For their achievements in stem cell research, John B. Gurdon and Shinya Yamanaka have been jointly awarded The Nobel Prize in Physiology or Medicine 2012, The Nobel Assembly at Karolinska Institutet, Sweden, announced today. The Assembly added that the prize was for their work in discovering that mature cells can be reprogrammed to become pluripotent stem cells.
The Nobel Assembly described their findings as a revolution in our understanding of how organisms and cells develop. Gurdon and Yamanaka discovered that mature, specialize cells may be reprogrammed so that they revert back into immature cells that have the potential of developing into all tissues of the body.
The specialization of cells is reversible – in 1962, John Gurdon discovered that a cell’s specialization can be reversed. In a famous experiment, he took out the nucleus of a frog’s egg cell and replaced it with the nucleus from a mature intestinal cell. The egg with the gut cell nucleus eventually developed into a healthy tadpole. The mature cells’ DNA still carried all the data required to develop into all cells in the frog.
Reprogramming intact mature cells into immature stem cells – in 2006, Yamanaka discovered how an intact mature cell in a mouse could be reprogrammed so that it turned into an immature stem cell. With the introduction of just a few genes he managed to reprogram mature cells so that they became pluripotent stem cells. Pluripotent stem cells can develop into any type of cell in the body.
Their discoveries, described by the Assembly as “groundbreaking”, completely transformed how we see cellular development and specialization. Now we know that a mature cell does not necessarily have to remain as a specialized cell. Their discoveries meant that textbooks had to be rewritten and new fields of research had to be set up.
In a communiqué, Nobelprize.org wrote:
“By reprogramming human cells, scientists have created new opportunities to study diseases and develop methods for diagnosis and therapy.
We all develop from fertilized egg cells. For the first few days, after the sperm fertilizes the egg, the embryo consists of a collection of immature cells. Each immature cell has the capacity to turn into any type of cell in the human adult. Cells that have that potential are known as pluripotent stem cells.
As the embryo develops, these cells develop into liver cells, muscle cells, nerve cells – into all the cell types required to form a developed organism. Each cell is specialized to perform precise functions in the adult body.
Scientists had thought that the journey from immature to specialized cells was a one-way-street; that there was no turning back, that it would not be possible for them to return to an immature, pluripotent state.
John B. Gurdon wondered how right this theory was, and decided to challenge it. He hypothesized that a specialized cell’s genome may still have all the data required to drive its development into any type of cell. He tested his hypothesis in 1962. He replaced a frog’s egg cell nucleus with the mature, specialized cell from a tadpole’s intestine.
The frog’s egg cell with the nucleus of the cell of a tadpole’s intestine developed into a healthy, cloned tadpole. He repeated the experiment several times and managed to yield many adult frogs.
Gurdon had demonstrated that a mature, specialized cell had not lost the capacity to become, once again, a pluripotent stem cell.
When Gurdon initially presented his findings to the scientific community, it was received with skepticism. However, when other scientists confirmed what he described by repeating the experiment, his landmark discovery was widely accepted.
Gurdon’s breakthrough triggered intense research, and the technique developed further, until other animals were cloned.
Gurdon taught us that a mature, specialized cell’s nucleus may be returned to an immature pluripotent state. However, he had to remove the nucleus of the cell with a pipette and place it into another cell. What about turning a mature cell back into a pluripotent stem cell without doing that – returning an intact mature cell into a pluripotent stem cell?
Forty years later, Shinya Yamanaka answered this question in a scientific breakthrough. He experimented with embryonal stem cells – these are pluripotent stem cells that have been isolated from the embryo and cultured in the lab. Martin Evans (Nobel Prize 2007) initially isolated such stem cells from mice.
Yamanaka set out to identify which genes kept them in an immature state. He managed to identify several of these genes, and subsequently tested to see whether any of them could reprogram specialized mature cells so that they could turn into pluripotent stem cells.
Yamanaka and colleagues introduced the genes he had identified in different combinations into mature cells from connective tissue (fibroblasts), and observed them under the microscope. Eventually, they hit upon a combination that worked. They were surprised at how simple the right “recipe” was. They introduced four genes together and managed to reprogram their fibroblasts into immature, pluripotent stem cells.
These pluripotent stem cells are known as iPs cells (induced pluripotent stem cells). Yamanaka’s resulting iPS cells could develop into gut cells, fibroblasts and nerve cells. A fibroblast is a kind of cell found in connective tissue that produces collagen and other proteins which are found in between cells.
Nobelprize.org wrote:
“The discovery that intact, mature cells could be reprogrammed into pluripotent stem cells was published in 2006 and was immediately considered a major breakthrough.”
Gurdon’s and Yamanaka’s discoveries have demonstrated that mature, specialized cells can be reversed; the developmental clock can be turned back in certain circumstances. Although a cell’s genome changes slightly as it develops, these modification are reversible. Thanks to Gurdon and Yamanaka, “we obtained a new view of the development of cells and organisms.”
Today we can obtain skin cells from patients with certain diseases, reprogram them and observe them in the lab to see how different they are from the cells obtained from healthy people. By studying these cells, researchers gain considerable insight into the mechanisms of diseases, which can eventually lead to the development of new treatments.
Photo: Creative Commons Attr. 2.0 Generic license
- Sir John B. Gurdon, a developmental biologist.
- Born in1933 in Dippenhall, Surrey, England.
- Had his secondary education at Eton College, England.
- Studied classics at Christ Church, Oxford. He switched to zoology. He studied nuclear transplantation in the frog Xenpus with Michael Fischberg at Oxford.
- Became a postdoctoral fellow at Caltech (California Institute of Technology).
- Worked at the Department of Zoology of the University of Oxford
- Became Professor of Cell Biology and Master of Magdalene College at Cambridge University.
- In 1989, became a founding member of the Wellcome/CRC Institute for Cell Biology and Cancer (which later became Wellcome/CR UK) in Cambridge – he was Chair until 2001.
- Became a member of the Nuffield Council on Bioethics, and Master of Magdalene College Cambridge.
Gurdon became a Fellow of the Royal Society in 1971. He was knighted (became a “Sir”) in 1995. The Wellcome Trust/Cancer Research UK Institute for Cell Biology and Cancer was renamed the Gurdon Institute.
He has received several awards, medals and honorary degrees. In 2009 he was awarded the Albert Lasker Basic Medical Research award.
“You will never become a biologist”, his teacher said
Gurdon once mentioned a school report when he was 15 years old in which his teacher said that it would be a total waste of time for him to pursue a career in biology. “This whole idea should be immediately discouraged”, the teacher wrote.
Gurdon says he keeps the reports above his desk for his own amusement. Apparently, his mother did spot a love of biology and encouraged him. In an interview several years ago Gurdon said that as s child he used to grow thousands of caterpillars to make moths, something his teacher found most annoying.
His teacher also wrote in his school report:
“I believe Gurdon has ideas about becoming a scientist; on his present showing this is quite ridiculous; if he can’t learn simple biological facts he would have no chance of doing the work of a specialist, and it would be a sheer waste of time, both on his part and of those who would have to teach him.”
Gurdon said “But I had a fascination for these things, and I think it was really she particularly who enabled me to switch from my education, which was completely nonscientific, into a scientific direction.”
When he finished school, his father advised him to pursue a career either in banking or in the army. His doctor, who had diagnosed a slight cold as bronchitis, put an end to his chances of joining the army. Gurdon later on, when asked about not being able to join the army, said “Thank heavens!”
Key publication
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.
Photo: Creative Commons Attr. 2.0 Generic license
- Shinya Yamanaka, a Japanese physician and adult stem cell researcher.
- Born in 1962 in Higashiosaka, Japan.
- Studied medicine and became qualified as a doctor at Koke University.
- Obtained his Ph.D. at Osaka City University Graduate School.
- Did his residency in orthopedic surgery at the National Osaka Hospital.
- Received a postdoctoral Fellowship at the Gladstone Institute of Cardiovascular Disease, San Francisco.
- Currently is director and a professor at the Center for iPS Cell Research and Application in Kyoto University. He is also affiliated with the Gladstone Institute
Awards
- 2007 Osaka Science Prize, Inoue Prize for Science, Asahi Prize, Meyenburg Cancer Research Award
- 2008 Yamazaki-Teiichi Prize in Biological Science & Technology, Robert Koch Prize, Medals of Honor (Japan) (Medal with Purple Ribbon), Shaw Prize in Life Science & Medicine, Sankyo Takamine Memorial Award
- 2009 Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Research, Gairdner Foundation International Award, Albert Lasker Award for Basic Medical Research, March of Dimes Prize in Developmental Biology
- 2010 Kyoto Prize in Biotechnology and medical technology, Balzan Prize in biology, Person of Cultural Merit, BBVA Foundation Frontiers of Knowledge Award in the Biomedicine Category, Albany Medical Center Prize in biomedicine
- 2011 Wolf Prize in medicine, King Faisal International Prize, McEwen Award for Innovation, Millennium Technology Prize, Fellow of the National Academy of Sciences, Nobel Prize in Physiology or Medicine
Key publication
Takahashi, K., Yamanaka, S. (2006).
Cell 126:663-676.
Written by Christian Nordqvist
Original article date: 8th October 2012. Article updated: 10th October 2012.