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The Nobel Prize recognizes two scientists who discovered thatmature, specialised cells can be reprogrammed to become immaturecells capable of developing into all tissues of the body. Theirfindings have revolutionised our understanding of how cells andorganisms develop.
John B. Gurdon discovered in 1962 that the specialisation ofcells is reversible. In a classic experiment, he replaced theimmature cell nucleus in an egg cell of a frog with the nucleusfrom a mature intestinal cell. This modified egg cell developedinto a normal tadpole. The DNA of the mature cell still had all theinformation 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 becomeimmature 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 ofcells in the body.
These groundbreaking discoveries have completely changed ourview of the development and cellular specialisation. We nowunderstand that the mature cell does not have to be confinedforever to its specialised state. Textbooks have been rewritten andnew research fields have been established. By reprogramming humancells, scientists have created new opportunities to study diseasesand develop methods for diagnosis and therapy.
Life – a journey towards increasing specialisation
All of us developed from fertilized egg cells. During the firstdays after conception, the embryo consists of immature cells, eachof which is capable of developing into all the cell types that formthe adult organism. Such cells are called pluripotent stem cells.With further development of the embryo, these cells give rise tonerve cells, muscle cells, liver cells and all other cell types -each of them specialised to carry out a specific task in the adultbody. This journey from immature to specialised cell was previouslyconsidered to be unidirectional. It was thought that the cellchanges in such a way during maturation that it would no longer bepossible for it to return to an immature, pluripotent stage.
Frogs jump backwards in development
John B. Gurdon challenged the dogma thatthe specialised cell is irreversibly committed to its fate. Hehypothesised that its genome might still contain all theinformation needed to drive its development into all the differentcell types of an organism. In 1962, he tested this hypothesis byreplacing the cell nucleus of a frog’s egg cell with a nucleus froma mature, specialised cell derived from the intestine of a tadpole.The egg developed into a fully functional, cloned tadpole andsubsequent repeats of the experiment yielded adult frogs. Thenucleus of the mature cell had not lost its capacity to drivedevelopment to a fully functional organism.
Gurdon’s landmark discovery was initially met withscepticism but became accepted when it had been confirmed by otherscientists. It initiated intense research and the technique wasfurther 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 withpipettes followed by their introduction into other cells. Would itever be possible to turn an intact cell back into a pluripotentstem cell?
A roundtrip journey – mature cells return to a stem cellstate
Shinya Yamanaka was able to answer thisquestion in a scientific breakthrough more than 40 years afterGurdon´s discovery. His research concerned embryonal stem cells,i.e. pluripotent stem cells that are isolated from the embryo andcultured in the laboratory. Such stem cells were initially isolatedfrom mice by Martin Evans (Nobel Prize 2007) and Yamanakatried to find the genes that kept them immature. When several ofthese genes had been identified, he tested whether any of themcould reprogram mature cells to become pluripotent stem cells.
Yamanaka and his co-workers introduced these genes, in differentcombinations, into mature cells from connective tissue,fibroblasts, and examined the results under the microscope. Theyfinally found a combination that worked, and the recipe wassurprisingly simple. By introducing four genes together, they couldreprogram their fibroblasts into immature stem cells!
The resulting induced pluripotent stem cells (iPS cells) coulddevelop into mature cell types such as fibroblasts, nerve cells andgut cells. The discovery that intact, mature cells could bereprogrammed into pluripotent stem cells was published in 2006 andwas immediately considered a major breakthrough.
From surprising discovery to medical use
The discoveries of Gurdon and Yamanaka have shown thatspecialised cells can turn back the developmental clock undercertain circumstances. Although their genome undergoesmodifications during development, these modifications are notirreversible. We have obtained a new view of the development ofcells and organisms.
Research during recent years has shown that iPS cells can giverise to all the different cell types of the body. These discoverieshave also provided new tools for scientists around the world andled to remarkable progress in many areas of medicine. iPS cells canalso be prepared from human cells.
For instance, skin cells can be obtained from patients withvarious diseases, reprogrammed, and examined in the laboratory todetermine how they differ from cells of healthy individuals. Suchcells constitute invaluable tools for understanding diseasemechanisms and so provide new opportunities to develop medicaltherapies.
De cv’s van de twee winnaars leest uhier
Sir John B. Gurdon was born in 1933 inDippenhall, UK. He received his Doctorate from the University ofOxford in 1960 and was a postdoctoral fellow at CaliforniaInstitute of Technology. He joined Cambridge University, UK, in1972 and has served as Professor of Cell Biology and Master ofMagdalene College. Gurdon is currently at the Gurdon Institute inCambridge.
Shinya Yamanaka was born in Osaka, Japanin 1962. He obtained his MD in 1987 at Kobe University and trainedas an orthopaedic surgeon before switching to basic research.Yamanaka received his PhD at Osaka University in 1993, after whichhe worked at the Gladstone Institute in San Francisco and NaraInstitute of Science and Technology in Japan. Yamanaka is currentlyProfessor at Kyoto University and also affiliated with theGladstone Institute.