Stem-Cell Research Moves Forward


http://chronicle.com/free/v51/i06/06a02201.htm


Despite restrictions imposed by the Bush administration, the field is
growing -- at least for now

By JEFFREY BRAINARD

Madison, Wis.

Sean C. McConnell is the kind of budding young researcher who some
scientists and politicians fear could develop a permanent case of the blues
over the Bush administration's current policy on stem-cell research.

Research advocates have predicted that President Bush's approach, which is
to provide federal funds for only a limited set of embryonic stem cells,
will force young scientists like Mr. McConnell to consider moving to another
country where the rules are more lenient, or to drop out of the field
altogether.

But Mr. McConnell, a second-year doctoral student in biochemistry and
molecular genetics at the University of Alabama at Birmingham, doesn't think
the prospects are so dim, at least in the long term. That is why he and four
other young researchers attended a two-day training session on growing human
embryonic stem cells this past summer at the place where they were first
isolated in 1998, the University of Wisconsin at Madison. The group of five
-- including other doctoral students, a young junior faculty member from the
University of Kansas Medical Center, and a recent college graduate whose
parents paid his $900 fee for the course -- learned to handle and monitor
the fragile, finicky cells with pipettes and microscopes.

"It's hard for the administration to ignore that many scientists wanting to
study this, especially with the lobbying by people like Nancy Reagan," says
Mr. McConnell. "President Bush's policy is a dam holding back a wall of
pressure."

Mr. McConnell's guarded optimism illustrates how issues related to the
development of the nascent field of embryonic-stem-cell research are often
more nuanced than the political debate suggests. When Mr. Bush decided in
2001 to limit federal funds to studying only human embryonic stem cells
existing at that time, scientists predicted it would stymie the field's
development. But since then the discipline has experienced a growth spurt,
judging from attendance at conferences and from the number of scholarly
papers published on the subject.

Attendance at the annual meeting of the International Society for Stem Cell
Research, for instance, doubled from 700 in 2003, when the organization was
formed, to 1,400 this past June. Of those, 70 percent were from North
America.

As the field begins to mature, though, advances in the research are running
up against the Bush administration's restrictions. That was especially true
after scientists created a bevy of new colonies, or lines, of embryonic stem
cells this year using private funds. Scientists and university officials who
want to study those cells say they must jump through cumbersome logistical
and accounting hoops to ensure that no federal research dollars are used.

In the end, James A. Thomson, a pathologist and veterinarian at the Madison
campus whose research team first isolated human embryonic stem cells,
believes that if scientists demonstrate that their research can improve
medical treatment for serious diseases, political pressure will force the
Bush administration to amend its policy, should Mr. Bush be re-elected.

"As the benefits of the work get shown, the policy will change," he says.
"I'm completely confident of that."

Human embryonic stem cells have captured the attention of politicians and
advocates for patients because of their potential application for treating
disease. The cells are taken from embryos at an early stage of development,
about five days after fertilization, when the embryo numbers only about 200
cells. All of them are still in a pliable stage, capable of specializing
into all of the cells that make up the body, such as heart muscle or brain
neurons.

The cells are then grown into distinct colonies, or lines, containing
millions of identical copies. Researchers can freeze each line indefinitely,
periodically thawing samples to study or give to other scientists.
Scientists speculate that they can learn to coax the cells to grow into
adult tissue, such as heart cells and neurons, to treat conditions like
heart failure and Parkinson's disease.

The work has been controversial, however, because researchers must destroy
embryos to obtain the stem cells, and some people, including religious
conservatives, regard the embryos as human lives, morally equivalent to
babies. Supporters of the research point out that the embryos have been
donated from in vitro fertilization clinics and would otherwise have been
frozen in limbo or discarded.

Mr. Bush kicked off the current debate with his August 2001 decision to
provide federal funds for research only on the embryonic-stem-cell lines
that existed at that time. Officials at the National Institutes of Health
had estimated that as many as 78 separate lines existed worldwide. But to
date, the NIH has identified just 22 for which researchers may request
federal funds. Many of the remaining reported lines are believed to have
come from researchers who reported disassembling embryos in an attempt to
derive stem cells but were unsuccessful.

In addition to the burgeoning attendance at stem-cell conferences, more than
40 scholarly papers mentioned human embryonic stem cells in the first five
years after they were discovered. That was a higher rate than what was
published five years after scientists discovered embryonic stem cells in
mice, in 1981, according to Dr. Thomson of Wisconsin.

NIH funds for research on the human embryonic stem cells have also
increased, although not as rapidly as some scientists had hoped. For the
2003 fiscal year, which ended last fall, the NIH provided $24-million for
118 grants, up from $10-million the previous year. Those numbers are
expected to rise in 2004, but figures are not yet available.

Although private foundations have provided several million dollars for
stem-cell research, the NIH is the largest source of funds for university
research, and scientists say the growth of stem-cell research will depend
heavily on how much the agency spends on it.

In all, suppliers of the 22 stem-cell lines now eligible for federal funds
have shipped more than 500 batches of the cells to researchers. The NIH
doesn't track exactly how many separate scientists are receiving those
shipments, but if Wisconsin's experience is a guide, the cells are being
spread around.

In 1999 the Wisconsin Alumni Research Foundation, which holds patents to the
human embryonic-stem-cell lines first isolated at the university, set up a
separate nonprofit corporation, the WiCell Research Institute, to provide
them to other researchers. WiCell has since shipped about 200 batches of the
cells to 189 research groups at 132 separate institutions.

Even so, "the field is actually still very small in terms of the
high-quality labs that are actually doing the work, certainly less than 50
senior scientists," says Leonard I. Zon, a professor of pediatrics at
Harvard Medical School and president of the stem-cell society.

Showing Trainees the Ropes

Training more researchers is one growing pain that the field must handle as
it expands beyond its early stage.

But formal opportunities for training are still limited. The NIH tried to
help by giving five institutions three-year grants last year to run training
sessions. Those are expanded versions of the two-day session that Mr.
McConnell attended at Wisconsin's WiCell.

The NIH-financed courses, which run from one to three weeks, generally train
15 to 25 scientists at a time. Just one or two courses a year have been
offered, however, and generally there have been twice as many applicants as
slots available, says James F. Battey Jr., chairman of the NIH Stem Cell
Task Force, which promotes and finances stem-cell research.

The NIH will evaluate the training courses before the grants expire in the
2006 fiscal year and may decide to pay for more of them, he says. However,
Dr. Battey acknowledges that expanding the training may be a challenge. The
trainers at the institutions that received NIH funds for the work have told
him they believe that the labor-intensive training competes with time for
research.

As in other new scientific disciplines, growth in the stem-cell-research
workforce may take years as graduate students are trained and fan out to
other universities, says Dr. Thomson, who is scientific director of WiCell.

"We haven't come anywhere close to saturating how many people will be using
the cells," he said during an interview in his office in the university's
primate-research center. On one wall is a memento of the national attention
his work has attracted: a series of Doonesbury cartoons in support of
stem-cell research, autographed by the cartoonist, Garry Trudeau.

"It's not clear how big the plateau will be," he says, "but it's just clear
it's going to be a lot bigger than it is now."

Another challenge for scientists is figuring out how to obtain and work with
new stem-cell lines that have recently become available but are not eligible
to be used in studies paid for by the NIH.

Since 2001, researchers worldwide have created several dozen new lines of
embryonic stem cells. Seventeen of them were announced this year by Douglas
A. Melton, a Harvard University researcher, and an additional 100 by the
Reproductive Genetics Institute, a fertility clinic in Chicago. Researchers
cannot use federal funds to study those cells because they were created
after President Bush's policy was announced.

But researchers say further study of those cells may be the key to unlocking
the potential of embryonic stem cells to advance medicine. Mr. Melton's
lines are described as somewhat easier to grow in the laboratory than the
federally approved lines are.

Twelve of the Chicago cell lines came from embryos diagnosed as carrying
genes that cause serious diseases, like Fanconi's anemia. Scientists want to
study the cells to learn how those diseases develop from a step-by-step,
biochemical perspective. That in turn may help them develop new drugs to
successfully treat those diseases.

In fact, Dr. Thomson and other scientists argue that such laboratory studies
may ultimately prove more useful than efforts to use embryonic stem cells as
a source of replacement tissue to treat such ailments as heart disease and
Alzheimer's. That is because to treat those conditions scientists would have
to learn how to make, for example, heart muscle physically integrate with
beating heart muscle and work properly. In addition, such transplants might
be damaged by the same, unknown physiological causes that contributed to the
original disease.

The NIH's Dr. Battey notes that it may be possible to do biochemical studies
of disease using the existing, federally approved stem-cell lines.
Scientists are hoping to use genetic engineering to splice particular
disease-causing genes into those stem-cell lines, which lack them.

Nevertheless, with such techniques still under development, scientists are
seeking out the new cell lines now available. The Harvard group says it has
received requests from 154 laboratory groups for its cells.

Researchers also have an economic incentive to seek the new lines: Both
Harvard and the Chicago laboratory have offered to distribute the cells to
researchers free. In contrast, Wisconsin's WiCell and other suppliers charge
academic scientists $5,000 each time they ship a batch of a single stem-cell
line, which they say is necessary to cover the costs of production. For cell
biologists, that represents a high start-up cost for research.

Scientists are also interested in obtaining new cell lines created in
Singapore and South Korea that would be more suitable for transplantation
because they were not grown in the presence of animal cells. All of the
federally approved lines were grown this way because researchers found the
embryonic stem cells did not reproduce otherwise.

Complex Accounting?

The growing interest in the newly available cell lines has raised a series
of accounting questions for researchers using federal funds, and for their
universities. At issue is whether scientists can study such cells in the
same lab space where they do federally financed research, including that
with the 22 approved lines of embryonic stem cells.

Faced with mounting questions, the NIH has issued some guidance on the
topic. Scientists can study nonapproved cell lines in space financed with
federal funds as long as they don't use the federal money to directly
support the research. In addition, they can't bill the federal government
for the share of overhead, or "indirect" costs, such as office lighting and
administrative support, related to that work.

Figuring out what that means in practice is another matter, and scientists
have drawn different conclusions.

Some say that scientists already do this kind of precise accounting
routinely, especially when they receive funds from the NIH and another
source, such as a private philanthropy. Both entities require scientists to
accurately apportion the time and equipment costs to the respective source
of funds.

"I've personally spent hours on those discussions" with university
administrators to get the accounting details right, says Dr. Zon of Harvard.
"That's how the policy ends up really slowing the field. In any other
biological system that you wanted to study, you would just start doing the
work."

But other university officials insist that it will be impossible to satisfy
the requirement for separate billing of indirect costs, like buildings. They
also note that the NIH issued its guidance in the form of "questions and
answers," an informal, friendly type of advice that is considered less
binding and more susceptible to change than a formal policy.

In the face of uncertainty, some see just one solution: Move the research to
a separate laboratory.

"You don't want to be seen as violating these rules on a very sensitive area
of research," says Lawrence S.B. Goldstein, a professor of cellular and
molecular medicine at the University of California at San Diego.

He is among the scientists who want to work with newly derived stem cells
like the ones from Harvard. In order to satisfy the federal rules and his
own university administration, he is moving his lab to another building on
the campus, where his overhead costs will be paid entirely by nonfederal
sources, mostly by the Howard Hughes Medical Institute. He plans to study
some NIH-approved lines there using federal funds, as well as studying
nonapproved lines. But he will use separate lab supplies, marked with green
and red tags, for work with each kind of cells.

"As decisions have to be made in the field by investigators and the
university administrators, everybody errs on the side of conservatism, which
I think is appropriate," he says. "But if I were a junior scientist
beginning my career, or a postdoc in a small lab, these are daunting
obstacles. You couldn't practice science for long this way and hope to get
anywhere."

Mr. McConnell, the Birmingham doctoral student, is realistic about these
kinds of obstacles. He worries, for example, that focusing his thesis on
embryonic stem cells could be a bad idea if the existing federal policy
bottles up and constrains the research.

On the other hand, he predicts, the policy and the scientific environment
may well loosen up in just a few years. Speaking of himself and other young
researchers, he says, "I think people are pretty patient, and that patience
will be rewarded."




  _____

UNIVERSITIES DOING STEM-CELL RESEARCH

Several universities have established centers or programs to focus on
stem-cell research. Among them:

*       Cornell U. (Weill Medical College)
*       Harvard U.
*       Johns Hopkins U.
*       Rutgers U. at New Brunswick with U. of Medicine and Dentistry of New
Jersey (Robert Wood Johnson Medical School)
*       Stanford U.
*       U. of California at San Diego
*       U. of California at San Francisco
*       U. of Georgia
*       U. of Michigan at Ann Arbor
*       U. of Pittsburgh and Carnegie Mellon U.
*       U. of Washington at Seattle
*       U. of Wisconsin at Madison (WiCell Research Institute)

SOURCE: Chronicle reporting


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