The Niche

Nature has just posted a thoroughly reported feature on how the California Institute of Regenerative Medicine and its billions of dollars will change the shape of stem-cell science and infrastructure. (For a more personal view from a Texas scientist, see our commentary by Peggy Goodell .)

One point the feature makes is that CIRM’s board members also serve the institutions that receive funding from the institute. There are, of course, a welter of rules aimed at avoiding conflicts of interest, but CIRM has still found itself subject to strong criticism. One retired journalist has even started a blog devoted to the institute’s scrutiny. An editorial accompanying the Nature feature calls for strong governance.

Still, CIRM is not the only stem-cell agency facing such charges. A report this week from Integrity in Science reports that “at least 11 of the 25 voting-members of Health and Human Services’ Advisory Council of Blood Stem Cell Transplantation have financial ties to cord blood-banking and transplantation industry despite a committee charter stating that such conflicts should be limited.”

What does seem unique to CIRM are the multiple sources of “two-masters” tension: it must support basic science and clinical applications ( see my interview with Marie Csete) ; it must succor biotech companies but make sure that patients and other scientists can access their technology (see my article on CIRM grants to businesses ). Even its organizational structure is split. (See my article on CIRM’s search for a president .)

I’ve asked CIRM officials about this before. I’m told that such strains are indeed difficult to balance, but done right they are a source of strength. I’ve asked non-CIRM experts about it too. They tell me it’s easy to make bad investments in hot new fields, but good ideas often wither early because they can’t prove their worth. And I've asked everyone whether CIRM’s funds are a good use of money, and they say what journalists hate to hear: time will tell.

Posted by Monya Baker on April 30, 2008
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The entrepreneurial spirit may boost efforts to turn stem cells into fried chicken. It has already expanded the ability to clone dogs. If ideas like these could be tweaked just a bit, they could help spawn research tools the biomedical community really needs.

An idea that might boost cutting edge research (and save animal lives) is coming from a surprising source, People for the Ethical Treatment of Animals. Saying that stem cell science could make in vitro meat possible, PETA has just put up a $1 million prize for the first candidate to make a palatable in vitro chicken product and sell at least 2,000 pounds of it over 10 states.

If PETA had picked pork instead, the research might have had some benefit for the biomedical research community (though it may also have facilitated more experiments using pigs.) No one has worked out a way to get robust pluripotent stem cells in sufficient quantities from species besides mice, monkeys, and men.
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Posted by Monya Baker on April 29, 2008
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An article in Tuesday’s LA Times patiently explains that expensive bottles of skin cream sold in doctors’ offices and online do not actually contain stem cells. They don’t have much science either. Other companies are marketing services to store stem cells in menstrual blood. The uterine lining is highly regenerative, but the science is early.

In San Diego, four independent institutions are planning to build a common $115-million facility for stem cell science. Teri Somers covers it well, and some commentators are passionately against. The California Stem Cell Report has comments on this, plus a lively discussion on the meaning of “trivial” in terms of the contribution the California Institute of Regenerative Medicine claimed to have made and actually made to research leading to clinical trials. (The posts are on April 17 and April 15) Back in August, Nature Reports Stem Cells conducted a survey on how recipients of innovation grants intended to use them, noting that the Institute had been kept from disbursing most of the funds it had been awarded)

Keep reading for most posts that caught my eye

Continue reading "Stem-cell skin creams, a San Diego collaboratory, and legal blogs" »

Posted by Monya Baker on April 22, 2008
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There’s some cool papers out this week.

Rudolf Jaenisch and Jacob Hanna and others at the Whitehead Institute has not only reprogrammed a fully differentiated cell, but has also generated reprogramming-ready mice. According to everything that’s been published so far, reprogramming specialized cells to an embryonic-like state meant transfecting them with viruses and hoping random chance went your way. Cells in these chimeric mice already contain copies of the transgenes necessary for reprogramming, and these versions of the genes become active when exposed to doxycyclin.

Mike Clarke and Bolaji Akala and others at Stanford use triple mutant mice to help explain a looming question in stem-cell biology is why haematopoietic stem cells (HSCs) self-renew but their progenitors cannot.

Continue reading "Mini-research round-up" »

Posted by Monya Baker on April 17, 2008
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“Now we have the technology that can make a cloned child” reads the headline of the most-read article in the Independent right now. But the article does not actually break any news, nor does it use the common method of cloning; rather it discusses a well-understood implication of that recent reprogramming breakthroughs might yield yet another weird way of making a baby.

If a technician wanted to do this, here’s how it would work: First, cells would be gathered from an existing human, probably through a skin biopsy. Second, these cells would be reprogrammed to an embryonic like state. (Current techniques to do this require engineered viruses to insert copies of genes into the reprogrammed cells. This makes the cells’ behavior less predictable and more prone to form tumours, but many scientists believe that new reprogramming techniques will soon be available that don’t require genetic modification.) Next, the reprogrammed cells would be merged with an early stage embryo, created by sperm fusing with egg in a laboratory dish. The “chimeric” embryo would be cultured for a few days and then implanted into a woman. If a baby was born, he or she would contain cells from two genetic individuals: the embryo and the human who supplied the cells. The baby would have three parents: two who gave the gametes for the embryo, one who gave the cells from a biopsy. (Such an individual would not be a clone. However, it is feasible that the chimeric embryo could be manipulated such that the original embryo only forms placenta and the reprogrammed cells form the body. This has been accomplished with mixtures mouse embryonic stem cells and mouse embryos, but not with mixtures of reprogrammed mouse cells and mouse embryos. )

The results of some quick internet research suggests that using human iPS cells this way would not be allowed: In the UK, creating or using embryos outside the body requires a special license from the government, so I’d guess that permission would need to happen proactively. The US lacks legislation on reproductive cloning, though some individual states ban it. Australia distinguishes between research embryos (created through technical manipulation or by mixing genes from three or more people) and reproductive embryos (created through fusion of sperm and egg) and allows only reproductive embryos to used to create an embryo. A document dated to 2004 from Japan banned, among other things, the creation of chimeric human-human embryos for research.

Continue reading "Cloning by reprogramming?" »

Posted by Monya Baker on April 15, 2008
Categories: Cloning, Ethics, Reprogramming/Pluripotency | Permalink | Comments (2) | TrackBacks (0)

On Thursday, April 10, the FDA held its first public advisory committee on assessing safety risks of cell therapies derived from embryonic stem cells. In a hotel ballroom just outside Washington, more than two dozen committee members and invited specialists weighed in. Separated from the discussion area by a yellow plastic chain, were about 200 prominent academics, consultants and industry representatives, and members of the press.

Prior to the meeting, the FDA had released a 12-page briefing document outlining the safety questions to explore, particularly how cells should be characterized and assessed for safety before transplantation and how patients could be monitored afterwards.

The biggest concern is that once placed in human subjects, cells could proliferate and differentiate in ways that are harmful and uncontrollable, and that studies of human cells in mice and rats won’t reliably predict their safety in human patients. A transcript of the session should be available from the FDA in a few months. Here’s about 2,000 words of what I found salient. (Disclosure: I was fresh off a red-eye from San Francisco, and I’m writing this on the plane back.)
Previously, I ran around asking attendees for their top-level thoughts. You can read that here. The consensus of the advisory committee for cellular, tissue, and gene therapies seemed to me to be both “Onward!” and “Careful!”

The sections that follow are 1) company presentations 2) wanted: fortune-tellers for teratomas 3) why can’t a mouse be more like a patient? 4) cell products are special and 5) once a trial enrollee, always a subject?

Continue reading "Gearing for nitty-gritty questions on making safe products from embryonic stem cells" »

Posted by Monya Baker on April 12, 2008
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On Thursday, an FDA advisory committee meeting met to figure out how to decide whether products derived from embryonic stem cells were ready to be tested in human participants. There was much talk, even more questions, and no firm decisions.

Even so, the attendees I spoke with told me they felt certain that the FDA was serious about moving stem cells to the clinic. One consultant said that previous to today’s meeting, investors had expressed worries that today’s meeting would serve to kill the field. Several years ago, patient deaths in gene therapy trials caused the FDA to halt all such trials under its jurisdiction, another consultant told me, and that field has never recovered.

Now, the consensus was, the agency seems cautious about moving forward, but not spooked. Three companies, Geron, Advanced Cell Technology, and Novocell described their work bringing embryonic-derived cells in (respectively) acute spinal cord injury, visual impairment, and diabetes. One expert who wasn’t on the committee said that the discussions had been impressively grounded in science, even getting into specifics about what assays might be considered. Attendees were surprised that no opponents of embryonic stem cell research showed up, but the FDA's announcement said explicitly that it was only the cells' safety that was under consideration.

The director of the FDA’s Office of Cellular, Tissue, and Gene Therapies Celia Witten called the meeting useful. “We got enormous information in three areas: preclinical, product characterization, patient monitoring.” She added that within each area there were lots of recommendations. She declined to speculate on when or if a guidance document would come out, but it didn't seem soon.

But the recommendations were really approaches to answering lots and lots of questions. How do we know what cells we have? How do we know what the cells will do in the body? Where do you put cells? Where do they go? What do they do? How many cells might be dangerous? How many can be useful? What can animals tell us? If the cells “go rogue” in a human participant, will we be able to stop them or even to track them? What’s the best way to balance risk and benefit?

“I don’t know that there’s a one-size fits all answer,” said committee member Steven Goldman, a professor of neurology at University of Rochester Medical Center. At the time, he was making the point that different stages of differentiation will be appropriate for different diseases. (Neurodegenerative diseases may need progenitor cells that proliferate and integrate; diabetes seems best off with fully differentiated islet cells.” Still, the notion “it depends” applies to disease, cell type, patient characteristics, delivery route, etc. etc. ( See our interview with Marie Csete, head of the California Institute of Regenerative Medicine, which is also wrestling with these issues.)

I thought attendees would be disappointed in this attitude. After all, aren’t researchers reaching for the clinic looking for the list of assays they need to do to put cells into human subjects? But I spoke with four people, including Witten, and everyone seemed quite satisfied; that every product was already assessed individually no matter what it was and that potential risks always had to be titrated to potential benefits.

In the open public session, Amy Rick head of the Coalition for the Advancement of Medical Research asked the committee to consider the risk of living with and dying from a horrible disease when assessing risks to clinical trial participants; that’s a tough request, since the earliest trials set out to show safety rather than efficacy.

Other issues will need to be wrestled with if ES-cell therapies move from potential experimental procedure in human participants to potential therapies: providing access to care and applying treatments to a heterogeneous population. Its roots can be seen in the attendees, mostly white, with a smattering of Asian. The mixture of men and women attending was slightly tilted to men, more so on the advisory panel. Most people seemed closer to 60 than to 30.

Posted by Monya Baker on April 11, 2008
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This Thursday and Friday, the FDA deliberates on how to decide that cells derived from embryonic stem cells are ready to be tested in humans. On Saturday and Sunday, patient advocates and stem-cell researchers meet in San Francisco to talk about how to accelerate discoveries and therapies.

Both indicate a growing momentum for moving stem cells into applications. I wrote a preview article on the FDA discussions. The FDA’s got a difficult job to do. It has to make sure that it doesn’t slow down therapies for horrible, debilitating diseases and that human subjects aren’t exposed to dangerous procedures. This meeting is regarded as a first step for moving embryonic stem cells into well-regulated clinical testing.

I’ve never attended an FDA Advisory Committee meeting before, and I called several people to get a sense of what to expect. One of them was Michele Keane-Moore, a former cell-product reviewer with FDA who is now with the Biologics Consulting Group. She told me that the public forum marks a good learning opportunity for the agency. FDA officials have discussion with many companies, she says, “but all of that work is confidential and can’t be discussed.” Now, she says, “A lot of the questions will be aired in a public forum, so all the stakeholders can say what their concerns are.” the transcripts will eventually be made available for this meeting. Keane-Moore believes the discussion will be similar to the one held in July 13 on stem cells in neurological diseases. You can get to it here.

You can read more in the Nature article, but the FDA is mainly worried that the animal tests used to assess safety problems aren’t good enough and that they won’t know until too late that the transplanted cells are causing harm rather than benefit. The FDA has to make these calls all the time, but there are a couple reasons why these cells are cause for concern. One is that the animal safety tests often require animals to be bred to lack immune responses or to be on immunosuppressive drugs (mouse bodies would attack human cells otherwise), so they want to figure out the limitations of these tests.

Also, stem cells are very different from drugs because cells can multiply and change. That makes them harder to predict. If you put the cells in an environment where they can grow quickly, a low dose of cells could become a high dose. That can’t happen with drugs. Of course, everyone also hopes that these cells can bring about cures for diseases that so far seem intractable to regular drugs.

If you have something you want me to have my eyes out for at either of these meetings, please send me an email or add a comment below.

Posted by Monya Baker on April 08, 2008
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Skin cells taken from patients with some eight different diseases have been reprogrammed to an embryonic-like state. These could be invaluable for studying disease and testing drugs.

Here’s the statement from the UK’s Science Media Centre, which announced the result:
‘Dr Willy Lensch from the Children's Hospital in Boston and colleagues in his laboratory have generated stem cell lines from iPS cells with the genetic characteristics of more than six different diseases, including Huntingdon’s disease, Down’s syndrome and a type of muscular dystrophy. These can be used to study how these diseases affect fundamental development. They also can be used for surrogate testing for drug development, accelerating the development of therapies for devastating diseases.’ The announcement has been reported by the BBC. UPDATE: When I asked folks at Children's Hospital about this, I was told that the work wasn't ready for coverage; it had simply been mentioned at a seminar, and the fact that the UK press picked it up was surprising.

Reprogramming human cells was first reported in November, using cell cultures that could be bought commercially. Converting cells from a fresh patient biopsy was reported the following month by the lab led by George Daley and where Willy Lensch works as a senior scientist. By now, multiple labs have independently reported reprogramming cells, demonstrating that the technique is reliable and reproducible.

There are a variety of steps that will need to happen before the cells will start yielding information that will be useful for clinical applications. These are discussed in a commentary by the California Institute of Regenerative Medicine and a feature article written after mouse cells were fully reprogrammed.

The cells will need to be differentiated into the cell types that are affected in the various diseases. According to the BBC, a team at Nottingham University is already using reprogrammed cells to study heart conditions. Human cells differentiate very slowly compared to mouse cells. Turning embryonic stem cells into apparent photoreceptors, for example, took close to a year.

The first step in telling if cells are differentiating is checking out the molecules they display on their surfaces. Then comes the much more arduous task of looking at cells’ shape and function. (If it’s a nerve cell, does it release neurotransmitters? If it’s a heart cell, does it beat?) Even then scientists worry whether the cells in a dish behave like the ones in the body.

Other obstacles are getting enough of the cells and purifying the differentiated cells away from other cells growing in the dish that have not transformed fully.

Finally, drugs that are known to treat particular diseases will be tested on the differentiated cells. Results from these cell-based tests will be compared to established tests, most likely tests carried out on mice and rats.

Developing cells to become therapies (transplanting them to perk up or replace diseased hearts, brains, or other organs) will require considerably more work than developing cells to test therapies. One worry is that techniques to reprogram cells change them genetically, and clinical work in gene therapy resulted in patients’ deaths, making researchers leery of trying again.

Posted by Monya Baker on April 07, 2008
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Newcastle University says researchers led by Lyle Armstrong have made hybrid embryos containing material from cows and humans. The announcement comes just as the government gears up on whether or not the creation of such embryos should be legal. Newcastle University, which already had approval for the research from UK regulatory authorities, decided to push forward so the research would not risk being stalled by an upcoming vote in the House of Commons, reports the BBC.

The embryos lived for three days, and were not used to make embryonic stem cells, according to that report. They were made by putting human DNA into cow eggs after the cow chromosomes had been removed. Scientists argue that such procedures are valuable both to understand how embryos develop, to develop better techniques for making embryonic stem cell lines, and to develop more useful embryonic stem cells. The hybrid embryos cannot, by law, be allowed to develop for more than two weeks, when some precursors of nerve tissue develops. The first reported human-animal chimeras combined human nuclei with rabbit eggs; other chimeric animals have been made as well. Here’s an old summary. Here’s a newer one.

See Nature Reports Stem Cells commentary on a scientific argument for chimeras by Ian Wilmut , a theological argument for chimeras by Ted Peters, and an argument against creating and destroying embryos for research by Markus Grompe. We also summarized the UK Academy of Medical Sciences’ report on this issue.

The UK press has been roiling with accusations by the Catholic Church that the work is monstrous. Scientists have responded that the Church is misrepresenting the science and have offered to meet with religious officials. For a recent example, see the New Stateman.

Newcastle has a history of dramatically announcing accomplishments before work appears in the peer-reviewed literature. In February, they announced the creation of embryos using material from three people. See Erika Check Hayden’s article in Nature News.

The Science Media Centre has already released statements of scientists’ responding to the news, all saying that they lack data to assess research. Here are those statements:

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Posted by Monya Baker on April 01, 2008
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