"Natural Killer" Cells Score Points for $10.6 Million California Stem Cell Investment

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Stem Cell Hype: The Latest Warning from Researchers

The Scientist journal last week carried a cautionary note concerning iPS cell therapies, particularly a recent, "exciting" announcement concerning their use for treatment of spinal paralysis.

"Ethical Challenges in Using iPS Cells to Treat Paralysis," was the headline on the opinion piece. It carried a subheading that said,

"Uncertainties about the cells’ risk profiles and the potential for hyping unproven therapies mean scientists and the media must tread carefully."

The article dealt primarily with what it termed "exciting" news about an experiment in Japan. But the article has broader implications for the entire field including in California, where the state stem cell agency is currently helping to fund 46 research projects involving iPS, induced pluripotent stem cells. 

The piece was written by John D. Loike, a professor of biology at Touro College and University Systems in Brooklyn and who has a regular column on bioethics in The Scientist, and Martin Grumet, a professor of cell biology and neuroscience at Rutgers.

Writing about the Japanese research, they said, 

"Caution is warranted here, for at least three reasons: the uncertainty of the stem cell type to be used in their clinical trial, the safety of transplanting stem cells into humans, and the responsibility of scientists and the press to communicate clearly the benefits and risks of the stem cell treatments, especially to desperate patients who would seek such unproven treatments."

They continued.

"The excitement of the press release may be misinterpreted by patients, who may think that now is the time to treat human spinal cord injury with stem cell transplants. With difficulties getting admitted to legitimate sub-clinical trials, could this hype for hope lead poorly informed patients to seek out other “stem cells” to treat their spinal cord injuries or other conditions? We must avoid anything that may promote “medical tourism” to unapproved interventions.

"The fact that there are more than 700 'stem cell clinics' advertised in the United States alone highlights the desperation of so many patients with terminal illnesses seeking unapproved or unproven therapies. There are no studies documenting the therapeutic successes of these clinics and some of their patients have developed serious side effects. Scientists and the press must ensure an ethical and realistic presentation and communication of new and potentially exciting discoveries and caution readers about the realities of initial clinical trials.

A Scripps Scientist Deflates Cancer-Stem Cell Nexus

The sky is not falling, says a Scripps Research Institute scientist, despite headlines that seem to link "mutation" and "cancer" and "stem cells."

That comes from Jeanne Loring, head of the stem cell program at Scripps, who was writing on the blog of UC Davis stem cell researcher Paul Knoepfler. Loring said,

"'Mutation' and 'cancer' are eye-catching words for a headline; add 'stem cells' and there is a good chance that a lot of people will hear about it. These words have been liberally used in the press to describe the results of a recent publication: 'Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations.'"

Loring said she has been on a soapbox on this issue since 2000.  She said, 

"Every time a scientific report suggests that human stem cells are dangerous, I feel the need to reassure both scientists and non-scientists that we should not panic.  The sky is NOT falling (contrary to Henny Penny), and pluripotent stem cells remain valuable for cell replacement therapies."

Loring went into the rather technical reasons for her position as well as identifying issues having to do with not knowing enough about the cells used in research. She also provided some tools for researchers to use to identify cells with "functionally important mutations."

Loring's bottom line to researchers:

"Don't panic! Check your cells instead."

Cancer and Stem Cells: A Look at the Safety of iPS cells

The safety of reprogrammed adult stem cells was much in the news during the past few days as a result of work at the Scripps Research Institute that was funded by California’s $3 billion stem cell agency.

The press release from Scripps triggered a spate of stories quoting Jeanne Loring, who led the work. The Scripps release said,

“A new study led by scientists at The Scripps Research Institute (TSRI) and the J. Craig Venter Institute (JCVI) shows that the act of creating pluripotent stem cells for clinical use is unlikely to pass on cancer-causing mutations to patients.

“The research, published February 19, 2016, in the journal Nature Communications, is an important step in assessing patient safety in the rapidly developing field of stem cell therapies.”

The stem cell agency took a deep dive into the research today on its blog, The Stem Cellar, by Karen Ring, a former stem cell researcher who is the agency’s web site and social media manager. Ring wrote,

“It’s good news that reprogramming methods are relatively safe, but the fact that maintaining and expanding iPS cells in culture causes cancerous mutations is still a major issue that scientists need to address.

“Jeanne Loring recognizes this important issue and says that the next steps are to use similar genomic analyses to assess the safety of reprogrammed iPS cells before they are used in patients.”

Scripps’ press release reported that funds from five different stem cell agency grants were used in the research. Additional funds were also provided by a variety of sources.

Researcher Takahashi Honored as Stem Cell Person of the Year

Riken photo

Masayo Takahashi, the scientist in Japan who is leading the first clinical trial involving reprogrammed adult stem cells, today was named the stem cell person of the year.

The announcement was made by Paul Knoepfler, the UC Davis stem cell researcher who sponsors the award and personally funds its $2,000 prize.

Knoepfler said,

“In an astonishing feat, Takahashi's team transplanted its first macular degeneration patient recently on September 12, only 7 years after human IPSCs (induced pluripotent stem cells) were first ever published.”

The development of IPS cells, which also originated in Japan, has been hailed because they remove the moral objections that some persons have concerning the use of human embryonic stem cells. Many scientists, however, continue to consider the human cells as the gold standard.

Takahashi is a physician-scientist and a faculty member and project leader at the Laboratory of Retinal Regeneration at the Center for Developmental Biology at RIKEN.

Last December, Takahashi said she was wary of the high economic expectations surrounding potential stem cell therapies. In an article in the Financial Times by Jonathan Soble, she said, 

“Start-up companies are already involved and the road to commercialization is there, but to assume that the concept of iPSCs and regenerative medicine will yield a lot of money is naïve. Only parts of the field will become industries. It’s dangerous to think that all of regenerative medicine will.”

Takahashi was introduced to the field of stem science in 1995 when she followed her husband to the Salk Institute in the San Diego area in California.

Soble wrote,

“Paradoxically, because she had chosen clinical research, academia’s mix of glass-ceiling sexism and disdain for applied science worked in her favor. ‘I could do what I wanted because I was a woman,’ she says. ‘I didn’t think about career advancement.’”

She said barriers to women in science have largely disappeared in Japan although the comment was made before the STAP scandal that involved Riken. A key figure in the STAP research was a woman scientist, and persons prejudiced against women in science may well to use it to justify their biases.

Takahashi did say last year that traditional cultural values remain a problem in Japan. She said,

“'Japanese women don’t want to stand out, they don’t want to be leaders. They don’t think, ‘I want to have my own lab and reach the top in my field.’ I certainly didn’t until Salk.’ But Dr. Takahashi believes things are changing, in part because of the growing number of role models such as herself. ‘Sometimes,’ she says, ‘I meet young women who tell me, ‘You’re cool.’”

'Immortal' Stem Cells and Informed Consent in California

The California stem cell agency is looking for some help in connection with a $32 million stem cell banking program to be sure that people who donate tissue understand that their cells will be transformed and made “immortal.”

The agency has issued a $150,000 request for proposals (RFP) for a 12-month study dealing with informed consent matters in the banking effort. The agency's RFP said it is “a unique program because it involves the creation of 9,000 iPS cell lines, from 3,000 individuals” that could increase to 5,000.

The RFP requests a report that will provide “in-depth analysis of donors' current understanding with respect to the informed consent process” and “recommendations for education materials that may improve program performance over time.”

Issues dealing with informed consent and research were highlighted a few years ago in a book, "The Immortal Life of Henrietta Lacks," that was on the New York Times hardcover bestseller list for more than 40 weeks. 

The California stem cell agency's RFP said,

“Unique aspects of the tissue collection for disease modeling awards that is critical for donors to understand include that researchers intend to:
“• Test donors blood and skin samples for infectious disease
“• Transform donor cells and make them into immortal iPSC lines
“• Record the genetic sequence of donor their cells
“• Distribute donor cells and associated medical and genetic information widely
“• Use cells and associated information to develop commercial medical products with no financial compensation to donors.
“In addition, minors and/or individuals with cognitive impairments will be recruited for this research and consent may be obtained from their legal guardian."

The proposed California study is linked to a $4 million segment of its $32 million stem cell banking effort approved in March of 2013. Former CIRM President Alan Trounson said at the time,

“This initiative will provide scientists with access to multiple cell lines that should have much of the genetic variations that represent the variety within any human disease such as Alzheimer’s, heart disease, lung fibrosis and autism.”

The deadline for applications is June 1. Here is a link to a 2010 CIRM report on issues involved in the stem cell banking program, which was only a proposal at the time.

Cost of a Stem Cell Therapy? An Estimated $512,000

(Editor's note: Updated figures on costs can be found in this 2017 item.)

The likely costs of potential stem cell therapies and cures receive almost no attention in the media as well as publicly from scientists and the biotech firms.

Usually any public discussion is obliquely framed in the context of “reimbursement,” as if industry is owed something instead of making a business decision about what will make a profit. Euphemisms and jargon cloak unpleasant realities such as astronomical patient costs. But what reimbursement really involves are, in fact, pricing decisions and profit margins along with lobbying campaigns for inclusion of therapies in normal coverage of health insurance and Medicare. 

And today a singular figure – $512,000 for one stem cell treatment – appeared in the Wall Street Journal . The story by Kosaku Narioka and Phred Dvorak dealt with what would be the first-ever human study of a treatment that uses reprogrammed adult stem cells.

They reported that the study received preliminary approval on Wednesday from a key panel of the Japan Health Ministry. The treatment involves a form of age-related macular degeneration, which has also been targeted by the California stem cell agency with different approaches.

Buried deep in the Wall Street Journal article, with little other discussion, was this sentence:

“One eventual obstacle, even if tests go well, could be cost: (Masayuki) Yamato (of Tokyo Women's Medical University) says initial estimates for the treatment run around ¥50 million ($512,000) per person."

The subject of costs for potential stem cell treatments has rattled around in the background for years without much deep public discussion. One reason is that high costs of treatments are controversial and can trigger emotional debate. Another reason is that it is very early in the therapy development process and estimates are not likely to be entirely reliable.

A few years ago, however, the California stem cell agency commissioned a study involving costs of stem cell therapies. The UC Berkeley report said,

“The cost impact of the therapy is likely to be high, because of a therapy’s high cost per patient, and the potentially large number of individuals who might benefit from the therapy. This expense would put additional stress on the Medicare and Medicaid budgets, cause private insurance health premiums to increase, and create an incentive for private plans to avoid covering individuals eligible for a therapy.”

The findings did not seem to be exactly welcomed. The agency sat on the 2009 study for seven months until it was uncovered by the California Stem Cell Report in April 2010. Then the agency was careful to say that the study did not reflect the view of CIRM management or board leadership.

Their wariness of being out in front on the issue could be well-advised. The pharmaceutical industry received some unpleasant attention this spring when more than 100 influential cancer specialists from more than 15 countries publicly denounced the cost of cancer drugs that exceed more than $100,000 a year.

Nonetheless pricing is critical to both patient accessibility and therapy development. If companies cannot make a profit on a possible therapy, it is virtually certain not to appear in the marketplace.

While the subject remains in the background, it does not mean there is a lack of interest. The copy of the Berkeley stem cell cost study that was posted online by the California Stem Cell Report has been read 11,701 times since it was made available in April 2010 on scribd.com.

(For a 2015 look at costs for non-government approved procedures, see this item.)

A copy of the Berkeley study can be found below.

Stem Cell Therapy Costs by DavidJensen

A Patent War on iPS: One Researcher's View

As the California stem cell agency pushes ever more aggressively to turn research into cures, the second largest share of its awards, in terms of numbers of grants, has gone to efforts involving induced pluripotent cells, also known as reprogrammed adult cells.

But questions do exist whether those efforts can surmount barriers that have to do with patents and ownership of the intellectual property.

UC Davis stem researcher and blogger Paul Knoepfler discussed some of the problems in a post yesterday. He wrote,

“All the talk and the slew of publications about potentially using iPS cells to develop therapies to help patients is exciting in theory, but unfortunately the reality is that it is not entirely clear if most researchers are, from a legal standpoint, even allowed to develop and commercialize iPS cell-based therapies at all.

“The patent landscape for iPS cells is complicated to put it mildly. A Google patent search for “induced pluripotent stem cells” produced almost 200,000 results.

“A search for “cellular reprogramming produced more than 1,000 results.
I’m not sure all of these results are really separate patents, but still….that’s a big complicated mess.…..

“It is no exaggeration to say there are likely dozens of institutions around the world wanting to commercialize iPS cell-based products.

“Will they all have to pay expensive licensing fees or end up in court?
…or will the patent holders voluntarily and freely allow others to commercialize iPS cell-based medical treatments?

“I don’t think so.

“This could get really messy.”

Yamanaka and the Golden State

The iPierian biopharmaceutical company in South San Francisco was quick to make a change in its web site this morning after the Nobel Prize for medicine was announced.

Altered was the bio for one of its scientific advisors, Shinya Yamanaka, to note that he had won the Nobel. The bio is tucked away on the site, but it is likely that the company, which specializes in iPS work, will figure out how to put the news out front on its home page as well as issue a press release.

It was all part of the reaction today in California to the Nobel for Yamanaka, who has substantial links to the Golden State, including UCSF and the Gladstone Institutes.

Both enterprises moved with greater deftness than iPierian. Yamanaka is a professor at UCSF and a senior investigator at Gladstone, and the organizations quickly put together a news conference this morning that featured Yamanaka on a video hook-up from Japan.

UCSF, which is allied with Gladstone, issued a press release that quoted the president of Gladstone, R. Sanders Williams, who also mentioned the California stem cell agency. Williams said,

“Dr. Yamanaka’s story is a thrilling tale of creative genius, focused dedication and successful cross-disciplinary science. These traits, nurtured during Dr. Yamanaka’s postdoctoral training at Gladstone, have led to a breakthrough that has helped propel the San Francisco Bay Area to the forefront of stem cell research. Dozens of labs — often supported by organizations such as the California Institute for Regenerative Medicine (CIRM) and the Roddenberry Foundation–have adopted his technology.” 

CIRM, which is the state's $3 billion stem cell effort, published an item on its blog quoting CIRM President Alan Trounson. He said,

"There are few moments in science that are undisputed as genuine elegant creativity and simplicity. Shinya Yamanaka is responsible for one of those. The induced pluripotent stem cells he created will allow us to interrogate and understand the full extent and variation of human disease, will enable us to develop new medicines and will forever change the way science and medicine will be conducted for the benefit of mankind. An extraordinary accomplishment by a genuinely modest and brilliant scientist. He absolutely deserves a Nobel award.”

The CIRM item by Amy Adams, the agency's communications manager, said that just five years after Yamanaka's research,

“CIRM alone is funding almost $190 million in awards developing better ways of creating iPS cells and using those cells to develop new therapies (the full list of iPS grants is on our website).”

One of the recipients of CIRM's iPS cash is the well-connected iPierian, which has taken in $7.1 million. Yamanaka, however, has never received a grant from the agency, and it is not known whether he ever applied since CIRM releases only the names of researchers whose applications were approved.

UCD's Knoepfler's 'Somewhat Provocative Paper' on iPS

UC Davis researcher Paul Knoepfler is the rare stem cell scientist who blogs about his work as well as writing about issues in the field.

Over the weekend, he posted an item on what he described as a “somewhat provocative paper” published by his lab in “Stem Cells and Development.”  He said the paper argued that iPS cells “are very similar in some ways to cancer cells.”

Most of his item deals with the technical details and background of the research. But at the end of this item, Knoepfler wrote,

“So what does this mean in the big picture? 

“I believe that iPS cells and cancer cells are, while not the same, close enough to be called siblings. As such, the clinical use of iPS cells should wait for a lot more study. Even if scientists do not use iPS cells themselves for transplants, but instead use differentiated derivatives of iPS cells, the risk of patients getting malignant cancers cannot be ignored. 

“At the same time, the studies suggest possible ways to make iPS cells safer and support the notion of reprogramming cancer cells as an innovative new cancer therapy. 

“Stay tuned in the next few days for part 2 where I will discuss what this paper went through in terms of review, etc. to get published. It wasn’t a popular story for some folks.”

The UC Davis press release on the research, which was financed by the California stem cell agency and the NIH,  was picked up by several online sites, including Redorbit, Medicalexpress and geekosystem.