While they might not be household names, Gurdon and Yamanaka have helped kick-start an entire new field of regenerative medicine, writes Tim Dean.
Regenerative medicine, as they say, is a growth industry. Although it's still in its embryonic stages.
Puns aside, many see a not-too-distant future where the ability to grow bespoke cells to replace damaged or diseased tissue is another key tool in our medical kit. One day we might even be able to clone entire organs for transplantation should our original ones fail.
That said, one day we may also be able to clone entire humans too, a prospect that is as existentially and ethically troubling as it is scientifically intriguing.
The technical and regulatory hurdles to overcome are not insubstantial, and there are still some gnarly ethical issues to manage, but the tremendous therapeutic potential of stem cells means there are many people beavering away to make regenerative medicine a reality.
And this vision would have been impossible without the contributions made by two pioneering scientists, who were awarded the Nobel Prize in Physiology and Medicine last week.
The first is Sir John Gurdon, who helped overturn some established scientific dogma of his day and in the process opened the door to the possibility of creating stem cells - and cloning whole organisms. Before delving into his key discovery from half a century ago, it's worth stepping back and reflecting on the state of play at the time to reinforce how genuinely revolutionary Gurdon's discovery was.
We know that human beings are made up of well over 200 different specialised cell types - everything from skin cells, bone cells, neurons, liver cells, immune cells and so on. Their diversity is truly startling.
Yet we all start out as just a single fertilised egg cell: a zygote. Incredibly, we manage to transform from that single cell into a fully developed human being, with all the right specialised cells in all the right places. And at the core of (almost) every one of our 50 trillion-odd cells is a nucleus containing an identical genetic blueprint.
It'd be like giving 1,000 workers in a corporation copies of every job description in the company without telling them which one is theirs, and expecting them to spontaneously figure out where they should work. Only scaled up by a few million times.
By the 1960s, scientists had already gone a long way towards understanding how a zygote develops into a whole organism. They had also uncovered some of the processes that enable cells to differentiate, transforming from early 'pluripotent' (from the Latin plurimus, meaning 'very many,' and potens, meaning 'having power') stem cells to increasingly more specialised types.
However, a series of experiments from the 1950s indicated that the specialisation process was a one-way street: once a cell had differentiated, it could never be turned back. The experiments looked solid, so that became the dogma and few even thought to question it.
In stepped John B Gurdon, who was blessed with two characteristics that make for truly great scientists: a healthy maverick streak; and a reverence for the empirical method.
His Nobel Prize-winning experiment was actually conducted in the late 1950s when he was a graduate student, and wasn't published until 1962 - precisely 50 years ago. He began with the observation that the nucleus of most cells contain the genetic blueprint for the whole organism, and wondered what would happen if you put that blueprint in an appropriate egg cell.
So he took egg cells from the frog species, Xenopus laevis, and stripped them of their nucleus. He then took the nucleus from an intestinal cell from an adult frog, and placed it in the enucleated egg. The end result, remarkably enough, was a bunch of wriggling little tadpoles, each one genetically identical to its adult 'parent,' which had donated the intestinal cell.
Gurdon had created the world's first clones by means of a technique called somatic cell nuclear transfer (SCNT), and in the process had rewritten the textbook on cellular development and differentiation.
Gurdon's discovery would eventually lead to the cloning of more complex organisms, including the infamous Dolly the sheep in 1997, and since then a menagerie of other species, including mice, cows, pigs, wolves and African wildcats. It could, in principle, also be used to clone a human, although such an experiment has been outlawed in most countries around the world, including here in Australia.
However, it is legal to use SCNT to create new early-stage embryos from human eggs, a process called 'therapeutic cloning'. Embryonic stem cells can then be gathered from the embryo to be used for research or, potentially, therapeutic treatments. There are strict guidelines around how such embryos can be created and how they can be used, but the creation and destruction of human embryonic material causes consternation to many and is an ongoing ethical issue.
Thus 1962 proved to be a big year in stem cell biology, for more reasons than one: in that year Gurdon's key paper was published; and Shinya Yamanaka was born.
Decades later, in the early 2000s, Yamanaka added another piece to the cellular differentiation puzzle by figuring out how to take fully differentiated adult cells and step them back to an earlier undifferentiated state.
Yamanaka and his team discovered that while all cells are built upon the same genetic blueprint, specific 'transcription factors' govern which bits of the blueprint are called upon to direct the cell. By meddling with these transcription factors, he could effectively turn back the clock, transforming adult cells into pluripotent cells - known as induced pluripotent stem cells (iPSCs).
Where Gurdon's method required an egg cell, and the harvesting of stem cells from an early stage embryo, one benefit of Yamanaka's approach is that (virtually) any old adult cell would do the trick, thus bypassing one potential ethical and regulatory hurdle in producing stem cells for research or therapeutic applications.
Together these two discoveries opened the door to the possibility of producing pluripotent stem cells on demand in order to treat injury or disease. However, we're still a fair way from seeing any stem cell therapies employing either technique become available at our local clinic. Before that happens there are some substantial hurdles to overcome.
For one, SCNT might now be a well established process, but it is still rather inefficient: it took 440 attempts to produce Dolly. The process also has a tendency to produce abnormalities in the cloned organism, although the technology is constantly improving. There's also the ethical problem of requiring eggs and the destruction of embryos to harvest stem cells.
iPSCs avoid the ethical concerns of SCNT because it uses adult cells and doesn't involve embryos, but it's still a process in its infancy, so to speak. Producing a population of healthy iPSCs is still a tremendous technical challenge, and it appears as though iPSCs are prone to forming tumours. Clearly, more work must be done before iPSCs are ready for the clinic.
What iPSCs can be used for right now, though, is gaining a better understanding of disease. Basically, you can take a diseased cell - say a malfunctioning insulin-producing beta cell - and revert it to a pluripotent state. You can then 'recapitulate' the disease and see how it unfolds, hopefully pinpointing where the cell begins to malfunction. You can also use iPSCs for drug development, applying various potentially therapeutic agents to them to see how they respond, all in the lab rather than in the body.
A final stage would be to use the process to produce healthy cells, say by growing happy new beta cells, which could be transplanted back into the patient - although even here there are challenges in making sure the new cells aren't rejected by the immune system. Yet, presuming the technical barriers can be overcome, regenerative medicine could radically transform many areas of healthcare.
As a rule of thumb (Peace Prizes not withstanding) the Nobel committee doesn't hand out its gongs lightly. It often takes decades for a discovery to be deemed of sufficiently lasting impact to get the nod. In fact, it's a rarity for a researcher to receive a Nobel so soon after publishing their breakthrough research, as has Yamanaka.
While they might not be household names, Gurdon and Yamanaka have helped kick-start an entire new field of regenerative medicine. Science being the fickle and unpredictable process it is, it might take a decade or more before stem cell technology translates into real therapeutic benefits, but whether it's us, our children or our grandchildren, we'll owe Gurdon and Yamanaka a great deal of thanks that a Nobel Prize can only partly express.
Tim Dean is a science journalist and editor of Australian Life Scientist magazine.