Mouse embryonic stem cells stained with a fluorescent green marker for embryonic germ cells. Picture: Niels Geijsen, Massachusetts General Hospital/National Science Foundation
US stem cell research isn't being stymied by a lack of interest from biologists, students and patients who may one day benefit from new therapeutics. An investment shortfall lies behind the pinch in embryonic stem cell research.
Unlike in the UK, where the taxpayer-funded Medical Research Council and other research councils have allocated nearly £31 million pounds in 2005-2006 to make stem cell research a priority, the US government policy limits federal funding to research on carefully defined, stem cell lines existing before.
And while the government says about 70 cell lines worldwide meet these guidelines, some researchers have said that only a dozen may be of high enough quality to be useful.
"Britain has said that reproductive cloning is a criminal offence and therapeutic cloning is allowed. The dividing line is the implantation of the cloned embryo in the uterus," Rudolf Jaenisch, a founding member of the Whitehead Institute for Biomedical Research, told a recent meeting at that institute in Cambridge, Massachusetts. "Other countries are adopting this, and California, Massachusetts, Connecticut and New Jersey have adopted this, but not the United States as a whole."
What's in a stem cell?
Stem cells have two main characteristics: 1) they can renew themselves,
that is, divide and create two identical cells and then keep dividing,
and 2) they can be differentiated, that is, they can be changed to
become any type of cell in the body.
There are two main types of stem cells: embryonic stem cells and
adult stem cells. Embryonic stem cells are derived from a stage when
the embryo is a blastocyst, which is when the egg is about five days
old and about one week away from when it would attach to the wall of
the uterus if it were inside of a woman. Embryonic stem cells are
plentiful, they can live forever, and they can form all types of organ
and tissue cells in the body. Adult stem cells are far fewer in number,
they have a limited life span, they form specific tissues and organs,
and they are more difficult to isolate.
Controversy surrounds using embryonic stem cells for multiple
reasons, including ethical and religious ones. The UK allows use of
embryos up to 14 days old for research or potential therapeutic use,
while the US only allows the federal funding of research on embryonic
stem cell lines that were created before 2001, when the US enacted its
rules for using such stem cells.
"Funding for most of our lab is from philanthropy," said Melton. "I don't think the nation will continue on this path in this important area. The limited resources are holding research back now." The Harvard Stem Cell Institute hasmore than 500 students and post docs, and includes Harvard Medical School, Harvard University and eight affiliated hospitals.
States step up
Philanthropists have stepped up in the state of California as well. While California has been particularly aggressive among US states in funding stem cell research, setting up the California Institute for Regenerative Medicine, for example, the state currently is embroiled in several lawsuits challenging the constitutionality of the $3 billion in bonds that voters approved for funding research on medical treatments using human embryonic stem cells.
The suits have kept the state from issuing any of those funds to the
institute. So far the stem cell programme has been kept going by a $3
million loan from the state and a $5 million donation by Ray Dolby, a
pioneer in sound equipment. But the money could run out within a couple
months, and the lawsuits could take until next spring to
conclude.
On 4 April state officials approved stopgap funds via the sale of $14 million of so-called "bond anticipation notes" to six philanthropic foundations throughout the state. The notes will be repaid with interest if the litigation is resolved and the $3 billion in bonds are issued, but the money won't be repaid if the state loses the lawsuits.
The largest purchaser of bond anticipation notes, taking $5 million, is the Jacobs Family Trust, set up by Irwin Jacobs, co-founder of wireless equipment company Qualcomm Inc. of San Diego. Those each buying $2 million of the notes are: the Beneficus Foundation; William K. Bowes Foundation by venture capitalist William K. Bowes; the Broad Foundation by former homebuilder Eli Broad; and the Moores Foundation by San Diego Padres baseball team owner John Moores. The Blum Family Partners will buy $1 million in notes.
In a separate move in Maryland, a state that has actively been trying to lure bioindustry companies and researchers, Governor Robert Ehrlich Jr. signed a bill on 6 April that would allow the state to use tax dollars for stem cell research. He initially proposed allocating $20 million for next year, but the General Assembly of the state cut that to $15 million when it approved the law, which makes Maryland the fourth US state to approve funding for embryonic stem cell research.
New Jersey became the first state to finance the research in 2004. The state's legislature is now considering a $250 million bond for stem-cell research, including a new stem-cell research institute. Connecticut in 2005 approved a 10-year, $100 million stem-cell funding plan. And that same year Massachusetts legislators approved a bill giving state health officials regulatory control over stem cell research.
New cell lines
In his work on Type I diabetes, Melton found the so-called "presidential" lines of existing stem cells approved by the US federal government were not useful. Nor were the less controversial adult stem cells that already exist in the body. While embryonic stem cells can quickly replicate themselves and be made into any type of cell, the same is not true of adult stem cells. The adult stem cells are in limited supply, and they do not exist for all the types of organs and tissues in the body, including the pancreas.
"There's no evidence that there are adult stem cells that can make pancreatic beta cells," said Melton. Pancreatic beta cells are attacked and destroyed by the body's immune system, a two-pronged process that causes Type I diabetes. In healthy people, the beta cells secrete insulin, which processes sugar for use by the body. Without beta cells, patients with Type I diabetes, which typically starts at age 14, must check their blood sugar several times a day and take daily insulin shots for the rest of their lives. Without insulin, they will die.
"About one in 200 newborns in the United States will be fully insulin-dependent by the time they are eighteen," said Melton. He said the only way to treat the disease is by rejuvenating any existing beta cells in the patient that might not have been killed off by the immune system. But if all of the beta cells are killed, the answer may be to make new embryonic stem cells that are beta cells and that potentially can be implanted into the pancreas so that it will secrete insulin.
"We know an embryonic stem call can become a beta cell, but we are working on a way to do that efficiently and on demand," Melton said. In addition to trying to develop therapeutics, which are years away from becoming a reality, the stem cells also can be used to learn about diseases.
"We really don't understand the details of what causes Type II diabetes or effective therapies except to say stay as thin as possible and control your diet," said Rick Young, principal investigator at the Whitehead Institute. There are about 200 different types of cells in the human body, each with a unique gene expression program to specify the cell type. The gene expression programs are controlled by 2,000 gene regulators encoded in the genome. "The regulatory circuitry that controls the gene expression programs is not known for any human cell," Young emphasised.
Studying stem cells can help researchers understand the regulatory circuitry and how it instructs various cells in the body to act in certain ways.
A view from industry
The road to stem cell therapeutics is a long one, fraught with the need to break new ground. Take Geron Corp. of Menlo Park, California, which is collaborating with the University of California BioSTAR Project to with the aim of deriving oligodendrocytes to treat acute spinal cord and related central nervous system injuries.
Jane Lebkowski, senior vice president of regenerative medicine at Geron, said that before human embryonic stem cell therapies can be tested in the clinic, several technological developments must be accomplished. They include: simplified and standardised large-scale production of differentiated (embryonic stem cells that are turned into a particular type of cell like skin or brain) cell types; reproducible methods to differentiate selectively the cells; defining the efficacy, potency and safety of cell populations, including in clinical trials; and developing methods to deliver the cell therapies to the target tissue.
"No syringes exist that are approved for transplantation of cells into the spinal cord, so we need to develop these," she said as an example.
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