The Philosopher’s Stone

Ordinary cells can now be reprogrammed to more valuable cell types, and scientists are already pushing this breakthrough into exciting new areas
By GARY C. HOWARD, PHD
Kathy Ivey
Kathryn N. Ivey, PhD
June 27, 2013: In the Middle Ages, alchemists searched in vain for a philosopher’s stone that they believed would turn common metals, such as lead, into gold. In modern times, biomedical scientists have sought ways to transform common cells into those that could be used to repair damaged hearts, brains, and other tissues.
 

Reprogramming Cells
Gladstone investigator Shinya Yamanaka is no alchemist. However, his discovery might be a sort of modern day philosopher’s stone that allows biologists to “reprogram” one cell type into another.

“With this discovery, Dr. Yamanaka has revolutionized the way biologists think about cell fates and won the 2012 Nobel Prize in Medicine,” said Kathy Ivey, director of the stem cell core laboratory at Gladstone.

Cells are the basic unit of life. Over 200 different types of cells make up the human body, and each type plays a unique role in both normal human physiology and in disease. Until recently, a cell’s fate was thought to be unchangeable; the process of development results in fixed cell identities and that was believed to be an irreversible phenomenon. The recent discoveries by Dr. Yamanaka have challenged that paradigm, revolutionizing biology and paving the way for novel approaches to disease modeling, therapeutic discovery and regenerative medicine.

Kathy Ivey talks about stem cell reasearch [3:30]

Dr. Yamanaka’s experiment seems almost magical in its simplicity. By introducing just four genes into adult skin cells, he was able to “reprogram” those cells to become stem cells, which he called induced pluripotent stem cells or iPS cells. The term pluripotent means that these cells can develop into any cell type in the body.

That he succeeded is amazing. A cell contains a very large number of genes and proteins. Scientists estimate that humans have 25,000 to 30,000 genes and many more parts of the DNA that regulate those genes. The four genes used by Dr. Yamanaka encode what are known as transcription factors, which bind to DNA to turn genes on or off. The idea that four simple factors could change that cell from its adult state back to an embryonic-like state is almost unbelievable, except for the fact that it works.

What's Next?
How can this biological philosopher’s stone be used to advance stem cell biology and regenerative medicine?

“These are profound discoveries,” said Dr. Ivey, “but they are only the beginning.”

In fact, Dr. Yamanaka’s discovery has transformed our knowledge of biology and medicine. Scientists all over the world are applying iPS cell technology to tackle some of the world’s most challenging diseases, and Gladstone is among those leading the efforts.

Direct Reprogramming
Gladstone investigators have been pushing the boundaries of reprogramming. Deepak Srivastava showed that, with the right combination of factors, one type of adult cell can be directly reprogrammed into a different type without entering an intermediate iPS-like state. More amazingly, he showed that this can be done in the heart of a living mouse. He used the factors in mice that had been induced to have a heart attack and showed that, by reprogramming non-beating heart fibroblasts into beating heart myocytes, the mouse hearts were improved. This advance has astounding implications for repairing hearts damaged by a heart attack.

Using similar techniques, Sheng Ding and Yadong Huang have directly reprogrammed skin cells into brain cells. These are the first steps in harnessing reprogramming to rebuild brains damaged by Alzheimer’s, Parkinson’s, and stroke.

Reprogramming Figure
Cell reprogramming has changed the way biomedical scientists understand cell development. (a) For many years, scientists believed that development was a “one-way” street. A stem cell developed into an adult cell. (b) Dr. Yamanaka showed that an adult cell can be reprogrammed to a stem cell and then redirected to develop into another type of adult cell. (c) Since then other scientists have showed that an adult cell can be directly reprogrammed to another type of adult cell.

Reprogramming with Chemicals
Most of the reprogramming methods so far rely on the introduction of genes—short pieces of DNA—into cells. Using DNA in a laboratory setting is one thing, but it poses certain potential dangers for humans. So to realize the benefits of reprogramming in the clinic, the DNA must be replaced by small chemicals that can do the same thing. Dr. Ding is working on just that. In fact, he has already replaced three of the four basic factors with chemicals. Improvements such as this will accelerate the clinical applications of reprogramming.

Reprogramming Is Already Producing Results
While rebuilding damaged body parts is still some way off in the future, reprogramming has already shown its value in modeling disease and for drug testing. Scientists use disease models to study basic biological processes and to test potential treatments before testing in humans. Models can be non-human cells or animals that have been genetically modified to replicate certain features of human disease. In many cases, those models work quite well. Many of our body systems are very similar to those in animals.

Unfortunately, although we have learned a lot from animals, humans and animals are ultimately different. In fact, a lot of drug tests have failed in human trials after yielded promising results in animals.

iPS cells offer several advantages over existing disease models. First, iPS cells can be made directly from people, providing an abundant, renewable source of human cells. What’s more, iPS cells have the same genome as the person from whom they are made. So iPS cells made from a patient with a specific disease contain a complete set of the genes that resulted in that disease. And these pluripotent cells can be converted into any type of cell in the body, which means that it is possible to make heart cells from patients with cardiac disease or brain cells from individuals with neurological disease.

Benoit Bruneau and Bruce Conklin, along with Dr. Srivastava, have taken full advantage of these features to study cardiovascular diseases. Steven Finkbeiner has developed models of amyotrophic lateral sclerosis and Huntington’s disease, and Dr. Huang is modeling Alzheimer’s disease. GIVI Investigators are also beginning to apply iPS technologies to study auto-immune diseases, such as diabetes, and to create humanized immune systems in mice for HIV research.

“Dr. Yamanaka’s discovery is a modern-day philosopher’s stone,” said Dr. Ivey. “It has already transformed biomedicine, and these advances are just the beginning.”

 
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