Reprogrammed frog and mouse cells win the 2012 Nobel Prize

This morning the Nobel Assembly announced that the 2012 Nobel Prize in Physiology or Medicine will be shared by John B. Gurdon and Shinya Yamanaka for their “discovery that mature cells can be reprogrammed to become pluripotent”.  Animal research played a key role in the research honoured by the prize, specifically the studies of frogs undertaken by Professor Gurdon and studies of mice performed by Professor Yamanaka.

Professor Gurdon’s key work showed in a series of studies undertaken at the University of Oxford in the late 1950’s and 1960’s that if the nucleus of a specialised cell from a frog of the species Xenopus laevis – initially from late embryonic cells and subsequently adult intestinal and skin cells – was transferred into an egg whose nucleus had been removed, it could give rise to normal frog that could themselves produce offspring. This demonstrated for the first time that the nucleus of an adult cell is totipotent, and that in under certain conditions it could give rise to all cell types, including eggs and sperm, that are required in a healthy adult.

In 2009 Sir John wrote an account of his research on nuclear transfer in Xenopus for Nature Medicine, which can be read online without subscription, after he and Professor Yamanaka were presented with the  Albert Lasker Basic Medical Research Award in 2009.

Almost 4 decades later Professor Yamanaka, then at the Kyoto University Institute for Frontier Medical Sciences, made another great step forward by proving that it was possible to transform adult mouse cells into a pluripotent stem cells without nuclear transfer. By inserting 4 genes whose expression is associated with the embryonic state into the adult cell, his team were able to create the first induced pluripotent stem (iPS) cells, cells that could give rise to any tissue in the body.

Earlier this year in a post congratulating Professor Yamanaka’s on winning the 2012 Millenium Technology Prize I noted that:

The work briefly described above was a technological tour-de-force where Prof. Yamanaka and his colleagues selected 24 genes which had previously been identified as having key roles in mouse embryonic stem cells, and developed a screening method using skin fibroblast cells derived from mice that had be genetically modified with an antibiotic resistance gene that was only expressed in embryonic cells, so that only cells that were in an embryonic state would survive in a culture containing the antibiotic. Different combinations of these 24 genes were screened for their ability to induce to the production of colonies of embryonic -like cells from adult fibroblasts.  They eventually identified just 4 genes – Oct3/, Sox2, Klf4 and c-Myc – that together could reprogram adult mouse fibroblast cells to a pluripotent embryonic-like state (1), and subsequently demonstrated that these iPS cells could give rise to a wide variety of  tissue types when incorporated into mice, either by subcutaneous injection into adult mice or incorporation into early mouse embryos. By modifying their method slightly to also include expression of an important developmental gene named Nanog  they were then able to generate chimeric mice (mice whose tissues are made up of a mixture of cells derived from their own embryonic stem cells, and cells derived from iPS cells) which were capable of transmitting the iPS cells to the next generation of mice (2).

Soon after this Prof. Yamanaka succeeded in generating iPS cells from human fibroblasts, using the same techniques used for the mouse cells, and a whole new and exciting field of biomedical research was born.

1)      Takahashi K, Yamanaka S. “Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.” Cell 2006 Vol. 126(4):663-76. PubMed: 16904174

2)      Okita K., Ichisaka T., Yamanaka S. “Generation of germline-competent induced pluripotent stem cells.” Nature Vol. 448:313-317 (2007). PubMed:17554338””

It’s worth remembering that this breakthrough did not come out of thin air, and built on years of research that followed the pioneering work of Martin Evans and Gail Martin who demonstrated that cells derived from mouse embryos could be cultured and give rise to all tissue types…the first embryonic stem cells.

The field of iPS cell research has progressed swiftly since the first mouse iPS cells were produced just 6 years ago, and the techniques used to produce the cells have been refined to address early concerns that the inserted genes might give rise to tumors, but as Prof Yamanaka outlined in a recent review of progress in the field there is still a lot of scope for improvement.  Nevertheless iPS cells are already showing promise in a variety of medical research applications – for example to create nerve cell lines from Parkinson’s disease patients in order to study the processes that trigger the degeneration, or  to evaluate the toxicity of new drugs – and are expected to join  human embryonic stem cells as key components of regenerative medicine.

This year’s Nobel Prize in Physiology or Medicine highlights once again the key role played by animal research in making groundbreaking discoveries that give rise to new fields of medicine, and we offer our heart-felt congratulations to John Gurdon and Shinya Yamanaka.

 

Addendum: In a statement to Reuters on the problem of the unproven stem cell therapies being offered for a myriad of disorders by private health clinics around the world – and widely touted on the internet -Professor Yamanaka highlighted the key role played by animal research in ensuring that real stem cell therapies are safe and effective:

Yamanaka, who shared the Nobel Prize for Medicine on Monday with John Gurdon of the Gurdon Institute in Cambridge, Britain, called for caution [on stem cell therapies – PB].

“This type of practice is an enormous problem, it is a threat. Many so-called stem cell therapies are being conducted without any data using animals, preclinical safety checks,” said Yamanaka of Kyoto University in Japan.

“Patients should understand that if there are no preclinical data in the efficiency and safety of the procedure that he or she is undergoing … it could be very dangerous,” he told Reuters in a telephone interview.

Yamanaka and Gurdon shared the Nobel Prize for the discovery that adult cells can be transformed back into embryo-like stem cells that may one day regrow tissue in damaged brains, hearts or other organs.

“I hope patients and lay people can understand there are two kinds of stem cell therapies. One is what we are trying to establish. It is solely based on scientific data. We have been conducting preclinical work, experiments with animals, like rats and monkeys,” Yamanaka said.”

 

Paul Browne