The California scientists most likely to receive state grants for making new cell lines were those who proposed comparing embryonic stem cell lines and induced pluripotent stem (iPS) cell lines. Overall, thirty-two percent of all grant applications (16 of 50) were funded. Four of the five grants that proposed comparisons got funds. The unfunded grant application crossed into less favored categories, as it also proposed making lines from parthenotes and through nuclear transfer. None of the grant applications that sought to make cell lines using human oocytes were funded. Two proposed cloning through nuclear transfer, one proposed stimulating unfertilized eggs to divide into parthenotes, and one application proposed using both methods.
Success rates for grants proposing the derivation of only ES or only iPS cells were each 33%, but there were twice as many grants for iPS cells. That’s astounding considering that the grant program was announced in October 2007, a month before the first publications that human cells could be successfully reprogrammed.
Four proposals to make pluripotent lines using cells derived from the placenta, testes, or amniotic fluid were rejected. But a proposal to make spermatagonial stem cells, ES cells, and iPS cells was funded and highly praised, with reviewers particularly keen to see a comparison of iPS and spermatagonial stem cells from the same individual.
Three proposals to derive lines from biopsied or unviable embryos were turned down on the basis that the work was technically difficult and that any lines produced would be at best comparable to lines derived from leftover embryos obtained from IVF clinics.
Of the 50 grant applications received, 12 were from for-profit companies (See CIRM press release in February). However, all 16 grants awarded went to academic institutions.
For some of the rejected grant applications, reviewers objected that the proposed lines were not sufficiently distinct from lines that already exist. Overall, the reviewers seemed particularly concerned that every approved grant would result in a cell line that might have clinical applications. This applied not just to the embryonic stem (ES) cell and somatic cell nuclear transfer (SCNT) grants, which aren’t eligible for federal funding, but also to the iPS grants, which are. For example, reviewers doubted that attempts to reprogram neurons would be successful and thought that even if attempts to reprogram cancer cells did work, such cell lines could not be used clinically; consequently, grants proposing these experiments were not funded. For SCNT applications, reviewers worried that researchers couldn’t get enough oocytes.
No joy for SCNT
Perhaps most vocally disappointed was Kenneth Woolcott of Cascade Therapeutics, a company co-founded by Shoukhrat Mitalipov, who successfully cloned embryonic stem cells from monkeys through nuclear transfer. Though Mitalipov works in Oregon, the company was established in California largely in hopes of capturing CIRM grants. One reason the reviewers cited for rejecting the grant was the difficulty of getting enough eggs for experiments, since the ratio of established stem cell lines to oocytes used was around 0.3%. Woolcott says the grant reviewers got the facts wrong because the reported efficiency is 0.67%. (According to their publication, the team needed 304 eggs to make two stem cell lines (0.67%); however, one was genetically abnormal, so the efficiency would be 0.33% if only the normal line was considered). But Woolcott adds that the current efficiency, based on unpublished work, is over 3%, and he discounts reviewers’ concerns that Mitalipov would have trouble getting to San Diego when human eggs were collected. (See Nature Reports coverage of this breakthrough as well as comments from scientists who reviewed the paper. )
Woolcott accused CIRM of moving the goal posts in the middle of the game. “Dr. Trounson [CIRM’s president] said he was concerned about the access to oocytes, and they weren’t going to do any SCNT funding at this time until they worked out the oocyte issue.” (This is covered extensively in the June 30 blog on the California Stem Cell Report.)
Another rejected grant proposing SCNT is most likely from Stemagen, which previously reported cloning a human blastocyst in the peer-reviewed journal Stem Cells.The reviewers were also worried about the access to oocytes in this case, and had additional concerns about the techniques proposed for creating and growing embryos. (See our free blog post which includes description and link to a Nature News story that requires a subscription.)
Also called therapeutic cloning, SCNT involves inserting the nucleus from one cell into an egg from which the nucleus has been removed. Then the egg is stimulated to grow into a blastocyst, which would be destroyed to collect the innermost cells from which embryonic stem cells can be derived. Though harvesting these inner cells is the typical way of creating embryonic stem cells, it hasn’t worked yet for SCNT in humans, a failure blamed on an insufficient number of eggs for the attempts required to generate healthy blastocysts.
The advantage of SCNT would be that the cells would be compatible with the cell donor, and that stem cell lines from people with specific diseases could be studied. Induced pluripotent stem cells promise similar advantages from a skin biopsy, but it’s still unclear what the differences between iPS and ES cells are, or whether those differences matter, and researchers are eager to study cell lines produced from both methods side by side.
That’s likely to fuel the debate over what incentives CIRM can or should offer to encourage women to give their eggs for research. Compensating egg donors is federally barred in the US and particularly forbidden to CIRM grantees.
This shortage has been sufficiently pronounced to merit a news article in Nature when a woman volunteered to offer her eggs to Harvard researchers so they could try to create embryonic stem cells through nuclear transfer.
The recent Nature news article covered it well. If you don’t have a subscription, you can’t read the entire article, but here are relevant paragraphs. I’ll put some more links at the end.
“The US National Academy of Sciences (NAS) guidelines barring compensation were set in part to protect poor people from being exploited by labs that might offer large sums of money — along the lines of rules barring compensation for organ donation. But Alta Charo, a lawyer and bioethicist at the University of Wisconsin Law School in Madison, who liaised with the NAS committee that set donor-compensation guidelines in 2005, says the move was as much political as ethical. In California, supporters of Proposition 71, which allows funding for stem-cell and cloning research in the absence of federal funding, adopted compensation prohibition in part, Charo claims, “to assuage a fringe group of the women’s movement” that was aligned against the assisted-reproduction community.
The NAS guidelines followed the lead taken by California and some countries to ensure that stem cells could easily cross state and international borders. The United Kingdom, however, essentially changed the rules two years ago. In 2006, Alison Murdoch of Newcastle University received approval for a plan to allow couples to defray the costs of fertility treatments if they are willing to share some eggs for research purposes. This could create disparity in the quality of care available to people who don’t have the money to undergo fertility treatments, says Charo, but it could also provide access to such treatments for more people. Murdoch has so far collected more than 100 eggs in this fashion.
Wood says that this egg-sharing workaround presents a problem; the eggs being used for research are from older individuals, presumably with fertility problems. Using eggs donated by women aged 20–24, he has reportedly achieved cloning success rates near 25%.
And there are ethical concerns. Marcy Darnovsky of the Center for Genetics and Society in Oakland, California, says that such schemes split the doctor’s duty of care three ways: between donor, fertility patient and researchers. And the focus on compensation, she says, distracts from concerns about risks from this one research avenue when other avenues seem open.”
The promised links:
An overview in the New England Journal of Medicine.
“The New Push for Eggs” by Jesse Reynolds, of the Center for Genetics and Society, which objects to cloning and believes the risks of egg-harvesting procedures are grossly under-reported. He also analyzes results of this round of CIRM grants. See also an earlier article on Egg extraction for stem cell research )
Charis Thompson of the University of California Berkeley says women who provide eggs are providing a service and should get paid. See her article in Regenerative Medicine.
Deborah Spar from Harvard on “The Egg Trade” in the New England Journal of Medicine. , also summarized and analyzed in a post by the bioethics blog that concludes “Spar’s proposals to understand and mitigate the risks of egg donation, insure that all consent to donation is informed, and have a serious debate on whether any women should be allowed to sell eggs are all sensible, but don’t look for any progress anytime soon.”
Some additional statistics
I went through the grant descriptions provided by CIRM to tally these.
For iPS: 24 grant applications, 8 funded.
For ESC: 12 applications, 4 funded. None of the 3 grants proposing SCNT were funded.
For comparing iPS, ES and other lines: 5 applications, 4 funded.
For other sources, including unfertilized eggs: 6 applications, none funded.
For using nonviable embryos or embryo biopsies, 3 applications, none funded.
If anyone wants to see my Excel spreadsheets tallying whether a grant was for ES, iPS, something else, or a combination, let me know and I’ll email it to you. Just let me know if you find a mistake or something interesting.