Here is a straightforward account from the Press Association and another from Reuters. The Science Media Centre has collected enorsements from prominent scientists and patient advocacy groups, that combining human chromosomes and animal eggs could lead to techniques for creating cells that could be used to treat devastating diseases.

Last year, Nature Reports summarized the UK Academy of Medical Sciences report on the benefits, risks, and unknowns on creating animal-human chimeras and comparing it to ethical guidelines from different scientific societies. Forgive the self-plug, but it’s one of the most comprehensive I’ve seen, particularly for something as short as it is. (If readers send in other good links, I’ll post them.)

Is it okay, for example, to genetically modify a human embryo so that its early development can be studied? (Ethics committees overseeing research on human embryos require that embryos are not implanted or allowed to develop to certain developmental milestones. This embryo was destroyed after five days. Human embryonic stem cells, which are derived from human embryos, are frequently modified this way, but human embryonic stem cells do not form embryos.)

Again, those interested might want to start learning the parameters of the debate with our summary.

The goal is to lift the federal funding ban on embryonic stem cells created after August 2001 and also set up the National Institutes of Health as a “key player” in a new system for ethical oversight over all cell-based research.

“All this private and state development is being done without ethical oversight,” DeGette’s spokesperson Kristofer Eisenla told me. “A lot of the substance of the bill is still in development, but the overall goal is that all cell-based research would be done under strict ethical guidelines that would be overseen by the NIH.”

How that would play out is still unclear, but it ould be a huge expansion of the Institute’s role. “Historically, the NIH does not have a regulatory role in research, that’s the FDA’s jurisdiction. It could create a very different dynamic [between scientists and the NIH],” said Michael Werner, head of a consultancy specializing in legislative issues affecting biotech. “All stakeholders want to make sure that research is done ethically and appropriately. We need more details of what the Congresswoman is proposing.”

The title of the hearing was “Stem Cell Science: The Foundation for Future Cures.” John Gearhart, a professor of medicine at John Hopkins University, said that he and others testifying before the committee had submitted testimony on that topic and had not known that DeGette would be proposing an oversight role. Otherwise, he said, there could have been discussion on the guidelines drafted by the National Academies of Science and research institutions' use of embryonic stem cell research oversight (ESCRO) committees. "We did not have the opportunity to respond to her, that all institutions are complying with ESCRO guidelines. We’re not just doing what we want."

DeGette’s spokesperson said that the Representative had been trying to bring the stem-cell hearing before the Committee for years, and that the intention was not to bring anything before President Bush but to lay groundwork for future legislation.

See more coverage by the Denver Post.

The hearing was scheduled late last week when another one was cancelled. Coincidentally, it was just two days after the National Institutes of Health had held a long-scheduled meeting on the challenges and promises of cell-based therapies.

Reports from the hearing said that conversation broke down mainly along party lines, with Democrats interested in scientific advances from embryonic stem cell research and Republicans stating that only adult stem cells were so far the only type that had been used in therapy. A report from BioWorld quotes Harvard’s George Daley that adult stem cells have been around for 40 years and embryonic stem cells around for a decade.

Story Landis, head of the NIH Stem Cell Task Force said that if there was any take-home lesson from the symposium, it was that the best source of cells for cell therapies would depend on the disease. For example, neurodegenerative diseases seemed much more likely to be amenable to work from embryonic stem cells, while blood-derived stem cells were effective with some blood disorders.

“It’s clear that adult stem cells are being used in approved trials or early stage clinical trials and other cases where it’s clear that those cells won’t be very helpful.”

Here is some coverage of this boon to scientific buildings.
The San Diego Tribune consistently does a nice job; this article focuses on the $43 million coming in locally. Another is more general.
The San Francisco Chronicle splashed it over much of its front page and seemed to me to do the best job of covering the impact on California.
The New York Times gave it a mere 600 words, and I couldn’t find it in the LA Times.
And of course, Nature had a full article on CIRM and the national impact on stem-cell science last week. ( See my ramblings and links )

I’d pulled clips on government investment in infrastructure several weeks ago (I thought I’d have time to write in-depth on this but haven’t), and I was surprised to discover that government really doesn’t traditionally invest that much in infrastructure. CIRM is limited to spending 10% of its funds for construction.

I found a lot of skepticism on academic construction in general but haven’t done much reporting. CIRM quotes Paul Berg saying that the hardest problem for people getting into stem cell research is the lack of facilities. Back in February, the head of the Buck told me that if they got the funds to construct a new building for stem cell research, they’d have little trouble filling it with scientists. ( The Buck got $20.5 million to fund the $41 million building.)

Here’s an article from the Economist on whether better facilities for universities are a good idea. (It does not address stem cells particularly, and you’ll need a subscription.) Journalist Dan Greenburg has also written on the unprecedented era of laboratory construction going on. Here’s a recent, statistics filled pdf on college construction.

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.

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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According to my web research, cloning new pigs means growing the embryo to the blastocyst stage, when the embryo is a hollow ball of cells, the same stage used for making embryonic stem cells; to clone a dog, even earlier stage embryos are used, so making canine embryonic stem cells could be even harder. But a team of researchers in Korea may be getting a whole lot more practice culturing dog embryos.

The dog cloning company in Korea could have revenue stream besides bereaved pet owners. A few months ago, I wrote about a California woman paying $150,000 in hopes of cloning her dead pet pit bull (named Booger). Now, an Associated Press story reports that seven puppies have been cloned from a talented drug-sniffing canine, a Labrador retriever. The cost came to between $100,000 and $150,000 a dog, and all seven cloned puppies passed a preliminary behavior, qualifying for further training. There are more tests to go. According to the article, only about three of ten dogs that go through the training regimen can be put into drug-sniffing service, even though the training costs just over $40,000 a dog. Assuming clones cost as much to train as normally conceived dogs, the technique would still not be cost effective even if all seven dogs make the cut. (The first set of dogs is a deal, since the animals are being made for academic purposes, the team has not requested payment.)

When I’ve asked around about why we don’t have more embryonic stem cells for more species, researchers tell me no one has had the patience or resources to optimize the derivation and culturing techniques for other species. Perhaps the kickstart will come from an unexpected place.

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

An interesting grab-bag of items was posted recently by the Center for Genetics and Society, a non-profit that worries about research cloning’s potential to lead to reproductive cloning.

Another blog from the center complains that one of our recent commentaries called “What comes after iPS?”does not point out that no one has yet produced human embryonic stem cells through nuclear transfer and that doing so requires using human eggs and creating a blastocyst (presumably, most people reading Nature Reports Stem Cells would know this, but point taken). What the critique fails to mention is the main point of the commentary: that directly reprogrammed cells will transform not just regenerative medicine but also cell biology.

Finally, thanks to Hematopoiesis for naming Nature Reports Stem Cells FAQs number one. I worked really hard on those (and so did those kind experts I harassed for feedback). They are one-year old now, so I’ll be spending the next couple weeks rereading them and bringing them up to date.

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?

Wanted: fortune-tellers for teratomas

Embryonic stem cells are partially defined by their ability to develop into strange lumps called teratomas that contain cells characteristic of all basic tissue types. Obviously, that’s not what clinicians hope the cells will do in patients. Though cells will be differentiated before being transplanted to patients, the advisory committee worried that undifferentiated cells might slip through and start to grow. Teratomas can, rarely, generate cancers growths called teratocarcinomas.

A big question is how many transplanted cells it takes to get a teratoma. Geron’s Lebkowski presented data in which ES cells were spiked into a population of progenitor cells and rodents were monitored for teratomas for twelve months. If ES cells were fewer than 5 percent of the total of two million transplanted, researchers never saw teratomas. There are lots of variables to be considered, though, site of implantation, whether cells are grown as aggregates, the cell line, and the primary cell population.

One committee member suggested that the differentiated cells in the transplant might suppress tumor formation. And so another question was whether the risk of teratomas depended on the absolute number of undifferentiated cells or the percentage; Ken Chien of Harvard Medical School and other committee members suggested this could be addressed by developing teratoma assays in large animals. Some committee members voiced support for developing large-animal assays, either putting human cells into animals or even (much more difficult) creating new species-specific cell lines to test. Results of such studies would be desirable, but requiring companies to develop a cell product other than the one intended for therapy seemed to be considered unreasonable. Some questioned whether the results of either sort of assay could be reasonably applied to humans.

Chien questioned whether studies in large animals need to use cells from the same species. “We could do all this and still leave the safety issues unsolved.” Still, Chien called for the development of more assays that could detect when a teratoma was growing. “We should not settle. We have not been aggressive enough in developing these assays.”

Benign tumors that develop in the brain or spinal cord would be much more dangerous than elsewhere, and the committee wondered if it should be less worried about procedures that would transplant cells to less vulnerable areas. One committee member said that the standard for tumorigenicity should be more rigorous than for toxicity for other toxicities that could result from cell therapy because the tumorigenicity issue was unique to embryonic stem cells and problems there would “be disastrous to the field.”

“We’re all talking about teratomas as if this were the only adverse events we expect to see,” Doris Taylor of the Center for Cardiovascular Repair at the University of Minnesota said. She emphasized that ES-cell-derived products is an even newer field than adult stem cell therapy and so other, unforeseen dangers might be more relevant. In particular, committee members wanted to know how progenitor cells might proliferate dangerously or even induce native tissue to grow aberrantly.

Why can’t a mouse be more like a patient?

Patients live longer, are bigger, and will likely be on immunosuppressive and other drugs. Human cells like to grow into bigger structures than mouse cells; introduced human cells will interact with native human tissue differently than with animal models of disease. It quickly became apparent that the necessary animal experiments would depend on the disease, cell product, and potential risks and benefits (an experimental therapy for patients on the brink of death may not require 5-year monitoring studies in pigs). Committee members sparred here, arguing for either the necessity or irrelevance of various animal models in various situations, and whether it made sense to monitor animals for a set period of time or for their entire lives.

Many factors need optimization to make cell therapies safe and effective, emphasized In his introductory talk before the committee, invited speaker Ole Isaacson who studies neurodegeneration at Harvard Medical School. “Cell concentration, dose, delivery, and implantation don’t sound very exciting to an academicians,” he said, “but are very important.”

All the more reason that experiments must be rigorous. For example, control studies for these experiments should not just mean injecting animals with saline solution but injecting them with other populations of cells, said one committee member. Ideally, researchers should be blinded so that they don’t know which animals receive the potential cell therapy.

“Preclinical studies have to be clinically relevant,” said Taylor. No one argued with that principle, but no one seemed to agree on how to apply it either. Depending on who was speaking about what, additional animal studies were either unnecessary barriers or the most responsible way to move to humans.

“It’s easy to say we want animal models with integrity to human diseases, but the truth is they are just crude approximations,” said Salomen. “What a sponsor should do with an animal model is answer specific questions that approach what they will do with a patient.”

“We need to be careful not to add an extra burden,” Taylor said, adding that the committee also had to recognize that no one know how long it will take for cell transplants to display adverse events. And it’s not just the cells that need to be considered; the age, sex of co-morbidities of patients will matter too.

Cell products are special
Small molecules interact chemically with cells; their presence in the body fades over time. Cells interact chemically and physically with cells; they travel through the body; they may persist for years and even expand in numbers. They behave differently at different densities and in different tissues.

While fully differentiated cells that are incapable of further divisions might behave most predictably, progenitors might be the only ones capable of integrating into degenerating tissue and surviving, particularly in the brain.

Committee members suggested repeatedly that a mixture of cell types is not only unavoidable but desirable for cell therapies. ( This is an issue that the leaders of CIRM raised in a recent commentary. ) Everyone accepted that the final cell products would be mixtures of cells. While heterogeneity can be tolerated, they said, it must be consistent from batch to batch.

Committee members stressed the need to use precedents from other cell therapies whenever possible. Matthew Allen of the Department of Veterinary Clinical Sciences at the Ohio State University urged members to remember which issues had already been hashed out and “only make alterations if we think the risk-benefit ratios merit it.” After all, other living cells are already being moved into patients without the extensive characterization being considered for ES-derived products. “This can’t be dissociated from the cell product and initial composition. Maybe we set more rigorous guidelines for understanding the composition of the product and then come up with a few assays that have to be employed.”

Both the starting material and the final product must be characterized for cell therapies derived from embryonic stem cells. For embryonic stem cells, that means assessing contaminants, genetic identity, and genetic stability. Committee member Meri Firpo of the Stem Cell Institute at the University of Minnesota suggested that cell banks were making useful progress with doing this. (Incidentally, the April issue of Cell Stem Cell has two reviews on stem cell banks.)

Genetic stability is important because genetic changes could affect tumorigenecity, but the size of genetic changes that should be monitored was unclear. Gross chromosomal abnormalities can be detected readily; smaller insertions and deletions may need to make up a large population of a culture before they can be detected. Ultimately, companies will be responsible for making sure their lines are characterized. One suggestion was that these products should be limited to early passage numbers.

An invited speaker, Jeff Bulte of Johns Hopkins University suggested several techniques to monitor cells that might be applicable for monitoring stem cells in vivo, mainly in animals, but also in patients. The committee members were highly interested, but frustrated by the number of potential artifacts and other limitations. For example, the half-life for the only FDA-approved cell tracker is only three days.

Once a trial enrollee, always a subject?

Committee members worried about their inability to remove cells from patients if they started awry, but a proposal for inserting a “suicide gene” into cells intended for therapy won little enthusiasm; one committee member suggested it could introduce as many risks as it eliminated.

“We should not create too many standards,” urged Jeffrey Chamberlain of the University of Washington School of Medicine. “A quarter of people who get the cells will die of cancer anyway.” (He also suggested that all cells come with a DNA profile.)

“We’re putting in those cells, and we don’t know what they’re going to cause in terms of trouble, so we need to be broad in terms of what they’re going to cover,” said one committee member. A patient registry would potentially allow clinical trial participants to be tracked long past trials’ end.

Kurt Gunter of Hospira suggested that following patients for a lifetime is “a lot to ask for.” He noted that when considering trials with retroviruses, patient follow-up was put at 15 years.

Richard Chappell, a biostatistician at the University of Wisconsin Madison Medical School tried to impress upon the committee how little information clinical trials can provide; no finite number of patients can demonstrate zero toxicity, he reminded them.

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.

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.

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:

Prof Colin Blakemore, former Head of the Medical Research Council, said:
"The creation of hybrid embryos is not illegal and researchers in Newcastle and London were granted provisional licences for such research in January, after an extensive consultation by the HFEA. This research is at a very early stage and no results have been peer-reviewed or published. However, these preliminary reports give hope that this approach is likely to provide stem cells for research without the use of human eggs or normal human embryos. The new Bill is intended to confirm the arrangements for regulation of this important area of research."

Dr Mark Walport, Director of the Wellcome Trust, said:
“It is too early to assess the significance of these results but this is an important area of science that has been scrutinised by the HFEA. The aim of the research is to advance human health. This work emphasises the importance of the parliamentary scrutiny of this area of research over the coming weeks.”

For those of you coming back from Easter weekend to see Monday’s headlines, Nature reported on this story on Friday, making it harder to find now. Here it is . Other reports come from Bloomberg and the Guardian. And just to keep things in perspective, here’s a report of a non-stem cell breakthrough in Parkinson’s in mice based on research published in Nature just over a year ago.

In the Nature Medicine paper from Sloan-Kettering’s Viviane Tabar and Lorenz Studer and others, researchers report that cells survived much better and mice’s symptoms improved if they were transplanted with genetically matched neurons. Matched neurons were made by taking nuclei from cultured mouse skin cells, placing the nuclei into eggs to create an early-stage embryo, and then destroying the embryo to make embryonic stem cells.

In fact, in some mice receiving non-matched neurons, no transplanted cells could be found. Also, the brains of mice receiving non-matched neurons showed several signs of an immune attack. Thus, the results indicate that immune rejection could be a big barrier in cell therapies.

It’s worth noting that these mice had Parkinsonian symptoms because the researchers’ killed brain cells in otherwise normal mice. There are many, many questions that will need to be answered before such work is transferred to the clinic, and a relatively late question will be on the therapeutic power of transplanting cells derived from people who got Parkinson’s naturally. The mice were observed for 11 weeks after transplantation before their brains were examined.

London’s Science Media Centre sent out some commentary to reporters concerning the paper, and I thought this analysis attributed to Robin Lovell Badge was interesting:

“This is a very well conducted study that provides further proof-of-principle of the idea of "therapeutic cloning" using a mouse model. The cloning technology was used to derive Embryonic Stem (ES) cell lines specific to individual mice with Parkinsons disease.
Dopamine-producing neurons obtained from these cell lines were then grafted back into damaged brains of the mice where they led to significant amelioration of Parkinsons symptoms. These "autologous"
grafts worked much better than heterologous grafts where the dopamine neurons were put into unrelated animals. This in itself is important as it had been thought that the brain was largely an "immune-priveleged site" (i.e. a site not seen by the immune system), but it is clear that the heterologous cells were attacked by the immune system. This would help explain some of the poor results in human clinical trials using grafts of midbrain cells obtained from aborted fetuses, as these would have been heterologous.

“The authors were also able to test several independent ES cell lines corresponding to individual mice, and could show that most seemed to work well. This is very encouraging as it indicates that the cloning process is a sufficiently robust method of reprogramming cells back to an early embryonic state, at least when the early embryos are used
to derive ES cell lines. There was substantial variation in the
numbers of cells found in the grafts, but this seemed to be animal-to-animal variation and generally not a cell line problem.

“In a few animals the authors noticed overgrowth of undifferentiated neural cells. This is a problem that requires more research, in particular to derive ways of eliminating immature cell types.
However, the authors did not detect any teratomas (a type of tumour containing many different cell types), which is very important as it suggests that they succesfully eliminated any undifferentiated ES cells during their in vitro differentiation protocol. This is again very encouraging, although the authors only waited 11 weeks post graft for the analysis and it would have been better to have left some animals much longer. Leaving them for longer would also have allowed a better test of functional recovery and whether this was really stable.

“Ideally one of the next steps will be to repeat the whole procedure with a monkey model, in which all the individual steps have now been established. This will allow much better tests of functional recovery and safety.”