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Published On September 12, 2016

TECHNOLOGY

Making the Leap

Ten years ago, researchers coaxed normal adult cells into stem cells for the first time

In 1962 a British graduate student named John Gurdon removed the nucleus of a fertilized egg cell taken from a frog. In its place, he inserted the nucleus of a mature cell taken from another tadpole’s intestine. The egg cell grew into a normal frog, genetically identical to the tadpole. The experiment and others like it inspired efforts to grow new organisms from the genetic material of an adult cell, and put the word “clone” into the popular vocabulary. In 1996 Dolly the sheep became the first cloned mammal to be born.

But even as Dolly became the world’s most photographed sheep, Gurdon’s work was also sparking a game-changing therapeutic application, halfway around the world. Shinya Yamanaka had been a resident in orthopedic surgery at Osaka National Hospital in Japan. Frustrated at his powerlessness to treat patients who suffered from incurable conditions, Yamanaka migrated to basic research, and became fascinated with the frontier of embryonic stem cells.

Found at the earliest stages of life, these cells exist in a state known as pluripotency: They can be nudged into becoming virtually any type of cell in the body. Many researchers hoped that the versatility of embryonic stem cells could someday enable them to replace diseased cells or even to grow new organs—a direction of research that came to be known as regenerative medicine.

But for some, regenerative medicine had an ethics problem: The only source of embryonic stem cells was destroyed human embryos. Most were the donated byproducts of in vitro fertilization (IVF), a process that produces more embryos than it requires. In 2001 Japan established strict limits on the use of embryonic stem cells.

Yamanaka set out to find another way to create them. He looked to Gurdon’s frog experiments for inspiration. If an adult intestine cell had enough genetic information to power the egg and grow a whole frog, he reasoned, adult cells could form any other type of cell. They only needed to be coaxed back into a pluripotent state. 

Yamanaka and colleagues at Kyoto University started their search with 24 genes they thought might play a role. Gradually they narrowed their focus to four genes which, when “turned on” at the same time, caused a cell to forget its specialized function and become pluripotent. They successfully converted mature mouse skin cells into what they called induced pluripotent stem (iPS) cells that had the same wide-open potential as embryonic stem cells—which the researchers showed by turning their iPS cells into nerve and connective tissue cells.

Cell published Yamanaka’s research, which led to a 2012 Nobel Prize in Physiology or Medicine. He shared the award with Gurdon, who had published his research on frogs the year Yamanaka was born.  And while there are now fewer obstacles impeding embryonic stem cell research, the promise of iPS cells has taken them beyond ethical considerations. Because iPS cells can be cultivated from the recipient’s own body, they minimize the risk of rejection by the immune system, making them an attractive vehicle for regenerative medicine treatments.

Yamanaka, 55, is now director of the Center for iPS Cell Research and Application (CiRA) at Kyoto University, which conducted the genetic analysis for the first iPS cells to be transplanted into a human. In 2014, a Japanese woman in her 70s with age-related macular degeneration—a common eye condition that can lead to blindness—had a tiny sheet of retinal pigment tissue made from her own skin cells implanted into one eye, which reportedly stopped the disease’s progression.

To date, researchers have used human iPS cells to make cardiac cells that repaired heart damage in a pig and insulin-producing pancreas cells that reversed high blood sugar in mice. The cells have also been turned into neurons that make dopamine, which could one day be used to treat Parkinson’s disease. iPS cell-based therapy could eventually be used for diseases ranging from cancer to spinal cord injuries— the kind of injuries that Yamanaka felt helpless to treat before he found his place in the lab.