Nobel Prize in Physiology or Medicine 2012: Reprogramming Mature Cells into Stem Cells

This note covers the Nobel Prize in Physiology or Medicine 2012: who won it, how Sir John B. Gurdon and Shinya Yamanaka showed that mature cells can be turned back into stem cells, how the discovery unfolded from a frog experiment in 1962 to induced pluripotent stem cells in 2006, why it matters for medicine, and quick facts for exams.

What was the Nobel Prize in Physiology or Medicine 2012 awarded for?

The Nobel Assembly at Karolinska Institutet awarded the prize jointly to Sir John B. Gurdon and Shinya Yamanaka with the citation: "for the discovery that mature cells can be reprogrammed to become pluripotent".

In plain words, the two scientists proved that a mature cell, one that has already specialised into a particular job such as a skin cell or a gut cell, is not stuck that way forever.

Under the right conditions it can be pushed backwards in development until it behaves like an early embryonic cell again, able to turn into almost any other cell type in the body. This "going-backwards" ability is called pluripotency.

The award is formally called the Nobel Prize in Physiology or Medicine, and this edition was announced on 8 October 2012.

The Nobel Assembly said the findings "have revolutionised our understanding of how cells and organisms develop," a judgement that reflects how fundamentally the discovery changed biology.

Who are the laureates?

The prize was shared equally between a British developmental biologist who worked with frogs and a Japanese physician-scientist who worked with mice. Their experiments were separated by more than forty years but answered the same question from two different directions.

Sir John B. Gurdon

Sir John B. Gurdon was born on 2 October 1933 in Dippenhall, United Kingdom, and died on 7 October 2025.

At the time of the award he was affiliated with the Gurdon Institute, Cambridge, United Kingdom, and held one half of the prize.

He earned his doctorate at Oxford, spent time at the California Institute of Technology, and later became Professor of Cell Biology and Master of Magdalene College at Cambridge.

His contribution was a 1962 experiment in which he replaced the nucleus of a frog egg cell with the nucleus from a mature intestinal cell of a tadpole.

The modified egg grew into a normal tadpole, showing that a specialised cell's nucleus still carried all the genetic information needed to build an entire animal.

Shinya Yamanaka

Shinya Yamanaka was born on 4 September 1962 in Osaka, Japan. At the time of the award he held the other half of the prize and was affiliated with Kyoto University, Kyoto, Japan, and the Gladstone Institutes, San Francisco, CA, USA.

He trained first as an orthopaedic surgeon, then earned a PhD at Osaka City University before working on embryonic stem cells.

In 2006, more than forty years after Gurdon's frog experiment, Yamanaka showed that inserting just four genes into intact mature mouse skin cells could reprogram them into pluripotent stem cells, which he named induced pluripotent stem cells, or iPS cells.

What problem were Gurdon and Yamanaka trying to solve?

Every human and animal begins life as a single fertilised egg. That egg divides repeatedly, and its descendant cells gradually specialise into nerve cells, muscle cells, liver cells and every other cell type the adult body needs.

For most of the twentieth century, biologists believed this journey could only run in one direction.

The researcher Conrad Hal Waddington pictured this idea as a landscape of mountains and valleys.

An immature cell is like a marble balanced at the mountain top; as it specialises, it rolls down into a particular valley and settles there as a fixed cell type.

Scientists assumed marbles never rolled back up, and that the genetic instructions for building other cell types were somehow lost or switched off for good once a cell specialised.

This mattered because, if true, it meant scientists could never take an ordinary adult cell and turn it into any other cell type the body might need to repair damage, such as the dopamine-making brain cells lost in Parkinson's disease or the insulin-making cells lost in diabetes.

Early attempts to test the idea used nuclear transfer in amphibians: Robert Briggs and Thomas King had shown in 1952 that nuclei from early embryonic cells could support development after transfer into an egg, but nuclei from more mature cells seemed to fail, which appeared to confirm the one-way dogma.

The open question Gurdon and later Yamanaka each tackled was simple to state and very hard to answer: does a mature, specialised cell's genetic material still contain everything needed to build a whole organism, and if so, can that cell be coaxed into using that information again?

How did Gurdon show that a mature cell's nucleus could be reprogrammed?

Gurdon worked with the African clawed frog, Xenopus laevis. He chose this species partly because a cell-tracing method developed by his supervisor's group let him clearly identify cells descended from a transplanted nucleus rather than from the host embryo.

1. Take an unfertilised frog egg cell and destroy its own nucleus using ultraviolet light, so the egg is left without its original genetic material.
2. Take a nucleus from a fully differentiated cell, specifically an intestinal epithelial cell from a feeding tadpole.
3. Transplant that mature nucleus into the emptied egg cell.
4. Allow the modified egg to develop and observe whether it can form a normal, swimming tadpole.
5. Repeat the transplantation in series to raise the efficiency, since many eggs failed to develop on the first attempt.

A small number of the manipulated eggs did grow into swimming tadpoles, and later experiments produced adult frogs.

This showed that the nucleus of a mature, specialised cell had not lost the genetic instructions needed to build every tissue in the body; those instructions were simply switched off, not destroyed.

Gurdon's result met scepticism at first, but it was later confirmed by other laboratories.

Draw an egg cell on the left with its nucleus crossed out and labelled "destroyed by UV light"; an arrow bringing in a nucleus from a labelled tadpole intestinal cell; the combined cell developing through an arrow into a swimming tadpole, with a side note that repeating the process led, decades later, to cloned mammals such as Dolly the sheep.

How did Yamanaka turn ordinary skin cells into stem cells?

Yamanaka began by studying embryonic stem cells, which had first been isolated from mice by Martin Evans.

He wanted to find which genes kept these cells in their immature, pluripotent state, reasoning that if he inserted the right genes into a mature cell he might force it backwards into the same state.

1. Select a list of candidate genes known to be switched on in pluripotent embryonic stem cells, starting with twenty-four candidates.
2. Insert all twenty-four genes together into mature mouse skin cells called fibroblasts, using a virus as the delivery vehicle.
3. Observe that some of the treated cells changed shape and began to resemble embryonic stem cells.
4. Remove genes from the mixture one at a time and repeat the experiment to find the smallest combination that still worked.
5. Confirm that a set of just four genes was enough, and test the resulting cells to check they could develop into different cell types, including nerve cells and gut cells.

Yamanaka called the resulting cells induced pluripotent stem cells, or iPS cells, and published this result in 2006.

Because the recipe needed only a handful of genes rather than a whole egg cell, laboratories worldwide could repeat it quickly, and within a year Yamanaka and other groups had produced iPS cells from human cells as well.

Draw a test tube holding the four selected genes, an arrow into a mouse skin fibroblast cell, then an arrow showing the fibroblast changing shape into a rounder stem-cell-like colony, with branching arrows at the end to different mature cell types the iPS cell can later form.

What can induced pluripotent stem cells be used for?

Because iPS cells can be grown from an ordinary skin or blood sample and then guided to turn into almost any other cell type, they give researchers a way to study diseases that are otherwise hard to reach inside the body, such as those affecting brain or heart cells.

One well-established use is called "disease in a dish". A skin sample is taken from a patient with a genetic condition, reprogrammed into iPS cells, and then coaxed to develop into the cell type affected by the disease, such as motor neurons for amyotrophic lateral sclerosis or brain cells for Alzheimer's disease.

Because these lab-grown cells carry the patient's own mutations, scientists can watch the disease process directly and test how drugs affect it.

A second, more distant goal is cell replacement therapy: growing dopamine-producing brain cells for Parkinson's disease or insulin-producing cells for diabetes, then transplanting them back into the same patient so the immune system is less likely to reject them, since the cells came from the patient's own tissue.

The scientific background document notes this remains an early-stage research area, since reprogramming can sometimes introduce unwanted genetic changes and two of the four genes used in the original recipe are known to be active in tumours, so safety work is still needed before such transplants become routine treatment.

How did the discovery unfold?

Why does this discovery matter?

Before this work, biology textbooks taught that cell specialisation only ran in one direction. The Nobel committee's scientific background document called the discovery "a paradigm shift in our understanding of cellular differentiation", attributed to the three scientific advisors who wrote it.

That single change in understanding opened an entirely new research field built around reprogramming cells rather than only studying how they specialise.

In practical terms, iPS technology gives researchers an almost unlimited, ethically simpler source of pluripotent stem cells, since they no longer always need to rely on embryos, which are harder to obtain and raise ethical questions for some people.

Scientists can now model many inherited diseases in the laboratory using a patient's own skin cells, and many laboratories worldwide now use the iPS recipe in some form.

Open questions remain. Early delivery methods used viruses that inserted genes randomly into the genome and could trigger tumours in mice, so researchers have since developed gene-delivery methods, such as RNA molecules, that avoid permanently altering the cell's own DNA.

Whether iPS-derived cells can be transplanted into patients safely, without a risk of uncontrolled growth, is still being worked out.

How does this connect to what you study?

This prize links directly to the biology topics of cell structure, genetics and reproduction taught at school level. The idea that a fertilised egg divides into cells that gradually specialise is the same process covered when studying development and differentiation.

The concept of the nucleus carrying all the genetic instructions for an organism, and genes being switched on or off rather than lost, builds on basic lessons about DNA and gene expression.

Students who study cloning, genetic engineering or biotechnology will recognise Gurdon's nuclear transfer method as the forerunner of the technique used to clone Dolly the sheep, and will find Yamanaka's iPS cells useful as a modern example of how a handful of genes can control a cell's entire identity and behaviour.

Quick facts for exams

The Nobel Prize in Physiology or Medicine 2012 was awarded jointly to Sir John B. Gurdon of the United Kingdom and Shinya Yamanaka of Japan, each receiving one half of the prize, for discovering that mature cells can be reprogrammed to become pluripotent.

The Nobel Assembly at Karolinska Institutet announced the award on 8 October 2012. Gurdon's 1962 frog-cloning experiment first showed that a mature cell's nucleus still holds the genetic instructions to build a whole organism.

Yamanaka's 2006 discovery that just four genes could reprogram mature mouse skin cells into induced pluripotent stem cells, or iPS cells, turned this idea into a practical laboratory technique used around the world today for disease research and, potentially one day, for therapy.

Note: Source. The prize facts in this note are from the Nobel Prize's official site, nobelprize.org.

Glossary

• Pluripotent — able to develop into almost any cell type in the adult body, but not placenta or amniotic tissue.
• Totipotent — able to develop into every cell type, including tissues outside the embryo such as the placenta.
• Multipotent — able to develop into only a limited family of related cell types.
• Nucleus — the part of a cell that holds the genetic material, or DNA.
• Nuclear transfer — moving the nucleus from one cell into another cell that has had its own nucleus removed.
• Enucleated egg — an egg cell from which the original nucleus has been removed.
• Differentiation — the process by which a cell becomes specialised for a particular job.
• Fibroblast — a common type of mature connective-tissue cell, often taken from skin, used in reprogramming experiments.
• Induced pluripotent stem cell (iPS cell) — a mature cell reprogrammed in the laboratory back into a pluripotent state.
• Transcription factor — a protein that switches particular genes on or off inside a cell.
• Cloning — producing a genetically identical copy of an organism, as first achieved in a frog by nuclear transfer.
• Embryonic stem cell — a pluripotent cell taken directly from an early embryo rather than reprogrammed.

Common errors and misconceptions

• Misconception: Gurdon and Yamanaka worked together on the same experiment. Correct: they worked more than forty years apart, Gurdon in frogs in 1962 and Yamanaka in mice in 2006, and shared the prize for two separate discoveries pointing to the same conclusion.
• Misconception: iPS cells are the same as embryonic stem cells taken from an embryo. Correct: iPS cells are mature cells reprogrammed in the laboratory, so they do not require an embryo at all.
• Misconception: once a cell specialises, its DNA has permanently lost the information for other cell types. Correct: the information remains present but is switched off, as Gurdon's and Yamanaka's experiments both showed it can be switched back on.
• Misconception: Yamanaka's technique needs dozens of genes. Correct: after testing twenty-four candidates, he found that just four genes were enough.
• Misconception: Gurdon cloned a mammal first. Correct: Gurdon cloned a frog in 1962; the first cloned mammal, Dolly the sheep, came later, in 1997, using an adapted version of Gurdon's technique.
• Misconception: iPS cells are already used routinely to treat patients. Correct: the sources describe cell replacement therapy using iPS cells as still at an early research stage, with safety questions unresolved.

Exam-style questions with model answers

Q1. In which year was the Nobel Prize in Physiology or Medicine 2012 announced? [1 mark]

1. It was announced on 8 October 2012.

Q2. State the official citation for the 2012 Nobel Prize in Physiology or Medicine. [2 marks]

1. The citation reads "for the discovery that mature cells can be reprogrammed to become pluripotent", awarded jointly to Gurdon and Yamanaka.

Q3. Describe Gurdon's 1962 frog experiment and what it proved. [4 marks]

1. Gurdon destroyed the nucleus of a frog egg cell using ultraviolet light, leaving the egg without its own genetic material.
2. He then transplanted into that egg a nucleus taken from a mature, specialised intestinal cell of a feeding tadpole.
3. Some of these modified eggs developed into normal, swimming tadpoles, and repeated attempts also produced adult frogs.
4. This proved that a mature cell's nucleus still retained all the genetic information needed to build every cell type in the body, overturning the belief that specialisation was irreversible.

Q4. Explain how Yamanaka produced induced pluripotent stem cells and why his discovery was considered surprising. [5 marks]

1. Yamanaka studied embryonic stem cells to identify genes that kept them in an immature, pluripotent state.
2. He selected twenty-four candidate genes and inserted all of them together into mature mouse skin fibroblast cells using a virus.
3. Some treated cells changed shape and began to resemble embryonic stem cells, showing reprogramming was possible.
4. By removing genes one at a time and repeating the experiment, he found that a combination of just four genes, Myc, Oct3/4, Sox2 and Klf4, was enough.
5. The discovery was surprising because it reprogrammed an intact mature cell, without needing an egg cell, using a remarkably simple four-gene recipe, and it was quickly repeated by laboratories worldwide, including on human cells within a year.

Q5. What is the difference between a totipotent, a pluripotent and a multipotent cell? [3 marks]

1. A totipotent cell can develop into any cell type in the embryo plus tissues outside the embryo, such as the placenta.
2. A pluripotent cell can develop into any cell type in the adult body, but not placenta or amniotic sac tissue.
3. A multipotent cell can develop into only a limited family of related cell types, such as adult blood stem cells forming only blood cell types.

Q6. Discuss how the discoveries of Gurdon and Yamanaka have been applied in medical research, and what limitations remain. [6 marks]

1. Both discoveries showed that mature cells are not permanently locked into their specialised state and can be returned to a pluripotent condition.
2. Yamanaka's iPS technique is now used to grow patient-specific cells for a "disease in a dish" approach, where a skin sample is reprogrammed and then differentiated into the affected cell type, such as motor neurons for amyotrophic lateral sclerosis or brain cells for Alzheimer's disease.
3. These lab-grown cells carry the patient's own mutations, letting researchers study disease processes directly and test how candidate drugs affect them.
4. A longer-term goal is cell replacement therapy, for example growing dopamine-producing cells for Parkinson's disease or insulin-producing cells for diabetes, using the patient's own reprogrammed cells to reduce the chance of immune rejection.
5. Limitations remain because early gene-delivery methods used viruses that could cause tumours, and even with newer methods, questions about long-term safety of transplanting iPS-derived cells into patients are still being investigated before this becomes routine therapy.
6. iPS technology also gives an almost unlimited, ethically simpler source of pluripotent cells since it reduces reliance on embryos, which are harder to obtain and ethically contentious.

Key takeaways

• Gurdon and Yamanaka shared the Nobel Prize in Physiology or Medicine 2012 for showing mature cells can be reprogrammed to become pluripotent.
• Gurdon's 1962 frog nuclear transplant experiment proved a mature cell's nucleus retains full genetic information.
• Yamanaka's 2006 discovery showed just four genes can reprogram mature mouse skin cells into iPS cells.
• The discovery overturned the long-held belief that cell specialisation only runs in one direction.
• iPS cells now let scientists model diseases in the laboratory using a patient's own reprogrammed cells.
• Cell replacement therapy using iPS cells, for conditions like Parkinson's disease, remains an early-stage research area.
• Gurdon's technique was the forerunner of later mammalian cloning, including Dolly the sheep in 1997.
• The prize carried 8,000,000 Swedish kronor, shared equally between the two laureates.

Test yourself

Who shared the Nobel Prize in Physiology or Medicine 2012?

Sir John B. Gurdon of the United Kingdom and Shinya Yamanaka of Japan shared the prize equally.

What animal did Gurdon use in his 1962 reprogramming experiment?

Gurdon used the African clawed frog, Xenopus laevis, transplanting a tadpole intestinal cell nucleus into an egg.

How many genes did Yamanaka need to reprogram mature cells into iPS cells?

Yamanaka found that a combination of just four genes was enough to reprogram mature mouse skin cells.

What did the Nobel Assembly say the discoveries had done to our understanding of development?

The Nobel Assembly said the findings had revolutionised our understanding of how cells and organisms develop.

Where was Shinya Yamanaka affiliated at the time of the award?

Shinya Yamanaka worked at Kyoto University in Kyoto, Japan, and also at the Gladstone Institutes in San Francisco, USA.

What is the difference between a pluripotent and a multipotent cell?

A pluripotent cell can become almost any body cell type, while a multipotent cell can only become a limited related family of cell types.

What name did Yamanaka give to his reprogrammed mature cells?

He called them induced pluripotent stem cells, or iPS cells, since they were induced to regain pluripotency.

What practical use of iPS cells is already established?

Researchers use iPS cells grown from patient skin samples to model diseases in the laboratory and test drug responses.