Introduction:
An important part a scientist’s work is being aware of the ethical issues surrounding their research and the implications these have on the wider community. Some scientists dedicate their careers to resolving these ethical issues. The winners of the 2012 Nobel Prize in Physiology or Medicine, John Gurdon and Shinya Yamanaka, have pioneered a method which hopefully represents a big step towards solving the ethical issues involved in the use of Stem Cells.
The Stem Cell Problem:
Imagine that there was a potential cure for illnesses such as Alzheimer’s, heart disease, spinal cord injuries, or any number of others. Then assume that in order to achieve this, an unborn embryo has to be destroyed. What would you do? This dilemma is at the heart of the Stem Cell Problem.
Embryonic Stem Cell’s (ES) are used in a number of areas of research. The use of these cells is controversial since they are taken from human embryos, initially created for In Vitro Fertilisation (IVF) but not implanted, these ‘spare’ embryos are then donated to scientific research. Unfortunately, during the course of the research the embryo is destroyed; a fact which has led some organisations, such as the Catholic Church, to claim that research using ES cells is tantamount to murder.
Embryonic Stem Cell’s (ES) are used in a number of areas of research. The use of these cells is controversial since they are taken from human embryos, initially created for In Vitro Fertilisation (IVF) but not implanted, these ‘spare’ embryos are then donated to scientific research. Unfortunately, during the course of the research the embryo is destroyed; a fact which has led some organisations, such as the Catholic Church, to claim that research using ES cells is tantamount to murder.
The reason ES cells are so important to medical research is that certain properties, only possessed by these young cells, makes them ideal for therapeutic manipulations. Mature cells in the human body are highly specialised towards their function, whether this is in the blood, liver, brain or elsewhere. However, stem cells are immature cells which have yet to develop into their final specialised form. Stem cells act as the body's master cells, providing the source material for all other cells. When required, the stem cell is stimulated by certain factors in its environment and eventually develops into a specific mature cell type, for example a blood cell. This means that an embryonic stem cell has the potential to become any cell in the body, given the right environment! ES cells are also able to replicate themselves many times over, unlike specialised adult cells. Therefore these cells are invaluable to scientists investigating cell behaviour and methods for regenerating damaged tissue.They could transform medicine by regenerating tissue for diseases ranging from blindness to Parkinson's disease. The therapeutic uses for stem cells range from understanding cancer to regenerating tissue in a whole number of degenerative disorders.
Creating embryo-like stem cells without destroying embryos gets round a key controversy by avoiding the need to process embryos left over at fertility clinics - a system that has led to political objections in the United States and elsewhere.
Creating embryo-like stem cells without destroying embryos gets round a key controversy by avoiding the need to process embryos left over at fertility clinics - a system that has led to political objections in the United States and elsewhere.
The journey to the Solution:
At 15, Gurdon was ‘bottom of the bottom form’ in biology and told his dream of becoming a scientist was completely ridiculous. Not only did he obtain the lowest marks in biology of all the 250 boys in his year but his school report in 1949 described his grasp of the subject as ‘disastrous’. Today, that school report, written by a museum curator drafted in to teach after the war, hangs in a frame in his office. The young Sir John scored just 2 out of 50 for one piece of work and repeatedly got into trouble for insisting on doing things his own way, rather than listening. Despite being ‘bottom of the bottom form’ in biology, he went on to study zoology at Oxford.
Sir John, now married with two children, said: ‘When there are problems, like when an experiment doesn’t work, which often happens, it is nice to remind yourself that perhaps after all you are not so good at this job and the schoolmaster may have been right
In 2012, as he share the Nobel Prize for Medicine, for work he began 50 years ago and Yamanaka capped with a 2006 experiment that has possibillity of transforming the field of "regenerative medicine”. His landmark discovery was initially met with scepticism, as the journey from immature to specialised cell was previously deemed irreversible. But his theory became accepted when it was confirmed by other scientists. More than four decades later, in 2006, Prof Yamanaka discovered how mature cells in mice could in fact be turned back to their youthful state. More than 40 years after Gurdon's discovery, in 2006, Yamanaka showed that a surprisingly simple recipe could turn mature cells back into primitive cells, which in turn could be prodded into different kinds of mature cells. Basically, the primitive cells were the equivalent of embryonic stem cells, which had been embroiled in controversy because to get human embryonic cells, human embryos had to be destroyed. Yamanaka's method provided a way to get such primitive cells without destroying embryos.
The duo, John Gurdon, 79, and Shinya Yamanaka, 50, discovered ways to create tissue that would act like embryonic cells, without the need to collect the cells from embryos. These two researcher have made extraordinary advances in cell reprogramming. Their pioneering work has given scientists a clearer understanding of how cells function and also provided a method of obtaining stem cells from adult tissue. Thus, potentially solving the ethical issues surrounding the use of ES cells in research.
Sir John, now married with two children, said: ‘When there are problems, like when an experiment doesn’t work, which often happens, it is nice to remind yourself that perhaps after all you are not so good at this job and the schoolmaster may have been right
In 2012, as he share the Nobel Prize for Medicine, for work he began 50 years ago and Yamanaka capped with a 2006 experiment that has possibillity of transforming the field of "regenerative medicine”. His landmark discovery was initially met with scepticism, as the journey from immature to specialised cell was previously deemed irreversible. But his theory became accepted when it was confirmed by other scientists. More than four decades later, in 2006, Prof Yamanaka discovered how mature cells in mice could in fact be turned back to their youthful state. More than 40 years after Gurdon's discovery, in 2006, Yamanaka showed that a surprisingly simple recipe could turn mature cells back into primitive cells, which in turn could be prodded into different kinds of mature cells. Basically, the primitive cells were the equivalent of embryonic stem cells, which had been embroiled in controversy because to get human embryonic cells, human embryos had to be destroyed. Yamanaka's method provided a way to get such primitive cells without destroying embryos.
The duo, John Gurdon, 79, and Shinya Yamanaka, 50, discovered ways to create tissue that would act like embryonic cells, without the need to collect the cells from embryos. These two researcher have made extraordinary advances in cell reprogramming. Their pioneering work has given scientists a clearer understanding of how cells function and also provided a method of obtaining stem cells from adult tissue. Thus, potentially solving the ethical issues surrounding the use of ES cells in research.
The process: Cell Reprogramming:
In 1962, at University of Cambridge, Gurdon transferred a nucleus (the part of the cell which contains DNA) from an adult frog cell into a frog egg cell. The egg developed into a normal tadpole, showing that DNA from a specialized adult cell could be reprogrammed to function in a developing embryo. This was a landmark discovery since, up until this point; Scientists thought it was impossible to turn adult tissue back into stem cells as it loses certain components of their DNA so could not function as part of a developing cell. Gurdon’s work showed that this wasn’t the case proving that mature differentiated cells contain a full complement of DNA; it’s just that some of the DNA in mature cells is inactive. This has also showed that the DNA in mature cells still had its ability to drive the formation of all cells of the body. At that time, the discovery had "no obvious therapeutic benefit at all," Gurdon told reporters in London. "It was almost 50 years before the value — the potential value — of that basic scientific research comes to light," he said. In 1997, the cloning of Dolly the sheep by other scientists showed that the same process Gurdon discovered in frogs would work in mammals.
In 1962, at University of Cambridge, Gurdon transferred a nucleus (the part of the cell which contains DNA) from an adult frog cell into a frog egg cell. The egg developed into a normal tadpole, showing that DNA from a specialized adult cell could be reprogrammed to function in a developing embryo. This was a landmark discovery since, up until this point; Scientists thought it was impossible to turn adult tissue back into stem cells as it loses certain components of their DNA so could not function as part of a developing cell. Gurdon’s work showed that this wasn’t the case proving that mature differentiated cells contain a full complement of DNA; it’s just that some of the DNA in mature cells is inactive. This has also showed that the DNA in mature cells still had its ability to drive the formation of all cells of the body. At that time, the discovery had "no obvious therapeutic benefit at all," Gurdon told reporters in London. "It was almost 50 years before the value — the potential value — of that basic scientific research comes to light," he said. In 1997, the cloning of Dolly the sheep by other scientists showed that the same process Gurdon discovered in frogs would work in mammals.
More than 40 years later, Yamanaka produced mouse stem cells from adult mouse skin cells by inserting a small number of genes. His breakthrough effectively showed that the development that takes place in adult tissue could be reversed, turning adult tissue back into cells that behave like embryos. He developed a line of cells called induced Pluripotent Stem Cells (iPSCs). He and his colleagues adjusted the expression of certain components within adult cells, enabling them to revert back to their young, stem-cell, form. These reprogrammed cells had similar characteristics to embryonic stem cells, including the ability to mature into a variety of different cell types. Yamanaka then used the same technique with human adult cells, reverting them to a state similar to an ES cell, further developing his concept to be used in the study of human cells and diseases. As they display many of the important properties found in ES cells, iPSCs could potentially be used as a replacement for ES cells, thus eliminating the controversy surrounding the use of embryonic cells in research.
Reprogrammed cells - known as induced pluripotent stem cells, oriPS cells - offer an ethically neutral alternative .Not only are these stem cells ethically sound but they are a perfect match for the person who donated the skin. This raises the prospect of people being given hearts or sperm or eggs or retina generated in a lab from a sliver of skin taken from their hand. In the short-term, tissue from such cells offers a window into brains ravaged by diseases such as Alzheimer’s and Parkinson’s and allows thousands of chemicals to be rapidly tested to see if they have potential as drugs. As patients may one day be treated with stem cells from their own tissue, their bodies might be less likely to reject them.
"The eventual aim is to provide replacement cells of all kinds," Gurdon's institute explains on its website. "We would like to be able to find a way of obtaining spare heart or brain cells from skin or blood cells. The important point is that the replacement cells need to be from the same individual, to avoid problems of rejection and hence of the need for immunosuppression."
In just six years, Yamanaka's paper has already been cited more than 4,000 times in other scientists' work.In a news conference in Japan, he thanked his team of young researchers: "My joy is very great. But I feel a grave sense of responsibility as well."
Reprogrammed cells - known as induced pluripotent stem cells, oriPS cells - offer an ethically neutral alternative .Not only are these stem cells ethically sound but they are a perfect match for the person who donated the skin. This raises the prospect of people being given hearts or sperm or eggs or retina generated in a lab from a sliver of skin taken from their hand. In the short-term, tissue from such cells offers a window into brains ravaged by diseases such as Alzheimer’s and Parkinson’s and allows thousands of chemicals to be rapidly tested to see if they have potential as drugs. As patients may one day be treated with stem cells from their own tissue, their bodies might be less likely to reject them.
"The eventual aim is to provide replacement cells of all kinds," Gurdon's institute explains on its website. "We would like to be able to find a way of obtaining spare heart or brain cells from skin or blood cells. The important point is that the replacement cells need to be from the same individual, to avoid problems of rejection and hence of the need for immunosuppression."
In just six years, Yamanaka's paper has already been cited more than 4,000 times in other scientists' work.In a news conference in Japan, he thanked his team of young researchers: "My joy is very great. But I feel a grave sense of responsibility as well."
In announcing the $1.2 million award, the Nobel committee at Stockholm's Karolinska Institute said the discovery has "revolutionized our understanding of how cells and organisms develop.”The discoveries of Gurdon and Yamanaka have shown that specialized cells can turn back the developmental clock under certain circumstances," the committee said. "These discoveries have also provided new tools for scientists around the world and led to remarkable progress in many areas of medicine." Recently, Japanese scientists reported using Yamanaka's approach to turn skin cells from mice into eggs that produced baby mice.
Applications:
The potential of iPSCs doesn’t stop at replacing ES cells. They could also herald a major advance in the science behind organ transplantation. Since, ES cells can both regenerate themselves several times over and become any cell type; their use in the replacement of damaged tissue is now being studied. Meaning it may soon be possible for patients to receive transplants composed of reprogrammed cells (iPSC’s) from their own bodies. This would solve the major problem of transplant rejection from donated tissues, caused by the recipient’s body recognizing the donated organ as foreign. In theory, an iPSC-derived tissue would not be rejected as it would be made from the patient’s own cells. In future, scientists would like to build on the work by John Gurdon and Shinya Yamanaka to create replacement tissues for treating diseases like Parkinson's and diabetes, and for studying the roots of diseases in the laboratory — without the ethical dilemma posed by embryonic stem cells.
Experts agreed that the pioneering work by the two new Nobel laureates had changed the field of stem cell research. Still, many experts believe the true promise of iPS cells is as unique research tools, rather than necessarily forming the basis of new medical therapies. They have a key advantage over embryonic stem cells in that researchers can take them from people with a known disease, offering a window into how currently incurable illnesses develop at the cellular level. Already, researchers have made iPS cells from patients with Gaucher's disease, Down Syndrome, Parkinson's and diabetes. "I see iPS cells more for use in drug discovery and in understanding the mechanism of different diseases, rather than therapy," said Dusko Ilic, a senior lecturer in stem cell science at King's College London. Traditionally, researchers have used stand-ins for human tissue such as yeast, flies or mice for their drug research. Now, they can use human cells containing a complete set of the genes that resulted in a particular disease.
"Everyone who works on developmental biology and on the understanding of disease mechanisms will applaud these excellent and clear choices for the Nobel Prizes," said John Hardy, professor of Neuroscience at University College London. "Countless labs' work builds on the breakthroughs they have pioneered." Yamanaka deserves extra credit for overcoming fierce objections to the creation of embryos for research, reviving the field, said Julian Savulescu, director of Oxford University's Uehiro Centre for Practical Ethics. "Yamanaka has taken people's ethical concerns seriously about embryo research and modified the trajectory of research into a path that is acceptable for all," Savulescu said. "He deserves not only a Nobel Prize for Medicine, but a Nobel Prize for Ethics."
Problem Solved?
The science of iPS cells is still in early stages. Among concerns is the fear that implanted cells could grow out of control and develop into tumors. Some scientists say stem cells from embryos may prove more useful against disease than iPS cells, and the ethics of working with embryos should be defended. Nevertheless, since Yamanaka published his findings the discoveries have already produced advances. The techniques are being used to grow cells in laboratories to study disease, the chairman of the awards committee, Urban Lendahl, told Reuters. "You can't take out a large part of the heart or the brain or so to study this, but now you can take a cell from, for example, the skin of the patient, reprogramme it, return it to a pluripotent state, and then grow it in a laboratory," he said.
Recently, however, different research groups have noticed problems with iPS cells, suggesting they may not be as good as embryonic ones. In one study, iPS cells died more quickly and another found multiple genetic mutations, raising concerns that they could cause tumors. Despite this, Japanese researchers hope to test iPS cells in clinical trials for a form of blindness as early as next year - catching up with recent successful eye trials using embryonic stem cells. Researchers in the West are generally more wary.
"There is a bit of a divergence between Japan and the rest of the world on this," Chris Mason, professor of regenerative medicine at University College London, told Reuters. "Scientists in Japan are trying to move very rapidly towards clinical trials of iPS cells, whereas many of us still feel there are a lot of issues to overcome, especially in terms of safety."
The future potential for reprogrammed cells is that they could be taken from sick people who could have their own "person specific cell replacement" to mend damaged organs or tissues. But key worries include the fact that iPS technology involves using genes which could also be tumor-inducing in some circumstances and that other as-yet undetected problems might crop up after the new cells have been put into patients.
Gurdon played down such worries and said regulatory authorities and governments should take a step back and let patients assess the potential benefits and risks for themselves. "If you explain to a patient what can be done, and what might be the downside - then you should let the patient choose. Don't have ethicists or ... doctors or whoever say you may or may not have replacement cells," he told reporters.
Last Word:
"There is a bit of a divergence between Japan and the rest of the world on this," Chris Mason, professor of regenerative medicine at University College London, told Reuters. "Scientists in Japan are trying to move very rapidly towards clinical trials of iPS cells, whereas many of us still feel there are a lot of issues to overcome, especially in terms of safety."
The future potential for reprogrammed cells is that they could be taken from sick people who could have their own "person specific cell replacement" to mend damaged organs or tissues. But key worries include the fact that iPS technology involves using genes which could also be tumor-inducing in some circumstances and that other as-yet undetected problems might crop up after the new cells have been put into patients.
Gurdon played down such worries and said regulatory authorities and governments should take a step back and let patients assess the potential benefits and risks for themselves. "If you explain to a patient what can be done, and what might be the downside - then you should let the patient choose. Don't have ethicists or ... doctors or whoever say you may or may not have replacement cells," he told reporters.
Last Word:
Many scientists would agree that the work undertaken by Gurdon, Yamanaka and their colleagues is incredibly exciting. It represents a great leap forward in our understanding of how cells work and new ways of studying them in a controversy-free environment.
So, does this Nobel prize-winning work signal a solution to the Stem Cell Problem? Alas, no. It is unclear whether iPSCs and ES cells are equivalent on the molecular level, casting doubt on the likelihood of iPSCs being able to completely replace ES cells in research. Another problem, as with many newly discovered techniques, is that the long-term effects of these technologies are unknown. For example, there are concerns that cells derived from any form of stem cells have a tendency to become cancerous. There has also been a surprising report that iPSCs still produce an immune response when transplanted in mice, which would lead to transplant rejection. This Nobel Prize-winning discovery offers a way to skirt around ethical problems with human embryos, but safety concerns make their future use in treating disease uncertain.
So, unfortunately we still don’t have a comprehensive solution to the Stem Cell Problem. However, this does not detract in any way from the discoveries of Gurdon, Yamanaka and their colleagues, and there is no doubt that their innovation, expertise and skills should have been rewarded by the Nobel Prize. Only time will tell just how much more useful their discoveries will be.
So, does this Nobel prize-winning work signal a solution to the Stem Cell Problem? Alas, no. It is unclear whether iPSCs and ES cells are equivalent on the molecular level, casting doubt on the likelihood of iPSCs being able to completely replace ES cells in research. Another problem, as with many newly discovered techniques, is that the long-term effects of these technologies are unknown. For example, there are concerns that cells derived from any form of stem cells have a tendency to become cancerous. There has also been a surprising report that iPSCs still produce an immune response when transplanted in mice, which would lead to transplant rejection. This Nobel Prize-winning discovery offers a way to skirt around ethical problems with human embryos, but safety concerns make their future use in treating disease uncertain.
So, unfortunately we still don’t have a comprehensive solution to the Stem Cell Problem. However, this does not detract in any way from the discoveries of Gurdon, Yamanaka and their colleagues, and there is no doubt that their innovation, expertise and skills should have been rewarded by the Nobel Prize. Only time will tell just how much more useful their discoveries will be.
