Tuesday, April 26, 2016

California Stem Cell Report Dark This Week

Since the publisher of this report is making a passage aboard the sailing vessel Hopalong this week along the west coast of Mexico, don't expect any fresh items. Postings will resume next week.

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Friday, April 22, 2016

California Stem Cell Research and a Super Doc: Inside a $4.4 Million Windpipe Grant at UC Davis

Paolo Macchiarini, Guardian photo 
Headlines around the world once hailed Paolo Macchiarini as a super-surgeon, a stem cell trailblazer who was responsible for the ground-breaking, first-ever stem cell-based trachea transplant.

It was good enough work, indeed, to be cited in 2013 as a starting point in a pitch by a team from the University of California, Davis, for $13 million from the $3 billion California stem cell agency. 

In their application, scientists Peter Balafsky and Alice Tarantal said they would build on the "first-in-human surgical successes with (the) stem cell-based tissue engineered airway implants" pioneered by Macchiarini

Last month, Macchiarini was fired from the prestigious Swedish Karolinska Institute. Six of eight of his patients have died. The institute said,
 "He has acted in a way that has had very tragic consequences for the people affected and their families."
The controversy has stirred up the international stem cell community with blog postings and sharp accusations. And in January, Vanity Fair carried an article that reported Macchiarini falsely claimed he was part of a “highly classified group of doctors from around the world who cater to the world’s VIPs,”including Pope Francis, Bill and Hillary Clinton, Emperor Akihito of Japan and President Obama.

The Italian doctor has denied the charges that led to his dismissal in Sweden and has been working in Russia.

The Macchiarini saga and its California connections offer a peek into the global nature of stem cell research and how scientists must rely on the integrity of others thousands of miles away --  as well as  the sometimes agonizingly slow search for cures. It also provides a deeper look at how the California stem cell agency goes about handing out money.

The California Stem Cell Report queried both Balafsky and Tarantal about their grant along with the California Institute for Regenerative Medicine (CIRM), as the stem cell agency is formally known.  

Kevin McCormack, senior director of communications, replied for CIRM. Asked whether the agency looked into the research by Belafsky as a result of the questions raised about Macchiarini, McCormack said,
"As with all the research we fund we have been carefully following the progress of Professor Belafsky’s project ensuring it continues to meet our rules and regulations."
Peter Belafsky, UCD photo
Belafsky, professor and director of the Voice and Swallowing Center at UC Davis, and Tarantal, professor in the Department of Pediatrics and Department of Cell Biology and Human Anatomy, said Macchiarini is not involved in the CIRM project. The point was stressed in boldface letters in their email response:
"Dr. Macchiarini has had no involvement in this project on any level, in any way, at any time."
(For the full text of the response, see here.)

Macchiarini was not always isolated from UC Davis and Belafsky. Macchiarini served on Belafsky's international team in 2010 when the Belafsky group performed the second-ever larynx transplant. The operation restored the voice of a Modesto, Ca., woman who had been unable to speak for a decade. 

UC Davis issued a press release saying Macchiarini served as an advisor and assisted in the surgery. The statement also said that Martin Birchall of the United Kingdom, a co-leader with Macchiarini on his ground-breaking 2008 transplant surgery, served as a scientific advisor and assisted with the California larynx surgery.

Birchall was identified as a collaborator on the CIRM grant that was approved for Belafsky and Tarantal.  A press release from University College London said that the work in Davis would serve as a "fundamental under-pinning" for two clinical trials in the United Kingdom.

Birchall received a $19,800 planning grant in 2011 to prepare an application for research that appears to be aligned with the current work at UC Davis. Birchall was listed by CIRM at the time as a researcher at the California campus.

Belafsky and Tarantal told the California Stem Cell Report that Birchall is no longer involved with their work. They said,
"Dr. Birchall was involved in our project at the onset, but due to the logistical difficulties of intercontinental collaboration, is not currently an active participant."
The Belafsky/Tarantal application originally sought $13.3 million. It was trimmed to $4.4 million on the recommendation of the agency's then president, Alan Trounson, who apparently agreed with reviewers that the initial scope and budget were high, but still recommended funding.

The application was given a score of 70 on a scale of 100 by agency's blue-ribbon scientific reviewers, all of whom came from out-of-state. As is their usual practice, the reviewers met behind closed doors and voted on the application. The action then went to the CIRM governing board, which has almost never rejected a favorable decision by its reviewers, whose economic and professional interests are not disclosed publicly.

The score of 70 placed the proposal just below the cutoff line of 75 for routine approval by the board, but the reviewers did not nix application.

The agency publishes a summary of reviewer comments, which does not identify applicants or their collaborators. The summary on the UC Davis application said the research "presents a unique opportunity to bring a world-leading regenerative medicine technology to California." The summary additionally said, without elaboration, "It was also noted that this project is unlikely to be funded by other agencies."

The summary said,
"Reviewers agreed that having already treated human patients (such as those involved with Macchiarini) using this approach is strong proof of concept(for Belafsky's work)."
Reviewers noted that "manufacturing and testing methods were not well described" but "the UK-based collaborators (Barchall and his group) will clearly play an important role in helping to establish the manufacturing process."

The summary added,

"Reviewers were unclear on the relationship between the California- and UK-based team members and whether the relationship and efforts were collaborative or duplicative."
Belafsky appeared before CIRM directors in Los Angeles in December 2013 to ask them to approve his research, saying good treatments for "complex breathing and swallowing problems" do not exist. With little debate, the board voted 8-0 to approve the award.

CIRM's McCormack said that the agency has paid out $3.3 million of the $4.4 million grant. He said, 
"Dr. Macchiarini has never been a part of the UC Davis project or any work that CIRM has funded.... The primary aim of the CIRM project is to determine the scientific reproducibility of research results from previously published studies regarding tissue-engineering for severe airway stenosis. The results are pending."

Belafsky said in his email,
"The translation of high-risk, complex innovation from the laboratory to suffering patient is not an easy road. The controversy surrounding Macchiarini has resulted in the redoubling of our efforts to explore the science behind what saves lives and what does not. This step is essential in order to lay a firm, evidence-based foundation upon which to build.
"Since your primary focus relates to the work of Macchiarini, I would like to re-emphasize that our project is fundamentally different. Our research is focusing on decellularized trachea only, whereas he has utilized synthetic grafts."
Belafsky continued,
"This is a work in progress, and we do not yet have the data to answer all the questions raised by the scientific community. We may apply to CIRM for funds to continue our research, but will not consider human implantation until we are satisfied that the science is sound and the technology is safe."
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Text of Belafsky-Tarantal Reponse

Here is the text of the response from scientists Peter Belafsky and Alice Tarantal of UC Davis concerning questions asked by the California Stem Cell Report. The questions first and then the response.
The questions
"Has Macchiarini been involved in any way, including informal consultation or contact, with your CIRM award? If so, please describe the nature of that contact.

"What is the nature of the collaboration with Birchall?

"Have the disclosures concerning Macchiarini altered your direction or delayed your CIRM research?

"Has UCD inquired concerning your CIRM research in the wake of the Macchiarini disclosures? If so, what is the status of that inquiry?

"What is the current status of your research? The CIRM progress report on its web site appears to be old, and you are nearing the final stages of the term of the award.

"Do you plan to apply to CIRM to advance your research into a clinical trial?

"Is there anything else that would be useful for the public to know?"

The response
"Hi, David.

"I appreciate your inquiry and dedication to advancing regenerative medicine. I am a head and neck surgeon specializing in the care of patients with complex airway collapse. In June of 2008 an international team performed what was then considered to be the world’s first tissue-engineered organ transplant to help save a suffocating mother who was failed by contemporary medicine. The team took a donor trachea stripped of innate cells, implanted it with autologous stem cells, and transplanted it into her failing windpipe. The operation was a success, and the patient is alive and well. Based on this achievement, similar technology was used in 2010 to save the life of a 10 year-old boy; he is now a thriving 15 year-old.

"Since the initial success with decellularized/re-cellularized human donor trachea, work on synthetic trachea implanted with autologous stem cells has not shown equal promise, and people have died. We have had no involvement in these procedures or investigations.

"An article published in 2013, by Gretchen Vogel (Science. 2013 Apr 19;340(6130):266-8), questioned the success of this work and urged caution before moving the science forward. She and others, our team included, have suggested that more research is required to determine the fate of the cells and the long-term viability of the grafts before making the implants widely available to patients. Our team at UC Davis is uniquely qualified to address these questions and we coordinated the CIRM proposal to fund the research to critically evaluate the donor trachea method. Our university’s support in this endeavor has not wavered.

"The ultimate goal of our work is to provide better treatment options for people with life-threatening airway stenosis. The primary aim of our CIRM grant is to take a step back and understand what happens with the grafts in the lab before initiating operations in people. This is a work in progress, and we do not yet have the data to answer all the questions raised by the scientific community. We may apply to CIRM for funds to continue our research, but will not consider human implantation until we are satisfied that the science is sound and the technology is safe.

"To answer your questions, Dr. Birchall was involved in our project at the onset, but due to the logistical difficulties of intercontinental collaboration, is not currently an active participant. Dr. Macchiarini has had no involvement in this project on any level, in any way, at any time. (Belafsky's boldface italics)

"The translation of high-risk, complex innovation from the laboratory to suffering patient is not an easy road. The controversy surrounding Macchiarini has resulted in the redoubling of our efforts to explore the science behind what saves lives and what does not. This step is essential in order to lay a firm, evidence-based foundation upon which to build.

"Since your primary focus relates to the work of Macchiarini, I would like to re-emphasize that our project is fundamentally different.  Our research is focusing on decellularized trachea only, whereas he has utilized synthetic grafts.

"Warm regards,
"Peter Belafsky, MD, PhD
"University of California, Davis"
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Wednesday, April 20, 2016

The California Stem Cell Effort -- $3 Billion, $6 Billion or $9 Billion?

Many persons know that the true cost of California's stem cell research effort runs closer to $6 billion rather than the $3 billion figure normally bandied about.

What if the cost were boosted to about $9 billion because of wasted research that cannot be replicated?

That's a question that comes up as the result of a piece yesterday on Slate, an online news site. The headline on the article by award-winning science writer Daniel Engber said,
"There's a replication crisis in biomedicine -- and no one even knows how deep it runs."
The Slate piece cited a $28 billion figure nationally for the amount of preclinical, biomedical research that cannot be reproduced and thus represents money wasted. The estimate was produced last June by two economists. They analyzed previous studies to come up with the dollar figure, calculating that 50 percent of the research they examined could not be replicated.

Engber's article also dealt with work by the Reproducibility Project for Cancer Biology.  He wrote,
"For some experiments, the original materials could not be shared, red tape notwithstanding, because they were simply gone or corrupted in some way. That meant the replicating labs would have to recreate the materials themselves—an arduous undertaking. (Elizabeth) Iorns (a member of the project team) said one experiment
Elizabeth Iorns, Science Exchange photo
called for the creation of a quadruple-transgenic mouse, i.e. one with its genome modified in four specific ways. 'It would take literally years and years to produce them,' she said. 'We decided that it was not going to happen.'
"Then there’s the fact that the heads of many labs have little sense of how, exactly, their own experiments were carried out. In many cases, a graduate student or post-doc did most of the work, and then moved on to another institution. To reconstruct the research, then, someone had to excavate and analyze the former student or post-doc’s notes—a frustrating, time-consuming task. 'A lot of time we don’t know what reagents the original lab used,' said Tim Errington, the project’s manager, 'and the original lab doesn’t know, either.'"
The increasing attention to the replication problem has definite implications for the California's stem cell research effort, which has had difficulty getting industry to pick up its research and move it into widespread use. 

The agency, formally known as the California Institute for Regenerative Medicine(CIRM), has embarked on a unique, $150 million effort to entice industry into advancing the Golden State findings. One of the agency's lures will allow its business partner to cherry pick the agency's research and lock up its selections for commercial use. 

But if 50 percent of CIRM's research can't be replicated, the agency may not be actually offering very much. 

As for CIRM's costs, it survives only on money that the state borrows (bonds). The $3 billion it will disperse carries interest costs that make the total bill roughly $6 billion, not counting non-replication waste. CIRM is slated to run out of cash in about four years. 

Seventy-eight comments have been filed on the Slate story, which is part of a collaboration called Future Tense that involves Arizona State University, New America and Slate. Tomorrow Future Tense will hold an event in Washington, D.C., on the reproducibility crisis in biomedicine.  The conference is called "Trust But Verify." Here is a link to the agenda. 
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Monday, April 18, 2016

Correction

The egg compensation item on April 18, 2016, incorrectly said that Gov. Jerry Brown vetoed a similar bill last year. He actually vetoed the bill in 2013. Sphere: Related Content

Pay-for-Eggs Legislation Up Again in California: Fertility Industry Trying to Repeal Ban on Compensation for Human Eggs in Research

The industry that deals in human eggs is once again pushing forward with California legislation to allow it to pay women thousands of dollars to harvest their eggs for research purposes.

The measure (AB2531) by Assemblywoman Autumn Burke, D-Inglewood, is now on the Assembly floor after clearing the Assembly Health Committee on a 17-0 vote. (See the March 31 legislative analysis of the measure here.)

The bill is essentially the same as the one vetoed by Gov. Jerry Brown in 2013. It is not clear whether the current author of the measure has been successful in removing Brown’s opposition.

The legislation is sponsored by American Society for Reproductive Medicine, the dominant trade group in the largely unregulated fertility industry.

When she introduced her bill in February, Burke said in a press release,
Autumn Burke on Assembly floor
Sacramento Bee photo
"It's perfectly legal for a woman to get paid when advertising through Craigslist to provide eggs for infertile couples, but she can't get paid for a donation in medical research. It's insulting to women, and it keeps California's research institutions in the dark ages. Instead of leading the way on women's health, we're stuck behind 47 other states all because of a misguided ban that assumes women shouldn't be allowed to make their own decisions."
Burke and the industry organization have an array of groups backing the legislation, ranging from California's district nine of  the American Congress of Obstetricians and Gynecologists to California Cryobank.

The bill is opposed by the Center for Genetics and Society in Berkeley along with groups ranging from the Catholic church to "We Are Egg Donors."

Marcy Darnovsky, NBC photo
Earlier this month, Marcy Darnovsky, executive director of the Center for Genetics and Society, wrote:
"The health risks of egg harvesting are significant, but they’re woefully under-studied. A well-known and fairly common short-term problem is ovarian hyper-stimulation syndrome (OHSS), but no one is sure how many women get the serious – sometimes life-threatening – version of it. Data on long-term outcomes, including follow-up studies on reports of cancers and infertility in egg providers, are notoriously inadequate.
"It is impossible for women to give truly informed consent if adequate health and safety information can’t be provided.
"Offering large sums of money encourages women in need to gamble with their health. It’s what bioethicists call 'undue inducement.'"
California's $3 billion stem cell agency bans compensation for women who provide eggs for research that the agency finances but it does allow reimbursement of expenses. The legislation would repeal a state law banning compensation.

(Editor's note: The original version of this story said that Brown vetoed an egg compensation bill last year instead of 2013.) Sphere: Related Content

Friday, April 15, 2016

CRISPR and Anti-HESC Updates from UC Davis Researcher

UC Davis stem cell scientist and blogger Paul Knoepfler has been busy this week, posting updates on CRISPR and two persons who have been behind the drive against the research use of human emrbryonic stem cells.

First, the information about the embryonic stem cell opponents, James Sherley and Theresa Deisher.

Sherley is running Asymmetrex, Inc., an adult stem cell firm in Boston. Knoepfler reported,
"I haven’t really seen Sherley out there in the public domain as an activist that much ever since the ES cell court ruling."
The negative ruling came in a federal court case challenging federal financing of human embryonic stem cell research.

Knoepfler cited a piece in Mother Jones magazine for his description of continuing activism on the part of Deisher. She was involved in the secretly recorded video tapes of Planned Parenthood officials. Among others, employees of Stem Express of Placerville, Ca., were also taped without their permission, and the California Department of Justice is investigating whether state laws were broken.

On the CRISPR front, Knoepfler has a series of links to good articles on the ongoing discussion involving the genetic modification technique. The debate continues unabated, although not in the mainstream media.

California's $3 billion stem cell agency held a daylong session on the matter some months ago. The agency is scheduled to take another look at it, but no date has been announced yet. Sphere: Related Content

Wednesday, April 13, 2016

Speak Up! California Stem Cell Agency Open for Comments Next Tuesday

Directors of the $3 billion California stem cell agency are scheduled to meet next Tuesday with many teleconference locations throughout the state, providing members of the public an ample opportunity to speak to the agency's governing board on any issue of concern.

The session is scheduled for only one hour and is expected to involve routine approval of changes in the agency's loan policy. So interested parties who want to be heard should not be laggard in being present. State law allows the public to speak on any issue at a meeting, not just items on the agenda.

Teleconference locations are in San Francisco, San Diego, Davis, Pasadena, South San Francisco,  Beverly Hills, Elk Grove, Fresno and two each in La Jolla, Los Angeles and San Francisco. The meeting will be home-based at the agency's headquarters in Oakland.

More detailed addresses can be found on the agenda.


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Tuesday, April 12, 2016

Growing Human Organs in Pigs? Time for California to Step Up?

Looking for a new heart? Need a new kidney? How about a pancreas?

All of those priceless human organs are in short supply. And a Stanford law professor says it is time to get moving on developing more of them.

In an opinion piece last week in the Los Angeles Times, Hank Greely said,
Hank Greely
"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.
"Every day about 30 Americans die because they can't get an organ transplant. Upward of 120,000 Americans are on transplant waiting lists. We are, medically, on the cusp of being able to save these lives in new ways: repairing failing organs with new genes or stem cells, building mechanical organs and growing replacement organs."
Greely pointed to a researcher at the Salk Institute in La Jolla, Juan Carlos Izpisua Belmonte. Greely said the scientist wants to "to grow a human pancreas in a pig to provide insulin-making cells for transplant into diabetics." Greely wrote,
"His research into how this can be accomplished is exciting but very early, yet even those preliminary steps have been threatened by a surprise moratorium announced last fall by the National Institutes of Health. NIH said it would not fund any research that involved putting human stem cells into earliest-stage nonhuman embryos. NIH said this wasn't a ban, but just a pause to consider the implications of such research and possibly to create a policy for it."
Greely did not mention it, but such research could be financed by California's $3 billion stem cell agency. In response to a question, Kevin McCormack, senior communications director for the agency, said,
"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."
The Salk scientist has already received $6.6 million in awards from the agency, but none of it involves growing people organs in pigs.

Greely noted that both California and the nation have an effective system for regulating such research and that the NIH should not be sitting on its hands. He said,
"That's no guarantee that human organs will grow in pigs, but we won't find out if Belmonte and others can't try."
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