Jason Burnett and his 10-year-old son, Andrew, both born with a genetic defect, have been recruited into an experiment designed to transform bits of their skin into stem cells that may someday hold the key to a cure.
The Burnetts inherited a heart disease that leaves the father exhausted after a short walk. The two are among the first patients working with scientists who are using a new stem-cell technique that may someday revolutionize care for disorders as diverse as diabetes, Alzheimer’s and muscular dystrophy.
Discovered by scientist Shinya Yamanaka, the method creates stem cells without using and destroying human embryos. By studying cells created from people with inherited disorders, scientists are observing, in ways never before possible, how diseases progress and react to treatments, said Doug Melton, a Harvard University researcher.
“This is the breakthrough the stem-cell field has been waiting for,” said Beth Seidenberg, a partner at Kleiner Perkins Caufield & Byers, the California-based venture-capital firm that helped start Google Inc.
Unlike embryonic cells, the cells created using the Yamanaka method opened a path to test drugs for genetic diseases, Seidenberg said.
The approach used in the Burnett family study, being conducted by researchers at the Gladstone Institute in San Francisco, also is being adopted by labs in the United States, Europe and Asia and helped persuade GlaxoSmithKline PLC to invest $25 million in a joint venture with the Harvard Stem Cell Institute.
Since human embryonic stem cells were first isolated in a laboratory in 1998, they have fired the imagination of doctors, scientists and patients, who envision a day when new tissues or body parts might be grown to replace diseased ones. The cells are pluripotent, meaning they can be turned into any other type of cell, such as those that make up skin, nerves or neurons.
Embryonic cells also stir controversy. Obtaining them destroys the embryos they come from, placing the research along the same ethical fault line as abortion. Former President George W. Bush limited federal support for the science — a policy overturned this month by his successor, Barack Obama.
While politicians and citizens debated the morality of using embryonic cells, Yamanaka, a professor at Kyoto University, developed a technology that may make the argument moot. Yamanaka, who has two daughters, started his effort 10 years ago, after peering at a tiny embryo through a microscope and reflecting that it might form a child if it wasn’t used to make stem cells, he said in an interview.
“That’s the moment I thought about this project,” he said. “I saw that if we could make pluripotent stem cells without using human embryos, that would be ideal.”
In 2006, he scored his first success. Using a virus to insert four genes into the skin cells of mice, he started a process that returned the cells to a primordial state able to form any other cell in the body. Yamanaka named them induced pluripotent stem, or iPS, cells. The next year, he repeated the feat with human cells.
Yamanaka and researchers elsewhere are now racing to find better ways to achieve the same effect. They would like to get rid of the virus, which can cause the genes to lodge permanently in the structure of the cell and may trigger the growth of tumors.
Yamanaka’s technique exploits a basic fact of human biology — that every cell in a person contains the genetic instructions that set that person’s traits, from hair color to inherited disease. By taking skin cells from a person with a disease and turning them into cells in the heart, brain or pancreas that are affected by a genetic disease, researchers can experiment with disorders at their earliest stages, Harvard’s Melton said.
Labs are now creating iPS cells because making them is far simpler than getting cells from embryos, said Jeanne Loring, founding director of the Center for Regenerative Medicine, part of the Scripps Research Institute in La Jolla, Calif.
“Every stem-cell researcher I know has made about a dozen,” Loring said.
She estimates that researchers have made 300 different so-called lines of iPS cells, a number that may double this year. Each line is a colony of cells descended from the first ones made. Scientists keep them alive in culture and the cells keep replicating.
Grants of $23 million awarded last June by the California Institute for Regenerative Medicine, the state’s stem-cell funding agency, show that researchers are embracing iPS cells. Of 16 grants awarded, eight went to teams developing new iPS cells and five to groups comparing iPS and embryonic cell types. Just three went to scientists proposing to work solely with embryonic cells, according to the San Francisco-based agency.
The day may come when either embryonic stem cells or iPS cells are transplanted into patients to repair or replace damaged organs. Yamanaka’s iPS cells may provide a different kind of payoff much sooner as they are used to develop drugs against ills such as Lou Gehrig’s disease and muscular dystrophy.
One way iPS cells are more useful than embryonic cells is that they can be made from the skin of someone known to have a particular disease, said Melton, who is also codirector of the Harvard Stem Cell Institute, in Massachusetts. The disease status of embryos that are left in fertility-clinic freezers, which are the source of most embryonic stem cells used in research, is almost always unknown.
IPS cells give researchers the means to create models of diseases in the laboratory, and use them to develop drugs.
“You can study these diseases not in a patient but in a petri dish,” said Melton, who is using the cells to study juvenile diabetes and hunt for therapies. “If you ask me what are the first treatments that will come from stem-cell biology, I think it will be drugs that slow the degeneration of disease.”
That is what Deepak Srivastava, the cardiologist who brought the Burnetts to San Francisco from their home in Dallas in December to work with stem-cell scientists, is betting on. IPS cells may allow him to exploit a discovery he made in 2005 when he identified the gene that causes heart defects that afflict about 2 percent of Americans.
In 2004, Srivastava, then working at the University of Texas Southwestern Medical Center in Dallas, went with colleagues to Sulphur Springs, Texas, to collect blood samples and perform ultrasound scans on members of the Burnett family.
The researchers analyzed the genes of family members and found that 11 had heart-valve defects linked to mutations in a gene called Notch1, which plays a role in the formation of many organs, including the heart.
People with this mutation make half as much of the Notch1 protein as they should and their heart valves develop abnormally. The protein shortage primes their valves to take on extra calcium, which, over time, makes them stiffen, malfunction and require replacement.
Four years after his Notch1 discovery, Srivastava, now the director of the J. David Gladstone Institute of Cardiovascular Disease, supervised as the Burnetts had a pencil-shaped skin punch pushed into their calves to extract a bit of skin. When the boy’s turn came, his 12-year-old brother, Ryan, laid a comforting hand on his back.
The iPS cells made from the Burnett’s skin will be coaxed to become heart cells that carry the Notch1 mutation, Srivastava said. He plans to use the cells to test for drugs that boost levels of the Notch1 protein. This, he reasons, should make the hearts of people like the Burnetts more resistant to the entry of calcium and reduce the mineral’s buildup on the valves.
A drug that could do this may essentially prevent the disease, Srivastava said. That is because the condition is present at birth, yet symptoms usually take decades to develop, giving a medicine ample time to work.
Within five years, Srivastava predicts, he will have found the right drug and be ready to start human clinical tests. A closely held company named iZumi Bio Inc., in California, will collaborate with Srivastava on this and other research involving iPS cells, Seidenberg of Kleiner Perkins said.
Yamanaka’s discovery was “the tipping point” that led Kleiner Perkins to start iZumi in 2007, she said.
GlaxoSmithKline, Europe’s largest drugmaker, is pursuing a similar strategy. The company made the $25 million investment with the Harvard Stem Cell Institute to find and test new medicines. Simon Tate, vice president of the London-based company’s discovery-performance unit, said iPS cells will speed drug development and allow testing for side effects in liver and heart cells.
“It’s a transforming technology,” Tate said.
Lawrence Goldstein, the director of the stem-cell program at the University of California, San Diego, has made iPS cells and neurons from 30 patients with Alzheimer’s, allowing him to study the ailment at an early stage rather than wait until patients die.
“When you get brains postmortem, you’ve got the plane wreckage on the ground,” Goldstein said. “You can learn a lot by studying the pattern of wreckage, but what you really want to know is what went wrong while the plane was still flying.”
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