Dr. Shinya Yamanaka invented a time machine.




"I was here, at Gladstone, the moment I learned we got human IPS cells," said Yamanaka last month, in an interview from his part-time office at San Francisco's Gladstone Institutes. Yamanaka did most of the IPS cell work at his main lab in Japan.

"My colleague sent me the image, and it was, wow," Yamanaka said, offering a brief, modest smile. "We had beating human heart cells, made from IPS cells."

Nobel validation

The Nobel, no doubt, validates the years of work by both Yamanaka and the British scientist he shared it with, Dr. John Gurdon. But in scientific circles around the world, his research hardly needed the validation. Yamanaka's IPS cells, developed just six years ago, have the potential to revolutionize medical research, his peers say.



Stem cells are the body's means of growing and regenerating all of the cells that make up muscles and organs and bones and blood - everything that forms our physical body. Everyone carries a supply of so-called adult stem cells that constantly replenish cells we need to survive.

But certain critical cells, including some in the brain and heart, can't be replaced once they're dead or damaged. The only way to grow those cells is from embryonic stem cells, which are only found in the earliest stages of human development.

Embryonic stem cells are pluripotent, which literally translates into "many potentials," referring to their ability to become any one of hundreds of cell types in the body. Yamanaka's cells are "induced" into their pluripotent state, thus the name he gave them.

It's that pluripotent ability that makes both embryonic and IPS cells potentially very important for medicine. When scientists first found human embryonic stem cells about 15 years ago, they hoped to one day be able to harness them and manufacture them in large quantities, providing an endless supply of regenerative tissue for damaged bodies.

But embryonic stem cells are controversial, and not efficient for mass production. Because they must be harvested from human embryos, which are usually donated by couples undergoing in vitro fertilization or by abortion clinics, many people have severe ethical reservations about using the stem cells. Additionally, there will always be a limited supply of embryos.

IPS cells will overcome both of those drawbacks if they prove to be identical, or nearly so, to embryonic stem cells. There's no ethical debate around their creation, since they can be made from any cell in the body - even a skin cell scraped from someone's arm or leg. And the supply is limitless.

The potential uses for IPS cells are incredible, stem cell scientists say. They could someday be used for transplants, or to help regrow neural cells damaged in a spinal cord injury, or to replace cardiac muscles after a heart attack. Because IPS cells contain all of the genetic information of the original cell sample, they also can be used for disease modeling.

There are major hurdles to IPS cell use. The cells, for starters, can sometimes produce tumors. And while Yamanaka and others agree that making IPS cells is a relatively simple process, manufacturing them in a speedy, efficient manner with stable, predictable results is complicated.

IPS cells are created by applying four genetic triggers - often called the "Yamanaka factors" - to a full-grown cell. Those triggers cause the grown cell to retrace its development process back to an embryonic-like state. From there, scientists apply different triggers to prod the cell into a new type of cell.

At the moment, it takes about six months to transform a full-grown cell to an IPS cell state and then to a different type of full-grown cell. And depending on the process and type of cell being created, IPS cell technology only works about 1 percent of the time.

Other approaches

That's fine for lab work, but not if the cells are going to be used in humans to treat diseases. Much of Yamanaka's work now, both at Gladstone and at his main lab at Kyoto University in Japan, is on improving the manufacturing process.

Meanwhile, scientists have already developed new techniques for reprogramming a full-grown cell directly into another type of full-grown cell, and skipping the IPS cell state altogether. For example, scientists say, someday they may be able to give drugs to a heart attack victim that trigger a reprogramming process in extraneous cells in his heart, and transform them into healthy, beating heart cells to replace the dead tissues.

These directly induced cells "are probably the hottest area in this whole stem cell field right now," said Dr. Marius Wernig, an investigator with Stanford's Institute for Stem Cell Biology and Regenerative Medicine. "We could avoid stem cells altogether if you could directly convert cells in the brain after a stroke, and try to coax them into neurons."

Most stem cell experts expect it will be years, if not decades, however, before scientists are able to use cellular therapy to treat human patients. Safety must be a priority, not just for obvious ethical reasons, but because even one clinical trial with bad results could set back the entire field of stem cell therapy, scientists say.

IPS trials coming

Around the world, several clinical trials involving embryonic stem cells are being conducted, but none so far involving IPS cells; a team in Japan plans to launch the world's first IPS cell clinical trial in humans next year, for a treatment for macular degeneration.

In the Bay Area, several stem cell scientists have grants from the California Institute for Regenerative Medicine - the state's primary means of funding stem cell projects - for research into using IPS cells in humans. But most of those trials are still at least two or three years off.

Perhaps more important, at least in the short-term, is the role that IPS cells already are playing in how scientists research and discover new drug treatments for dozens if not hundreds of diseases and conditions.

"I know that what people are excited about is cell therapies - when cells are going into people," said Dr. Bruce Conklin, an investigator with Gladstone's cardiovascular disease division. "But the actual important change that's going to happen is in drug development, and finding safer drugs."

IPS cells are proving critical in what's known as disease modeling - designing lab-based simulations of conditions like Alzheimer's disease or autism that can't be easily studied on a molecular level in human beings or in animals.

A disease like Alzheimer's is very complex and involves a wide variety of cellular processes that happen over years or decades. Scientists have been able to identify some markers of the disease, but targeting those markers with drugs hasn't proved helpful so far.

Using IPS cell technology, scientists could take skin cell samples from someone with Alzheimer's and regress them to their stem cell state, then prod them into brain cells. Those brain cells would still be affected by the Alzheimer's, and scientists would then be able to study the actual disease, instead of a simulation of it.

In addition, they could test drugs on those induced brain cells and know exactly what effect those drugs have on real human cells, instead of animal models or other simulations, which often produce different results than those seen in human patients. In fact, some pharmaceutical companies already have started testing large batches of drugs on IPS cell models of human diseases.

"The IPS discovery finally allows the opportunity for drugs to be tested on the most relevant type of human cells," said Dr. Deepak Srivastava, director of the Roddenberry Center for Stem Cell Biology and Medicine at Gladstone.

"Now you have the ideal cell type in front of you, for example the brain cell from a human patient with Alzheimer's," he said. "If you found a drug that worked on that brain cell, the likelihood of that working in a patient would be much higher than if it's from a mouse."

For patients, the discovery of IPS cell technology means they can play a new and critical role in research into their disease. Liane Wong, 51, was diagnosed with long QT syndrome in her 20s, and her teenage son has it too. The syndrome is a rare congenital heart problem that affects the cardiac electrical system and can cause sudden death.

Two years ago, Wong volunteered for a trial at Gladstone that has afforded her a type of immortality. Conklin, the lead researcher there, used cells taken from her calf to make IPS cells.

"They've turned my skin cells into heart cells, so they can study long QT syndrome and try to do different experiments with it," Wong said. "It was such a small thing for me to do that could have such a huge impact. There could be a cure, or just more advanced treatment.

"The future is just in a little patch of skin," she said. "It's really just mind-boggling. It feels like science fiction."
