Podcast Transcription

Steve:       Welcome to the Scientific American podcast Science Talk, posted on October 8th, 2012. I am Steve Mirsky. Just after 5:30 this morning Eastern time, Göran Hansson of the Karolinska Institute and Nobel Committee for Physiology or Medicine stepped to the microphone in Stockholm.

Hansson:   The Nobel assembly has concluded its meeting and made the decision. I'll read the announcement. The Nobel assembly at the Karolinska Institutet has today decided to award the Nobel Prize in Physiology or Medicine 2012 jointly to John B. Gurdon and Shinya Yamanaka for the discovery that mature cells can be reprogramed to become pluripotent. And with that I would like to ask Professor Thomas Perlmann of the Nobel Committee to present the science behind the prize.

Perlmann:          John Gurdon from Great Britain is a professor at the University of Cambridge and the Gurdon Institute. Shinya Yamanaka, born in Japan and a professor at Kyoto University. This year's Nobel Prize awards the discovery that has changed the way we understand how cells in the body become specialized, and it has provided entirely new tools for effective development of drugs and new therapies. A fertilized egg develops first into an embryo and then into an adult human with all its specialized cells, such as muscles, nerves and skin. As we all know, this process always moves in the same direction, from immature cells in the embryo to specialized cells in the adults. A common metaphor for this process visualizes how cells move downhill in a landscape to finally reach their destinations as specialized mature cells at the bottom of the valleys. Scientists believe for a long time that our genes are likely altered in this process, in ways so that this journey could never be set in reverse; and it seemed impossible for mature cells to travel back, all the way to the immature state at the top of the mountain. Now John Gurdon changed this view by a ground-breaking experiment in frog cells. He thought that if a gene's, contrary to the common view, were intact in mature cells, its nucleus should be able to develop when moved into the cellular context of an egg. So, he destroyed the nucleus of an egg and used a fine pipette to transfer and replace it with a nucleus from a mature intestinal cell from a tadpole. In most cases, this modified egg could not develop, but in a few cases, it developed into normal swimming tadpoles and later adult frogs. At first many were skeptical and surprised by this result, but this paradigm shifting discovery was confirmed. And we now know that the same experiment works to clone mammals, the first being Dolly the sheep, but later also mice, cows, pigs and other animals. Gurdon had shown that a nucleus of a mature cell retains all genetic information that is required to generate an animal. But could this also be done in intact cells, without dissecting out the cell nucleus and using a pipette like Gurdon did, and placing it in an egg. Shinya Yamanaka, over 40 years later, made a discovery that also whole intact mature cells can be reprogrammed and that this could be achieved by surprisingly simple procedure. Now Yamanaka, he studded genes that are important for the function of pluripotent stem cells. Pluripotent stem cells are found in the early embryo and can develop into all different types of mature cells in the body. And he thought that some stem cell genes may induce pluripotency if they would be transferred into mature cells in a mouse. Twenty-four candidate stem cell genes were selected. This target cell was the skin cell from a mouse. Now usually scientists transfer genes into other cells one by one, but in a strikingly bold experiment, all of these 24 genes were introduced in one single step into the skin cells, and a few cells became reprogrammed into cells that could generate all the mature cells in a mouse. They had now become pluripotent. Further experiments demonstrated that only four genes were needed for this induction of pluripotency. He named these cells induced pluripotent stem cells, or iPS cells. The iPS cell technique is a truly groundbreaking discovery that has opened up whole new research areas in cell biology and medicine. For example, iPS cells can now be generated from patients with disease and from these iPS cells, mature cells can be cultured so that we now have a procedure that gives success to new cell models for disorders that previously have been very difficult to study. Thanks to these two scientists, we now know that development is not strictly a one way street.

Hansson:   Thank you Thomas. So we are now ready for questions.

Boyce:       I'm Karen Boyce from the Swedish daily Dagens Nyheter; and how far away do you think those iPS cells are from treatment for people?

Hansson:   I'll ask Urban Lendahl, chairman of the Nobel Committee, to comment.

Lendahl:    So, it is difficult to give an exact time prediction for when things and stem cells of any kind move into cell therapy, but what is a more imminent area is actually to use them as platforms for drug screening and actually to learn about disease; because this is the first time where we can generate large number of cells and differentiate them into specific cell types, and often they actually recapitulate critical parameters of a disease. So that's where we are right now. But to give an exact time axis for when they reach cell therapy, I think that's beyond what we want to do today.

Louise:      Hi, Louise from the AP. I was wondering if you've been able to get a hold of the winners and how their reactions were?

Hansson:   Yes. This year, I spoke to both of the laureates on the phone and they were equally happy and are looking forward to coming to Stockholm later this year.

Louise:      I was wondering the exact age of the two laureates, and also how this can be applied for someone who doesn't really know what pluripotent means?

Hansson:   John Gurdon is 79 years old and Shinya Yamanaka, 50 this year—I don't know if he has had his birthday yet, but he was born in 1962. How to explain it? Who would like to take a shot at that? Yeah, Urban.

Lendahl:    I think we've always viewed development as going from the undifferentiated to the differentiated state, and I think it's such an important notion that all differentiated cells encapsulate a possibility to go back to the undifferentiated state; and I think that is very remarkable. And I think that that was very much an uphill battle, originally, from Gurdon to, sort of, prove the concept and then I think with the discovery that it was simple in the sense that it required a very limited set of genes, to actually do this in an intact cell from Yamanaka’s experience. I think both these discoveries really, sort of, sent shockwaves into the world and really, sort of, challenged and shattered dogma.

Landis:       Avan Landis with The Local. I was wondering if you could reflect a bit upon or elaborate how these discoveries affect the moral debate around stem cells in certain countries and how these advances affect that debate going forward?

Hansson:   Anna Wedell, professor of clinical genetics.

Wedell:     Well, of course, there can be different views on moral issues but in general in science, we have a very open debate and we, the Nobel Committee, does not really participate in that. But we as individual scientists and physicians do, and I think regulations evolve according to a general consensus in society—what is acceptable and what is not acceptable—and also another point is that every great discovery in biology that has applications in humans needs to be discussed, every individual application, and I think that is being done. That debate is continuously going on. We try to contribute to the best of our knowledge to that.

Landis:      How would you describe the main obstacles to therapy with iPS?

Hansson:   Therapy with stem cells, as of course, I mean, it's already used for hemapoietic stem cells in therapy, but the type of stem cells we're talking about here, pluripotent stem cells, we're still at a very early stage. I mean, there's a lot of promise and excitement and difficult disorders such as neurodegenerative disorders like Alzheimer's and perhaps more likely Parkinson's disease are very interesting targets. But we have to remember that we're at an early phase, even with pluripotent stem cells that have been known for quite a while. iPS cells can in theory solve the problem, the immunological problem, surrounding therapy with stem cells, but we have to remember that there are many obstacles and many of them are associated with safety. We have to be certain that pluripotent stem cells that are grafted, when they are, that they are totally safe and will not cause tumors and other problems. And we are not there yet, but for sure there is hope that it will progress.

The Press Release from the Nobel Assembly at Karolinska Institute

The Nobel Prize in Physiology or Medicine 2012 goes jointly to John B. Gurdon and Shinya Yamanaka for the discovery that mature cells can be reprogrammed to become pluripotent

Summary

The Nobel Prize recognizes two scientists who discovered that mature, specialised cells can be reprogrammed to become immature cells capable of developing into all tissues of the body. Their findings have revolutionised our understanding of how cells and organisms develop.

John B. Gurdon discovered in 1962 that the specialisation of cells is reversible. In a classic experiment, he replaced the immature cell nucleus in an egg cell of a frog with the nucleus from a mature intestinal cell. This modified egg cell developed into a normal tadpole. The DNA of the mature cell still had all the information needed to develop all cells in the frog.

Shinya Yamanaka discovered more than 40 years later, in 2006, how intact mature cells in mice could be reprogrammed to become immature stem cells. Surprisingly, by introducing only a few genes, he could reprogram mature cells to become pluripotent stem cells, i.e. immature cells that are able to develop into all types of cells in the body.

These groundbreaking discoveries have completely changed our view of the development and cellular specialisation. We now understand that the mature cell does not have to be confined forever to its specialised state. Textbooks have been rewritten and new research fields have been established. By reprogramming human cells, scientists have created new opportunities to study diseases and develop methods for diagnosis and therapy.

Life – a journey towards increasing specialisation

All of us developed from fertilized egg cells. During the first days after conception, the embryo consists of immature cells, each of which is capable of developing into all the cell types that form the adult organism. Such cells are called pluripotent stem cells. With further development of the embryo, these cells give rise to nerve cells, muscle cells, liver cells and all other cell types - each of them specialised to carry out a specific task in the adult body. This journey from immature to specialised cell was previously considered to be unidirectional. It was thought that the cell changes in such a way during maturation that it would no longer be possible for it to return to an immature, pluripotent stage.

Frogs jump backwards in development

John B. Gurdon challenged the dogma that the specialised cell is irreversibly committed to its fate. He hypothesised that its genome might still contain all the information needed to drive its development into all the different cell types of an organism. In 1962, he tested this hypothesis by replacing the cell nucleus of a frog's egg cell with a nucleus from a mature, specialised cell derived from the intestine of a tadpole. The egg developed into a fully functional, cloned tadpole and subsequent repeats of the experiment yielded adult frogs. The nucleus of the mature cell had not lost its capacity to drive development to a fully functional organism.

Gurdon's landmark discovery was initially met with scepticism but became accepted when it had been confirmed by other scientists. It initiated intense research and the technique was further developed, leading eventually to the cloning of mammals. Gurdon's research taught us that the nucleus of a mature, specialized cell can be returned to an immature, pluripotent state. But his experiment involved the removal of cell nuclei with pipettes followed by their introduction into other cells. Would it ever be possible to turn an intact cell back into a pluripotent stem cell?

A roundtrip journey – mature cells return to a stem cell state

Shinya Yamanaka was able to answer this question in a scientific breakthrough more than 40 years after Gurdon´s discovery. His research concerned embryonal stem cells, i.e. pluripotent stem cells that are isolated from the embryo and cultured in the laboratory. Such stem cells were initially isolated from mice by Martin Evans (Nobel Prize 2007) and Yamanaka tried to find the genes that kept them immature. When several of these genes had been identified, he tested whether any of them could reprogram mature cells to become pluripotent stem cells.

Yamanaka and his co-workers introduced these genes, in different combinations, into mature cells from connective tissue, fibroblasts, and examined the results under the microscope. They finally found a combination that worked, and the recipe was surprisingly simple. By introducing four genes together, they could reprogram their fibroblasts into immature stem cells!

The resulting induced pluripotent stem cells (iPS cells) could develop into mature cell types such as fibroblasts, nerve cells and gut cells. The discovery that intact, mature cells could be reprogrammed into pluripotent stem cells was published in 2006 and was immediately considered a major breakthrough.

From surprising discovery to medical use

The discoveries of Gurdon and Yamanaka have shown that specialised cells can turn back the developmental clock under certain circumstances. Although their genome undergoes modifications during development, these modifications are not irreversible. We have obtained a new view of the development of cells and organisms.

Research during recent years has shown that iPS cells can give rise to all the different cell types of the body. These discoveries have also provided new tools for scientists around the world and led to remarkable progress in many areas of medicine. iPS cells can also be prepared from human cells.

For instance, skin cells can be obtained from patients with various diseases, reprogrammed, and examined in the laboratory to determine how they differ from cells of healthy individuals. Such cells constitute invaluable tools for understanding disease mechanisms and so provide new opportunities to develop medical therapies.

Sir John B. Gurdon was born in 1933 in Dippenhall, UK. He received his Doctorate from the University of Oxford in 1960 and was a postdoctoral fellow at California Institute of Technology. He joined Cambridge University, UK, in 1972 and has served as Professor of Cell Biology and Master of Magdalene College. Gurdon is currently at the Gurdon Institute in Cambridge.

Shinya Yamanaka was born in Osaka, Japan in 1962. He obtained his MD in 1987 at Kobe University and trained as an orthopaedic surgeon before switching to basic research. Yamanaka received his PhD at Osaka University in 1993, after which he worked at the Gladstone Institute in San Francisco and Nara Institute of Science and Technology in Japan. Yamanaka is currently Professor at Kyoto University and also affiliated with the Gladstone Institute.

Key publications:

Gurdon, J. B. (1962). The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. Journal of Embryology and Experimental Morphology 10:622-640.

Takahashi, K., Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663-676.