In 2004, California voters decided to become what state officials believe to be the most generous funders of stem-cell research in the world. They approved Proposition 71, which funnels $3 billion of state funds into stem-cell research over the next decade. Supporters of the proposition argued that US federal policy, which limits on research on human embryonic stem cells (ES cells), squeezed shut a potential pipeline of therapies and other products. The measure, they maintained, would bring California prestige, prosperity, and cures. Critics countered that it was a waste of taxpayer's money and that it encouraged the destruction of embryos.

The California Institute of Regenerative Medicine, based in San Francisco, was created to disburse these funds. Grants totaling $210 million have already been awarded to individual researchers and institutions (Table 1). Nature Reports Stem Cells sent questionnaires to the 72 recipients of the so-called SEED (Scientific Excellence through Exploration and Development) grants that were awarded in February this year, asking about their research plans including which cell lines they had chosen and what hurdles they foresaw in working with ES cells. Forty seven researchers, or almost two-thirds of those surveyed, responded.

Table 1. Awards announced by CIRM CIRM plans to spend $85 million for grants to 25 new investigators for all kinds of stem cell research, and has earmarked $222 million to develop new research facilities. As of July 25, funds have only been distributed for the first-year of the training grants. In 2006, the U.S. National Institutes of Health spent $37 million to support 165 research projects in human embryonic stem cells.

Registry lines are the most popular choice

Only stem cell lines created before August 2001 and listed on US National Institutes of Health (NIH) stem-cell registry are eligible for funding. Of the 70-plus lines listed on the NIH registry, only 21 are available for shipping to laboratories for research. A report in 2006 estimated that approximately 300 cell lines had been derived.1 More have been derived since then. The federal ban on funding for research on newer human ES cell lines was one of the factors motivating Proposition 71.

Nature Reports Stem Cells particularly wanted to know whether recipients planned to use those human ES cell lines eligible for federal funding, or whether they had chosen non-registry ES cell lines. Responses revealed that 85% grant recipients will be using some of the human ES cell lines eligible for NIH funding. This is hardly surprising, given that these lines are the oldest, best characterized, and require the least paperwork for studies in laboratories that have US federal grants. However, overall, researchers also intend to use a wide variety of non-registry lines — a greater number in fact than the NIH registry lines.

Experiments using newer, non-registry lines are legal, but only if salaries, laboratory space, reagents, and other necessities have not been paid for with federal funds. Because federal money has contributed to so much scientific infrastructure, the policy severely restricts work on lines other than those on the NIH registry. But many researchers find the newer, non-eligible lines easier to work with, or prefer them for the conditions under which they were derived. As one survey respondent put it: “I applied to a CIRM SEED grant to be able to use 'real' cell lines.”

Non-registry lines are prominent in the SEED researchers' plans. Overall, the respondents plan to use at least 12 registry lines and 19 non-registry lines. The number of non-registry lines reported is likely to be an underestimate, and not simply because of those who did not respond to the survey. Several respondents named the country or laboratory where cells were derived rather than a specific line; these responses were counted as one cell line, but might be several. Plans to derive new human ES cell lines were also counted as single non-registry lines, even though the researchers hoped to produce multiple lines — and might not succeed in producing any. The 12 registry cell lines could also be an underestimate, as three researchers said they were using “registry lines” without being more specific.

The registry lines, however, are the most popular choice among survey respondents. Twenty-six laboratories plan to use registry line H9 from the WiCell Research Institute, based in Madison, Wisconsin (Figure 1). Of the eight lines mentioned by four or more laboratories, five are registry lines. Many of the researchers are already working with these lines in their laboratories. Overall, more than four-fifths of the researchers plan to use registry lines, and half said that their current research plans included only registry lines (Figure 2). However, some of these respondents indicated that they would switch to non-registry lines as they encounter experimental difficulties or gain experience. “We decided to 'get our feet wet' with the NIH-approved H9 cell line before moving on to non-approved stem-cell lines,” wrote one.

Figure 1. Registry lines H9 and H1 are most popular. Non-registry lines are green; data not shown for lines mentioned by fewer than three labs.
Figure 2. Most SEED recipients are using registry lines.

CIRM vs. NIH

The obvious question is whether state funding is necessary if researchers are using cell lines eligible for federal funding. SEED grant recipient Michael Teitell, a cancer researcher at the University of California, Los Angeles, is studying how mitochondria affect stem cells' ability to grow and differentiate. He chose registry lines because they are well-characterized and readily available. CIRM's review of Teitell's application concluded that his proposal was “very likely to provide fundamentally important insights.” But Teitell says he couldn't rely on federal support for his work. “There's no great funding source for doing this research outside of CIRM,” he says.

In 2006, the U.S. National Institutes of Health spent $37 million to support 165 research projects in human embryonic stem cells. Overall that year, 16% of competing applications for the NIH's standard research grants (R01s) received funding; for the NIH Pioneer Grants designed to foster high-risk research, the success rate was only 3% (2). CIRM's SEED grants provide funding for two years rather than five, but CIRM funded 31% of the applications. In fact, CIRM's press officer Dale Carlson point out that it originally planned to approve 30 SEED grants for $24 million, these numbers were increased to 72 applicants and $46 million, he says, because CIRM's board was impressed with the quality of the 231 applications.

Innovative projects without supporting data have trouble getting funding, even if they could launch fruitful lines of research, says Arlene Chiu, CIRM's scientific director. The primary purpose of the SEED grants is to jump start stem cell research in California by helping new ideas and investigators gain a foothold. She believes two years will buy researchers the time they need to get preliminary data. After that, she says, some will have results worthy of larger, longer term grants. Other ideas will fall through, she says, but researchers will report what they tried and what didn't work. Either way, more high-risk, high-reward ideas will get a chance.

Jennifer McCormick, a researcher in the Stem Cells in Society programme at Stanford University in California, is one of many who believe that federal policy is eroding the United States' competitive edge. Earlier this year, she published a literature survey showing that US groups published 26% of all human ES cell papers in 2004, whereas in 2001, before the ban, it was 36% (ref. 2). And the disparity is growing. She found that the number of American stem-cell papers published in 2004 doubled from the number in 2003 — but non-US papers nearly tripled.

McCormick believes that not only did federal hostility to stem-cell research starve the field of funds, it also scared researchers away. Stable sources of funding could lure them back. Forty per cent of the SEED grant recipients had never done ES cell research before, according to CIRM. For those people in particular, the choice of registry lines makes sense, says McCormick. “This is a class of people who are switching into these fields. They are going to want to use lines that other people have used — who they can go to for advice.” Besides, she says, “life is easier if you're using the federally funded lines,” particularly if a lab has already received federal funds and isn't ready to separate reagents and working space.

Jeanne Loring of the Burnham Institute in San Diego, California, thinks that researchers will start to use more non-registry lines as they become more comfortable working with ES cells. “You should do this survey again in a year,” she says.

Cell characterization most important to recipients

As the oldest lines, the registry lines are the most widely characterized, the criterion that survey respondents ranked as most important in their choice of lines (Figure 3). Though the survey did not ask specifically about access to people with expertise, several respondents described such access as essential, indicating that they chose cell lines based on colleagues' or collaborators' work, or because lab members already had experience with them. When answering the question “How will you make sure the cells are what you think they are?” eight responded by saying that they trusted the scientist who derived or was supplying the lines. Five of these respondents mentioned no other means of confirmation.

Figure 3. Laboratories want well-characterized, uniform lines Scientists were asked "What influenced your decisions?" (0= not 1=somewhat 2=significantly 3=overwhelmingly) The numbers reflect the sum of responses.

“There is certainly a danger in naive researchers just picking up whatever they find and going with it,” says Loring, who runs an NIH-sponsored training programme for human ES cell research. Loring says she's witnessed the problem in other hot young fields like knockout mice and microarrays. The best one can hope for, she says, is that the period of overshoot will be very short. She tries to “strike fear” into her students' hearts during her courses, warning them that failing to characterize cells upfront will mean useless experiments and rejected publications. She thinks planned resources such as more training programs and stem cell banks will help.

Long wait for clinical applications and funds

Just over a third of respondents felt that that their research would have clinical applications within 10 years or less (Figure 4). Another third did not answer the question, or said that their work did not have clinical applications per se but would enable clinical research. That's not unreasonable, says Chiu, particularly for innovative research in a young field that still needs many basic tools. “The person who makes the first step may not think that particular result is going straight to the clinic.”

Figure 4. Scientists were asked "What's a reasonable timeline for clinical application of your research?" Most SEED recipients think research will need more than 10 years for clinical applications.

Several factors are delaying the start of the SEED-funded research (Figure 5). When the survey was carried out in April and May, about a fifth of the respondents had not obtained the cell lines they needed. More than a quarter of the respondents said that they had not started their experiments because CIRM money had not yet arrived in their accounts. Teitell is one of 14 respndents who has started experiments before receiving the funds. “We spend in advance and hope that we can recover,” he says, “It makes my heart skip a few beats.”

The delay is partly due to a lawsuit brought against CIRM that barred it from disbursing Proposition 71 funds. This suit was derailed in May, and CIRM officials had originally hoped for the start of funding to be July 1, but much paperwork has to be cleared away before funds are released. For example, investigators have to certify that their research plans have been approved by ethical boards at their institutions. CIRM's Carlson says that notice of grant awards are in the works, and that these must then be signed by institutions and returned before the funds are supplied.

Figure 5. Funding is the most common reason to delay experiments.

When designing the grants, CIRM officials wanted to target human ES cell work because it has been particularly stunted by federal policy. Other than that, Chiu says, the goal was to give a wide variety of scientists a modest amount of money and a modest amount of time to see whether their ideas had legs. In California, several dozen researchers are starting to take their first steps.

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