Perhaps no medical technology ever has inspired more hope or generated more hype than stem cell therapy, now being touted as the key to curing everything from cancer to Parkinson’s to juvenile diabetes.
In a mature human body there are some 300 different types of cells – skin cells, liver cells, kidney cells, nerve cells, and so on. All this cellular variety derives from the almost miraculous ‘pluripotency’ of embryonic stem cells, which have the potential to become any type of cell. Over the past few years, medical researchers have come to believe that they will be able to harness this power and learn how to manipulate stem cells to generate any kind of tissue they desire. Herein lies the potential for combating a vast range of illnesses.
One recent example: two weeks ago in the journal Nature, Dr Ron MacKay at the US National Institutes of Health published a paper describing how he’d forced embryonic stem cells in a test tube to morph into the specialised nerve cells that produce dopomine. These dopomine-producing neurons are the cells that are lost in Parkinson’s disease, so MacKay’s work raises hopes for a cure to this debilitating illness.
Another example: at the University of Minnesota, a team of researchers have recently shown that bone marrow stem cells can be used to repair stroke damage in rats. Injected into the brain, the stems cells homed in on the specific regions needing repair and began to express the chemical markers typical of brain cells. In other words, the stem cells were turning into brain cells. Most importantly, the impaired rats regained the ability to move their limbs, a clear demonstration that this was more than just a theoretical exercise.
Stem cell researchers envision a future in which all sorts of failing body parts – from nerve cells to heart muscles to pancreatic tissue – will be replaced by vigorous new tissues.
One day, they dream, they may even be able grow whole new organs. With 75 000 people a year awaiting replacement organs in the USA alone, the potential market for this technology is enormous. In Australia there are just under 2000 people currently on this list.
With our own great tradition of innovative scientific work, Australia is a leader in stem cell research.
IVF pioneer Dr Alan Trounsen is a recognised authority in this emerging field. In late May the Federal Government backed its decision to support stem cell research with $43.5 million in funding for the new Monash-based Centre for Stem Cells and Tissue Repair to be headed by Dr Trounsen. The Centre will pursue work with both embryonic stem cells and also adult stem cells. The specific focus of the centre will be on tissue regeneration therapies for diabetes and for diseases of the blood, bones, kidneys and skin. The Victorian Government has promised a further $10 million in funding.
I said before that probably no medical technology has been so hyped, and yet probably none has been so hated. Again, it’s not hard to see why: at present, most research stem cells are derived from human embryos that are necessarily destroyed in the process. The major source of such embryos is the surplus created in IVF clinics. Earlier this year, opponents (led by Federal minister Kevin Andrews) fought to convince cabinet to enact a ban on all research in which human embryos are destroyed.
But given the immense potential (or at least the perceived potential) of this technology it’s hardly surprising to find that on the other side are also very powerful voices. Pitted against the largely religious alliance of the nay-sayers has been the medical establishment and the biotech industry. In Australia and the UK this side has largely prevailed.
In Australia, as I’m sure many of you are aware, the Federal Government eventually elected to allow the use of ‘spare’ IVF embryos for research purposes – though not the creation of embryos specifically for stem cell research. It should be noted here that under Victoria’s Infertility Treatment Act, spare embryos cannot be stored for more than five years, so most of the embryos used in this research would be doomed for destruction anyway.
Nowhere has the battle about stem cells been more acrimonious than in the US where Right-to-Lifers find themselves pitted against not only the biotech industry but also a cabal of Hollywood heavies.
Calling themselves CuresNow, a group of film and television executives have banded together to form a high-profile lobby group – many of these people are themselves parents of sick children, often children with juvenile diabetes.
Over the past month the US Senate has been debating whether or not to allow the use of so-called ‘therapeutic cloning’ – a process for deriving stem cells that are genetically the same as the person being treated. To date, however, the Senators have been unable to reach a resolution precisely because this issue pits two such powerful and opposing forces. It is far from clear which side will prevail here.
What are stem cells?
Before we look more closely at the ethical issues raised by stem cell research, let’s first take a look at the science.
Embryonic stem cells
The most obvious source of stem cells is a very early embryo. Stem cells begin to form when the developing embryo gets to around 100 cells in size, at which time it enters the blastocyst stage. Typically, stem cells are culled from an embryo when it’s around 5 or 6 days old. You don’t want to wait too much longer, because after about a week the stem cells themselves begin to differentiate. The embryo is necessarily destroyed in the culling process.
Cloned embryonic stem cells
A second, and by far the most controversial, source of stem cells is cloned embryos. This involves the process known as ‘therapeutic cloning.’ It begins with the same procedure that created Dolly the sheep. A cell is taken from the person being treated – in theory, any cell will do – and this cell is fused with a human egg to create an embryonic clone. There’s no intention, however, to let this clone mature: all we’re interested in are the stem cells which, again, can be culled when the developing egg reaches around 200 cells. Again, the embryo produced will be destroyed during harvesting.
As I mentioned before, Australia has banned the creation of embryos for research purposes so there will be no therapeutic cloning here. In the UK, the House of Lords has voted to allow the procedure under limited conditions, and the UK is now giving out its first research licenses. In the US, Congress enacted a ban in 1995 against the use of Federal funds for any research that would destroy a human embryo, but in the private sector researchers can pretty much do what they like. At least for the present.
In December last year, US company Advanced Cell Technology announced that they had indeed managed to clone human embryos. They were not, however, able to harvest any stem cells as none of their embryos developed beyond about half-a-dozen cells.
The first to have actually harvested clone human stem cells appear to be a team in China led by Lu Guangxiu of the Xiangya Medical College. According to reports in the Wall Street Journal in March, Guangxiu’s team had derived dozens of stem cell lines from human embryos they had grown to the 200-cell stage, far outstripping any Western efforts.
Adult stem cells
Interestingly, stem cells can also be found in adult tissue, notably in bone marrow. But at the University of Iowa, scientists have recently extracted stem cells from human skin!
Opponents of embryonic stem cell research tout adult stem cells as the morally viable alternative.
There’s no need to destroy embryos, they say; we can use adult cells instead. The problem is that it’s not clear the mature variety really possess the full plasticity of their embryonic cousins. Most stem cell scientists argue that at least for now we need to continue work with embryonic stem cells in order to learn how to actually manipulate these cells. There’s a great deal of science to be learned about how to get stemcells to become say liver cells or pancreatic cells, or whatever, and at present our grasp of this is pretty weak. So at least for the present most researchers believe we need to be exploring all options – particularly the most potent option, which is definitely the embryonic variety. In the future, with greater knowledge and skill it may be possible to work just with adult stem cells, but that does not seem to be viable at the moment.
Animal stem cells
Animals are another potential source of stem cells. Genetically engineered pig stem cells have already been injected into the brains of a few Parkinson’s patients. Most of the current excitement, however, focuses on the work on human cells.
Cord blood stem cells
A final source of stem cells is the blood that remains in the umbilical cord following birth. Around the world, hospitals and agencies are aggressively encouraging parents to collect and store this cord blood – for a healthy collection fee, and an ongoing yearly fee for storage. The idea here is that if you get sick in later life you will have an immediate source of genetically compatible stem cells – these cord blood cells don’t have the full potency of regular embryonic stem cells, but some of this power.
What is not mentioned here is that with current cryogenic technology it’s not at all guaranteed that cells frozen today would still be viable 20 or 30 years down the track.
Life as code
Having introduced the science, I want now to return to look at some of the ethical issues surrounding stem cell research.
Objection to this work is often premised on the view that destroying an embryo is an act of murder – it’s the classic anti-abortion argument projected back to the first instant of conception. In this view, therapeutic cloning is especially repugnant because a ‘person’ is being created only to be slaughtered.
Opponents of these technologies have deeply felt beliefs and I have no desire to belittle those beliefs, or the religious commitments from which they often spring. Myself, I was raised a Catholic and although I am no longer a Catholic, I retain a great respect for the Church and believe strongly in the value of religion in a pluralistic society.
At the same time I subscribe fully to a woman’s right to terminate a pregnancy and I reject the ‘murder’ argument – I do not accept that an undifferentiated ball of a hundred or so cells is a ‘human being’.
Nonetheless, I feel deeply ambivalent about stem cell research. What unsettles me is the underlying philosophy of life on which this technology is based.
Stem cell manipulation, along with genetic engineering, is an outgrowth of the idea that life is controlled by a computer-like code that we can reprogram to suit our own purposes. Two years ago, scientists in fact published a first draft of this code, a list of some three billion DNA ‘letters’ that collectively comprise the genetic blueprint for Homo sapiens. Today we take this infomatic organicism for granted, but a century ago most scientists would have deemed it insane.
The first to popularise such a view was not a biologist, but a physicist – the great Austrian quantum physicist Erwin Schroedinger. Schroedinger spent his life pondering the mysteries of subatomic particles, yet in 1944 he published a now-classic book entitled What is Life? Just 88 pages long, this slender text ignited a spark leading eventually to the whole conflagration of gene science.
As a physicist, Schroedinger studied things like protons and crystals whose behaviour conform to strict mathematical rules. Since he believed that all of nature is inherently lawful, Schroedinger concluded that living things must contain at their core some law-encoding structure, a special kind of molecule in which could be stored the instructions for building each creature.
By the 1940s, biologists understood that the inherited characteristics of organisms had something to do with the string-like chromosomes at the heart of each cell. In What is Life? Schroedinger proposed that the essence of each chromosome is an ‘aperiodic crystal’ – a molecular structure highly regular in its overall form but also allowing for local variation, and hence able to carry some molecular code.
Schroedinger’s book transformed the practice of biology, injecting into the organic sciences a reductionist sensibility and initiating the new science of ‘molecular biology’. In a sense this can be seen as the physics-isation of biological science. Within a decade James Watson and Francis Crick (along with Maurice Wilkes and the historically slighted Rosalyn Franklyn) had discovered the double helix, a crystallike form encompassing in its spiral embrace a molecular code of astonishing power. Next April marks the 50th anniversary of this discovery, one equating with fire and the wheel in its power to transform human experience.
For me personally there is one very comforting effect of this transition, for this infomatic view of life gives concrete substance to Darwin’s insight about the relatedness of all creatures. By DNA analysis our ‘distance’ from other species can now be empirically measured: genetically speaking, we are 98 per cent the same as chimpanzees. At truly bleak moments I console myself with the fact that for all our military might we humans share 25% (fully a quarter) of our genes with the lettuce!
But while an infomatic approach to life suggests a certain organismic democracy – no one code is intrinsically ‘better’ than any other – it also opens a Pandora's box. For if life is directed by a code, then he who controls the code controls life itself. Manipulating life is reduced in fact to the problem of manipulating the code, hence the dream of genetic engineering – note the term ‘engineering’.
Among the more bizarre demonstrations of this dream is artist Eduardo Kac’s fluorescent bunny, Alba. Created by a team of French scientists, Alba contains a jellyfish gene that encodes for the Green Fluorescent Protein. Under ultraviolet light she shines a fetching day-glo green. In another development, scientists genetically altered a mouse to make a critter just two-thirds the regular size. It’s not a dwarf; each of its cells is simply smaller than the norm.
The mind fairly boggles at the possibilities opened up here. I cannot help wondering where all this will end. Microscopic rodents the size of fleas? Herds of miniature fluoro elephants flocking on the front lawn? And who knows what more monstrous options?
And then there are stem cells, where again we encounter the fantasy that anything we want we can get simply by fiddling with the life-code. Here, of course, scientists don’t manipulate the code directly but rather by hijacking the potency of these special cells, which with the right chemical triggers can be prodded into producing any type of tissue we desire.
Moving us one step closer towards that goal, Dr Catherine Verfaillie at the University of Minnesota has recently isolated certain adult stem cells from bone marrow that at least in a test tube seem able to morph into all the major cell types.
Dr Verfaillie is hoping to use these cells to treat muscular dystrophy. The idea here is that these cells would be extracted from a donor’s bone marrow then injected into the bloodstream of the patient, where hopefully they could be induced to morph into muscle cells. American biotech company Athersys is already talking about clinical trials, which they say could begin in as little as 12 months.
In another development, Alan Trounsen’s team announced last December that they had discovered how to turn embryonic stem cells into the beating cells of a human heart.
Both developments are truly incredible. It really is extraordinary what molecular biologists are discovering and what they are able to do. I studied physics at university, but compared to this stuff, physics is kindergarten play!
Just in the past month, researchers at Advanced Cell Technology in the US successfully transplanted into cows miniature kidneys and other tissues generated through therapeutic cloning. The experiment provides the best evidence to date that this procedure can indeed be used to generate genetically compatible tissues that won’t be rejected as transplants. In this case the tissues were harvested from cow embryos that had been allowed to grow to a reasonable age, so it’s not an exercise they would repeat in humans. But it does demonstrate the viability of therapeutic cloning as a source for transplant tissues.
As an aside here, it is hard to imagine that someone somewhere is not going to pursue this approach with human beings, however morally repugnant most of us may find that. The idea of creating a clone to be used as an organ bank has been around for a while; now this possibility is becoming a technical reality. Can we really believe this capability is not going to be used once the genie is out of the bottle?
A further development which strongly hints at where this technology is heading came in March this year, when scientists at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, announced that for the first time they had combined therapeutic cloning with genetic engineering. The result was to partially correct an immune deficiency in mice. The team began with a cell taken from the mouse’s tail and fused this with a mouse egg to produce an embryonic clone. Stem cells were culled from this clone and then genetically altered to correct for the fault. Finally, these cloned and engineered stem cells were injected back into the original mouse. The results were dramatic: not a complete cure, but a good way there.
We see in these two experiments the extraordinary and explosive power of the infomatic view of life. In the age of the computer, the body also is coming to be seen as a computational system. Something is wrong, so you fix it by fiddling with the code. In this paradigm, illness becomes a bug in the organic computer and medicine becomes essentially a form of software engineering. The doctor’s job is now to be a cellular reprogrammer.
While no doubt this is all extremely technically impressive, and potentially lifesaving, personally I cannot help feeling somewhat unsettled by this work. What troubles me is the question of where we will draw the line. That issue has been raised in fact by the work of Melbourne artist Patricia Piccinini in her recent sculpture, ‘Still Life with Stem Cells’.
But let us come back to more immediate concerns. One critical issue that is too rarely discussed in stem cell forums is the subject of human eggs. As I mentioned before, Lu Guangxiu in China has apparently derived dozens of embryonic stem cell lines from cloned human embryos. At least three other Chinese groups are rumored to have made similar, or even greater, advances.
The Chinese research, while technically stunning, raises the question: where did the researchers get so many human eggs? Even with their impressive results, the Chinese team claimed no more than about a 5 percent success rate in terms of the number of fertilised eggs from which they could harvest viable stem cells. Most Western researchers have a much lower rate. It took 277 attempts to get Dolly. What this means is that for every viable stem cell harvest, dozens, if not hundreds of embryonic clones must be made – thus dozens, if not hundreds of human eggs have to be obtained
In the US, Advanced Cell Technology pays women $4000 US to donate eggs for their research. The whole process of egg harvesting costs them US$22,000 per shot – and at most they get 10 eggs, often many less.
These young women donors are put on a two-week course of drugs, similar to that of IVF patients, to force their bodies to super-ovulate. As anyone who’s been through IVF will know, this is not a process one can go through too many times. Lu Guangxiu, apparently, just asked patients at her clinic to donate their surplus eggs. The number she’s been able to obtain this way far exceeds those available to any Western researcher. In China and in much of South East Asia the whole regulatory structure for biotech research is considerably looser than in the West.
The problem of egg harvesting sets limitations on the use of therapeutic cloning. Donating eggs is not like donating blood – it’s an invasive procedure, the side-effects of which are not fully known. Already some researchers are beginning to question whether this technology can ever be viable on any large scale.
The problem here is that more successful the process becomes, the more patients will want it and the more human eggs we will need. Where will we get them?
This, of course, is also the dilemma raised by the success of organ transplant technology. Sure, surgeons can now replace kidneys and hearts and livers, but the bottom line is there are nowhere near enough donors to supply all the organs that might be replaced. In this case we have become victims of our success. Like organ transplantation, therapeutic cloning raises a problem of supply.
One possible source of eggs would be poor women, who may well be prepared to risk the side effects for a couple of thousand dollars – or, in the Third World, for a couple of hundred. But in that case one person’s health is effectively being bought at the expense of another’s. Personally, I have a hard time reconciling this trade.
Already scientists at places like Advanced Cell Technology are beginning to look for alternatives. One option would be to harvest eggs from cadavers – just as we harvest organs. That’s in fact what animal cloners do – cloned cows are generated using eggs extracted from ovaries obtained from local abattoirs.
But of course you still have the supply problem of getting enough donors to agree. Also, it’s hard to get this to work with human eggs.
Another solution may be to use animal eggs. Advanced Cell Technology has already tried to clone humans using cow eggs. They failed to make this work and created an ethical furore instead, but Chinese researchers claim to have had success with rabbit eggs.
In the long run, many researchers are hoping they can bypass the egg altogether and learn how to simulate its power by reprogramming the adult cell directly to generate the desired tissues. That is a truly extraordinary and sci-fi option – but we are a long way from that at present.
The economics of health care
I want to end this talk on another issue that seems to me even more urgent. By their very nature, stem cell procedures are complex and time consuming. The strength of stem cell therapy lies in the fact that one is getting a specifically targeted and individualised service – particularly when the stem cells are being custom-made for you. It’s this specificity that makes the technique so powerful. But herein lies the weakness. For just as with any commodity, individualised production is inherently expensive.
Designer cells, like designer clothes are likely to remain pricey. To effect cost reduction you have to go for economy of scale, but that’s just what you can’t do with stem cells. Even if scientists become a lot more efficient at these techniques, stem cell therapy is likely to remain a high-cost service.
So who is going to pay for this? And who is going to benefit?
As medical technology advances, and more and more powerful cures become available for an ever-broader spectrum of ailments, we increasingly face the question of how much of our national budgets we are prepared to devote to health care. In the US – the capital of high-tech medicine – 18 per cent of GDP is currently spent on health care, almost twice that of most Western European nations. In Australia the figure is 8.4% of GDP. One of the biggest debates in the US over the past several years has been whether or not the nation can afford to pay for prescription drugs for the elderly. More and more drugs are becoming available each year, but many are very expensive.
Drugs, at least, can be mass-produced. If we are having trouble providing mass produce-able drugs to all those who need them, how on earth are we going to afford a specialty service like targeted stem cell therapy
As we have been discussing, stem cell therapy can potentially be used to generate new tissues to replace sick and ailing ones. Alan Trounsen has said he is hoping to begin clinical trials of tissue regeneration within five years. The first recipients will no doubt be people suffering from serious illnesses, but another group who could benefit is the aged. As we get older our organs wear out – if we can generate new tissues then aged organs could also be revitalised. Thus the further we go down this path the more we are going to be faced with the issue of resource allocation. Who, at what age, and under what circumstances is going to have access to this technology?
I am not suggesting that I have the answers here. I have a friend with Parkinson’s disease – it’s an alarming and frightening illness – and I would love to see Ed cured. But how are we as a society going to pay for such treatments?
In the world today, access to medical technology is increasingly inequitable. In the USA, 43 million people lack even basic health insurance. What good will stem cell research do for any of them? No doubt with enough financial support researchers like Alan Trounsen will overcome the technical hurdles, but it seems to me that the real hurdles are the social ones.
The issue of medical inequity is not new: already there is an enormous inequity between the developed and the developing world. If you live in Africa, your access to AIDS drugs is virtually nil. Even access to basic vaccinations is not assured! What we are witnessing now is just a vast acceleration of this stratification – one in which we are increasingly likely to be the ones who miss out.
I am not suggesting here that we abandon stem cell work. What I am suggesting is that we need to look carefully at who is going to benefit here. Medicine is about more than Nobel Prizes and technological prowess; in the long run, surely, its primary aim must be the promotion of good health and well-being on the widest possible social scale. Whether stem cell research will further that aim remains an open question.
Transcript of the Redmond Barry Lecture 2002, State Library of Victoria, Tuesday 9 July 2002.