a link to the press release from the $3 billion agency. 

California Stem Cell Appeals: Zika, Parkinson's and 'Heart-on-a-Chip'

Three California researchers are asking the directors of the state's stem cell agency today to reject the decisions of its blue-ribbon scientific reviewers and grant them awards ranging up to $2 million.

The scientists are Alysson Muotri, director of the UC San Diego stem cell program; Birgitt Schuele, director of gene discovery and stem cell modeling at the Parkinson's Institute in Sunnyvale, and Kevin Healy, professor in the department of bioengineering at UC Berkeley.

Muotri is seeking $1 million from the California Institute for Regenerative Medicine (CIRM), as the stem cell agency is known. Schuele has applied for $2 million and Healy $1 million.

Alysson Muotri, UCSD photo

In a letter to CIRM's board, Muotri said he is attempting to "set up a human stem cell platform to measure the impact of the Zika virus in the nervous system and to screen potential drugs to alleviate the neurological problems associated with the infection." His application (DISC2-09095) is aimed at filling "fundamental gaps" in Zika knowledge. Muotri, who is from Brazil, wrote,

"I never debated over a grant fund decision before . However, in this case I feel I have the responsibility to alert the ICOC (the CIRM board) about neglecting studies on what we call now the ' Zika virus syndrome.' I can tell by personal experience dealing with this virus in my own lab that this is one of the most dangerous infectious agent I (have) ever seen – one can witness the virus killing brain cells in less than a day."

Birgitt Schuele, TSN photo

Schuele's letter pointed out a new study that she said demonstrated the feasibility of her research (DISC2-08953) involving a therapy for Parkinson's disease. She also included additional information that she hoped would be persuasive to the CIRM board.

Kevin Healy
photo by Laura Peterson, AAAS

In his letter, Healy said his research is aimed at developing "patient specific ‘heart-on-a-chip’ diagnostics that will have a significant impact on the early screening of drugs used to manage hypertrophic cardiomyopathy . Currently, there are no drugs that target specific disease alleles of hypertrophic cardiomyopathy."

He said the main criticism of CIRM reviewers involved the "level of maturity of cardiomyocytes" in his proposed study (DISC2-08990). But he said he proposed using the same protocol as already used by a number of currently funded CIRM researchers.

All three applications were ranked below the cutoff line for funding, which was 85. The score for Healy was 83, Muotri 77 and Schuele 72.

CIRM has funded some applications in the past with lower scores than 85. But in the last two years, it has revised its review and scoring protocols. Since then it has not overridden reviewers' negative recommendations.

The board is scheduled to act on about $30 million in awards today in a telephonic meeting with public locations throughout the state. (See here and here. ) The public can participate in the meeting at those locations, whose addresses can be found on the meeting agenda. The session will be audiocast on the Internet and through an 800-number. Complete information about the Internet access and phone number can be found on the agenda.

Search for a Diabetes Cure: California Stem Cell Agency Hits $60 Million Mark with ViaCyte

The California stem cell agency next week is slated to award  an additional $4 million to ViaCyte, Inc., a San Diego firm that is working with the agency to develop a "virtual" cure for diabetes.

ViaCyte has already received $56 million over the years from the California Institute for Regenerative Medicine(CIRM), as the agency is formally known. The latest award will be used to help prepare for a clinical trial for a new treatment for the highest risk diabetes patients.

In response to a query this morning from the California Stem Cell Report, Paul Laikind, president and CEO of ViaCyte, said that the new product, PEC-Direct, will deliver the same biologic component as used in the firm's current product, which is now in a clinical trial.

Laikind said PEC-Direct will allow direct vascularization, which "is expected to allow for a very robust engraftment and cellular performance."

Because the new device will require chronic immune suppression, Laikind said,

"It is being developed to treat patients with type 1 diabetes that are at high risk for acute complications such as severe hypoglycemic events associated with hypoglycemia unawareness syndrome."

(The full text of Laikind's remarks and research update can be found here.)

The agency's summary of the closed-door review of the Viacyte proposal said,

"There are over 100,000 people in the U.S. with type 1 diabetes so severe that they are at constant risk of hospitalization and/or death. Within months after administration, this product could naturally restore those patients’ blood sugar to normal healthy levels and save their lives." 

In addition to the $4 million, ViaCyte is putting up $994,343 of its own cash.

CIRM's blue-ribbon panel of scientific reviewers has already approved the award, which is part of a $30 million package of applications coming up next Thursday.  The governing board of the agency will ratify the approvals at its meeting next Thursday during a one-hour telephonic meeting.

The largest award, $10 million, will go to Humacyte, Inc., of North Carolina,  to produce an artificial vein for use in hemodialysis as reported yesterday on the California Stem Cell Report. More details of all the applications and review summaries can be found on the meeting agenda.

The session will be audiocast and carried on the Internet on a listen-only basis. Interested parties can participate in the meeting from telephonic locations throughout the state.

The main site for the meeting will be at the Sanford consortium in San Diego. Other locations include the agency's headquarters in Oakland and sites in Davis, South San Francisco(2), Napa, Los Gatos, Sacramento, Irvine, San Francisco and Los Angeles. For specific addresses and instructions for online access, see the agenda.