Stem Cells Roundtable
Dr Paul Andrews (Senior Scientist, ITI Stem Cell Technology Programme, University of Dundee), Professor Peter Andrews (co-Director of the Centre for Stem Cell Biology, University of Sheffield), Fergus McKenzie PhD. (Programme Manager, ITI-Life Sciences), Dr Stephen Minger (Senior Lecturer in Stem Cell Biology, Kings College London) and Will Rust (Section Manager, Cell Systems R&D, Lonza Bioscience) take part in a roundtable to discuss stem cell research…
1. What do you feel are the current changing attitudes to Stem Cell Research?
Paul Andrews: First of all are we talking throughout this roundtable about human stem cells? Are we differentiating between human embryonic stem cells and adult stem cells, or patient-derived induced pluripotent stem (iPS) cells? The differences in attitude and responses could be completely different. In addition: what do we mean by research: research aimed at therapy; for drug testing that might reduce reliance on animal models and lead to better drug safety; or basic cell biology research?
If we consider the public perception of human embryonic stem cell research then it depends on who you survey – for some there is negative entrenchment; for others there is no simple black-and-white answer; others might be quite positive. I would estimate that most sensible people appreciate the potential for cell-based therapy, as long as the risks are low and perceived benefits high. This is borne out by evidence from the recent BBSCR/MRC public engagement exercise. My estimation is that as long as the therapies are showing promise and that humans (admittedly “developed” world humans) stand to benefit in some shape or form, then a repeat of the GMO debacle will not arise. If the press decides to misconstrue and scaremonger, as seen with the human-animal hybrid embryo debate, then perhaps things will go a different way.
Peter Andrews: The term ‘Stem Cell Research’ encompasses a rather broad range and so any attempts to talk in these terms about stem cell research as a whole are inevitably simplistic. In fact what most people think of when this type of question is posed is the issue of ‘embryonic’ stem (ES) cells, and the ethical debate as to whether it is acceptable to work with cells that are derived from early human embryos which are destroyed in the process. Those who find this a problem particularly look to so-called ‘adult’ stem cells, which really represent a heterogeneous mixture of cell types, in the hope that these can be used instead of embryonic stem cells for particular purposes, especially regenerative medicine.
Certainly some such ‘adult’ stem cells can be used, and indeed the one well established ‘stem cell’ application is bone marrow transplantation. However, as more understanding of embryonic stem cells is obtained, and as it has become rather less clear that ‘adult stem cells’ can be used for all possible applications, recognition of the value of continued work with the embryonic cells is slowly gaining ground. Of course the appearance of induced pluripotent stem cells, produced by reprogramming adult cells back to an embryonic stem cell-like state has raised further questions about the need to work with embryo derived cells. But our understanding of iPS cells is still in its infancy so that it is far too early to conclude that these will inevitably eliminate the need for working with embryonic cells.
McKenzie: Stem Cell Research is a terrific ‘attention grabber’ and is therefore often in the headlines. This is also an indication of the wide-ranging ways in which stem cell research can impact on the whole of the drug discovery process, and eventually, the production of new medicines and therapies for degenerative diseases that are presently intractable. The research community is pushing onwards on a number of fronts because it is not yet clear where the answers are going to come from, Human Embryonic stem cells (hES), Induced Pluripotent stem cells (iPS), or indeed from adult stem cells isolated from specific tissues. One thing is certain, the greater the effort expended in ALL areas of stem cell research, the quicker we will find the solutions.
What would help the field enormously is a clinical success. If we can start to see novel therapies in the clinic that reach their endpoint, then the wave of optimism that presently surrounds stem cell research will start to be vindicated. Many commentators are resisting the call to put their weight fully behind the stem cell lobby until such clinical developments clearly demonstrate that stem cells can and will deliver on their potential.
Minger: Having just returned from Texas and California, I can see that within the scientific community there is a lot of optimism that things will change but exactly how much will change remains to be seen. The situation in the US is quite complex and what Obama is doing is really only one small facet of the whole picture. I think the Geron trial finally receiving approval is very encouraging, though many of us are concerned about whether this is the right thing to be doing first. The reason for that is that it will mostly be people who have injured their spinal cords, young guys playing sports for example, who will be the first patients to be transplanted with cells derived from human embryonic stem cells.
Obviously traumatic spinal cord injury is hugely debilitating but on the other hand, for example, a paper came out from Moscow recently that spoke of a boy who had had a transplant from human foetal neural stem cells, but four years later has developed tumours from them. Developments like that are of big concern especially with regards to tumour formation as a result of the stem cells. Somebody has to be first and Geron certainly pushed very hard for this. What the FDA has demanded of them is exhaustive. At the end it was about 22,000 pages of documentation which Geron presented to the FDA after working on it for four or five years. I think that is quite encouraging. It means the field is progressing and people can no longer say that nobody has ever done anything with human embryonic stem cells.
The work in China is progressing rapidly and the Chinese government are investing significant amounts of money into the development of the field. Therefore, on a global perspective I would say things are progressing rapidly despite the fact that the field seems to change almost every other week with new developments which drives us all off in many different directions.
People forget that Stem Cell Research is still a relatively young area of research. The first human embryonic stem cell lines were made ten years ago and really most people didn’t have access to cell lines until maybe 2003-2004, so you are looking at a field that is mostly about five years old. The fact we have made so much progress is actually pretty surprising so I think that will continue.
Rust: With regards to opposition to human embryonic stem cell (hESC) research, I don’t think that attitudes have changed. Those opposed to this research on purely moral grounds are still opposed, and this position is not likely to change. In addition, there has been no dramatic clinical success that could spur a shift in public perception of the value of hESC research. As time goes by, however, the issue fades from the forefront and other issues take precedence, allowing very visible research organisations to dip their toes into the field without garnering front page news articles. Additionally, many opposed to hESC research are willing to publicly embrace research with pluripotent cells established by reprogramming of mature tissue (iPS – induced pluripotent stem cells). Lastly, high potential research attracts more investigators. As the stem cell field has matured, its potential has been largely borne out, attracting laboratories that were never opposed to the work but had not yet entered the fray. In all, research investment involving stem cells is growing, but I don’t think this is due to changing attitudes.
2. How do you feel current legislation has impacted the potential effect of Stem Cell Research?
Paul Andrews: The regulatory framework in the UK gives the general public a sense of confidence that appropriate measures and safeguards are in place to avoid potential abuses of the technology. The use of stem cell based products in drug testing or academic research is appropriately regulated. Any new trial therapies have to comply with national and international standards for clinical trials and would have to be approved in the usual way – although as the field of cell-based therapies develops then constant reassessment of the regulations governing uses is both desirable and necessary. There is no doubt legislation in other countries has had a negative impact on the ability to perform stem cell research.
Peter Andrews: Clearly the legislation in some countries has had a marked detrimental effect on embryonic stem cell research. This was not only because scientists in certain countries have been restricted in what they can do, but also because it has sometimes impeded their ability to collaborate with scientists in other countries.
McKenzie: Legislation in the UK relating to stem cells and their use has been well thought out, and has been based on a consultative process with all the interested parties. As a consequence, the UK funding councils have been comfortable with the fact that appropriate, ethically approved research is being conducted and that funding should be in place to allow the field to advance. In the United States, the restriction on federally funded hES cell research has undoubtedly convinced some venture capitalists and private investors that stem cell technologies is not a good place to put their money. However, the lack of funding available for hES cell derived technologies may have served to increase the focus on adult stem cells. hES cell research’s loss is therefore adult stem cell’s gain.
Minger: If we look at the embryo bill that went through in the UK I think that was a huge success for science as it was a rare example of the scientific community working hand-in-hand with the government. There were a number of MPs, the PM and the Minister for Health who said that if the scientific community hadn’t spent a lot of time in parliament briefing MPs about why we need hybrid embryos, what the value of hybrid embryos might be and generally educating them, many, especially Conservative MPs would have naturally voted against it because they would have been naturally opposed to these kind of things. Therefore, I think we must have made a good case. I think it is a fantastic victory and one the scientific community can be pretty proud of and it certainly contrasts what has happened in the US because there George Bush really has shut the field down nationally and the scientific community has done very little to prevent it.
Stem cell scientists in the US are gagged either by their institutions or their own fear of what would happen if they publically spoke out about what they do. I know many of my friends at prominent American university’s are not allowed to talk about their research to the press. They can publish in scientific journals but they can’t freely, as I am doing now, talk about their work research-wise. Publically, the perception is that Obama is going to undo eight years worth of this ban and it’s all going to be roses. Individually, the states will have the ability to decide effectively what is allowed to go on in that particular state. There are states in the US, like South Dakota, where everything is banned, even the work which Bush allowed to go on, and there is big fear that that may happen in states like Texas as well. So while Obama can actually change the funding in terms of scientists being able to use NIH funding for stem cell research, it’s going to have no effect at all on a local level and states also have the right to decide what can go on in their state university’s and that’s even worse. There is nothing close to what we have here in the UK where there is a consistent policy across the board that has nothing to do with where you are doing your research, who funds your research, whether you are a commercial company or an academic research group. Everybody has to play by the same set of rules under the same restrictions so it makes it easier, I think, to know that I am going to be able to conduct my research today and in ten years from now. In the US, most of my colleagues don’t have that certainty to the extent where many of them won’t even use human embryonic stem cells because they are so fearful of using the time and energy to bring this work to the lab, getting it up and running only to be shut down by the state government when the conservatives takes over their state government.
Rust: Worldwide restriction on hESC research and hESC research funding over the last decade has delayed the impact that pluripotent cells will have on drug discovery and human medicine by an indeterminate amount of time. Although there are no unique restrictions on non-embryonic derived pluripotent or multipotent stem cells, our understanding of (and ability to use) these cells are greatly aided by basic research into the mechanisms of pluripotency and differentiation garnered from embryonic cell research. The field benefits from hESC research, even if these cells are not destined for the clinic.
Additionally, hESC restrictions have altered the geography of where expertise is developed and intellectual property (IP) is assigned. In the US, small businesses contribute to pushing academic research into practical application and many novel technologies are born from public/private collaborations. The lack of academic research funding contributed to a concentration of controlling IP being aggregated around a few private centres, which set license fees high enough to prohibit the entry of many small firms1. This made part of the argument for the recent (and unsuccessful) challenge of the Wisconsin Alumni Research Foundation’s patents by the Foundation for Taxpayer and Consumer Rights and Public Patent Foundation.
The production of new human embryonic stem cell lines at Harvard was only made possible by the creation of dedicated labs, which were privately funded and could demonstrate complete segregation of private from public funds for equipment, reagents, and operations. This sort of red tape surely blocked similar efforts in other institutions. Research powerhouses in countries such as Germany, Italy and Japan have seen their technological lead regarding hESC research shift to more permissive countries with a significant research budget, such as the U.K., Israel, Australia, and Singapore.
It can also be debated whether politics has impeded the development of hESC technology funded by purely private entities. The recent approval of the first clinical trial using hESC (oligodendrocyte progenitor cells as therapy for spinal cord injury) may or may not have been influenced by politicians, but the timing of the approval is enough to raise eyebrows. Geron announced that the FDA had placed a hold on the clinical trial for an unannounced period of time in May of 2008. Approval of the application occurred on 23 January 2009, days after the inauguration of the new president on 20 January 2009.
3. How do you foresee legislative changes occurring on a global scale and what effect could that have on Stem Cell Research?
Paul Andrews: At the time of writing of course the eyes of the community are on the potential changes in the US, which undoubtedly will lead to increased government funding for human embryonic stem cell research, which in turn will change the culture around use of these cells. However its worth remembering that independent initiatives such as those in California are ready to immediately capitalise on the legislative changes, and this taken together with the fact that privately-funded research was never prevented, makes for interesting times ahead. It is also worth emphasising that a huge amount of mouse stem cell research – and very recently induced pluripotent stem cell work – has gone on in the US and the latter in particular may be of great importance. On a global level China is a rising star and it will be of interest to observe how it’s freedoms in the area of clinical trials impact on the cell therapy area.
Peter Andrews: It is difficult to know how legislation will change: generally regarding embryonic stem cell research it has tended to become more relaxed and certainly some countries that had extensive restrictions have begun to relax them.
McKenzie: With specific regard to hES cells, each of the European member states has its own specific legislation relating to: the use of human embryos to produce stem cells, the use of human embryos for therapeutic cloning and the use of human embryos for reproductive cloning. With the exception of the latter, where the first law banning reproductive cloning was the Resolution of the European Parliament (16 March 1989) stating that criminal punishment was the only possible reaction to human cloning, there is no overarching legislation relating to stem cells research. Indeed, the United States does not have national legislation governing stem cell research. We can only hope that the legislative process starts to ‘even out’ to provide agreement across national boundaries, but I do not see any reason for this to happen anytime soon.
Minger: I think that Obama’s decisions are largely symbolic although it is an important symbolic gesture. It’s funny how science ends up being such a huge campaign issue when you’d think there would be more important things like health care reform, crime and finding housing for the homeless in the US. Yet stem cells seem to be a really, really important thing. The problem is, especially in the US, it’s not about the science – it’s more about the morality and the ethics. The other problem with the US, is Americans are not really well educated about these things because the scientific community generally does not go out to speak to people and the public, therefore people have a lot of misconceptions and its true here in the UK too, although to a lesser extent.
When you talk about stem cells, people automatically think of foetuses and tabloids like The Sun do nothing to help this portrayal. When they run an article about stem cell research, they like to show a 12-16 week old foetus with arms, legs and a head, sucking its thumb – and that’s the vision people have of what we are doing. That is even truer in the US than it is in the UK.
However, things are changing. The US is just a quagmire when it comes to legislation because of the state/federal government split, and so on a global scale I think Europe is moderating. An example of this is Norway where they used to have a blanket ban on Stem Cell Research. They couldn’t do anything. They couldn’t import cells, they couldn’t conduct research, and now you can import cells and you can probably derive some human embryonic stem cells. I think that is indicative of a landscape which is becoming more progressive. People are also trying to push very hard the situation in Ireland as well which has had a total ban but now researchers are saying enough is enough, we want access to cell lines. Therefore, people are beginning to realise that this technology, particularly now with iPS cells, has got legs.
I think it is going to lead to big developments because you cant sit in a country that doesn’t allow this work but yet in five, ten or twenty years from now reap the benefits of the therapies that come from it without really contributing in any way. This was the driving factor behind Norway’s decision, I believe, as there are prominent people in Norway who felt it was not justified for them to sit on the sidelines and not contribute to this and then reap the benefits of it.
This attitude seems to be taking over in other places as well. It is particularly interesting in Texas as there was proposed legislation that would not only ban all research in Texas using human ES cells, but they also wanted to ban anyone who went abroad and had cell therapies derived from HE stem cells. This would lead to them being prosecuted when they returned home and the doctors who had suggested this could have their licences revoked. That’s just insane. I recently went to the Italian parliament and said the same thing: “what are you going to do when these therapies are there? Are you going to ex-communicate everyone who has a therapy you won’t allow in Italy?” The cardinals or bishops will probably be at the front of the queue. So I think there is a kind of liberalisation and relaxation across the board. I think certainly with Geron going to the clinic and companies such as Novocell and ACT saying they are also close to being able to go to clinical trials, it is going to put real pressure on legislatures in countries where either this is really tightly regulated or totally banned to relax that. Once therapies start coming, I think the issues about embryos will start to fade away. There will still be some people who won’t benefit from that, and they won’t want to use cell therapies that are derived from embryos, but I think the vast majority of people really won’t care.
Rust: I think success will breed adoption of this technology, just as failure will hinder its spread. It was recently reported that a young boy developed glioneuronal tumours from fetal neural stem cells (from at least two donor sources!) injected for treatment of ataxia telangiectasia2. This treatment did not appear to benefit from a thoroughly controlled assessment of therapeutic safety, and serves to confirm known concerns about the tumourigenic potential of stem cell allografts, especially in diseases associated with a compromised immune system. This tragedy should serve to support and validate research efforts which address safety issues appropriately, but has the potential to turn public opinion, and thus legislation, against stem cell therapies. Positive results from clinical trials such as those run by Britain’s ReNeuron (for stroke patients) or an anticipated British trial for macular degeneration may help to counter such publicity.
It was announced on 10 March 2009 that the President would reverse current White House policies on hESC research, expanding use of federal funds for hESC research. Legislative changes are therefore anticipated in the US, but whether or not there will be any international ripple effect is unknown.
4. Which countries are currently at the forefront of Stem Cell Research and why do you think this is?
Paul Andrews: The US, the UK, Japan and China. In the case of the US (in the human ES cell area) they performed groundbreaking early work but with the exception of biotech ventures, which have taken great strides towards use in patients, researchers have been straight-jacketed. This is why so many labs are now making important discoveries in the area of iPS cells. I suspect the UK is very strong on human ES cell work because of the regulatory framework and public acceptance, however overall levels of funding are woefully inadequate and no doubt any leads will be lost to the US in the future – unless government and charities dedicate more money, and the pharmaceutical industry continues to show the relatively recent interest it has done, but in real partnerships with academia.
Peter Andrews: This is a difficult question because there are key stem cell researchers in many countries around the world. Of course it also depends upon to which types of stem cells the question relates. Undoubtedly the USA remains a major player in the area, even in the Embryonic Stem cell field, despite the restrictions on the use of Federal funding. But significant research groups are active in many other countries, including Canada, Europe and in Asia. It seems clear that substantial developments are taking place in China, Singapore and Japan. Also the technology for iPS generation came from Japan which must be regarded as a leading player in that area.
McKenzie: At the moment, it is probably easier to determine which countries are ‘lagging’ in terms of stem cell research, and this correlates with an extremely restrictive legislation. As a consequence, both Germany and Italy, despite having centres of stem cell excellence, are lower down the ladder than some of their European counterparts. On a global scale, countries such as Sweden and the UK, where research funding has been, and still is available, are at the cutting edge of stem cell research. Perhaps surprisingly, the United States is probably the main player in the stem cells field. This is despite the lack of federal funding to work with hES cells generated post- the 2001 cut-off date imposed by President Bush. Scientists in the States have pushed forward with both iPS and adult stem cells, as well as commercially-funded hES cell work. This will continue and is set to increase, if the anticipated changes to the funding restrictions are lifted.
Minger: I think the UK at the moment is one of the world leaders with its combination of really tight regulation and scientific permisivity. Here in the UK, we can use any cell line created any where in the world anytime, as long as it has been derived in a way that is commensurate with UK ethical policies. I think we have very strong support from the government and have had since day one. This goes all the way back to when the HFE Act was amended in 2000/01, first with Tony Blair and then with Gordon Brown, who have both been very supportive of this research. Certainly Brown came out in support of hybrids but before we did any work on hybrids or even had the ability to do the work on hybrids, we had the consultation, the select committee report, there was a year of debate and of public interaction and public discourse before licences were granted. I think that is indicative of the British system. For all these reasons I think the UK is in a really strong position in this field.
China is also looking very strong because they had a massive influx of government money. This is a high priority area of research for China. The government is really primed and they are managing to recruit back the very best Chinese scientists who went abroad years ago. A lot of these returning scientists, often referred to as ‘sea turtles’, are doing so by giving up big posts in large American and European university’s simply because what they are getting in China is huge and they have a large talent pool there with a lot of young students.
Of course, the US is also at the forefront of the research simply because in the absence of funding from the NIH individual states like California, New York and Wisconsin have generated huge amounts of money. California, for example, has $3 billion over ten years just to fund research on stem cells. The NIH only spends about $600 million per year on Stem Cell Research for the whole of the USA and here is half that in one individual state. This means all the states are competing against one another, either to keep the people they have in the state or to attract new people to move to the state. There is a lot of competition within the US and now suddenly a lot more money will come from NIH, but you also need people that are skilled stem cell scientists and there are not a lot of them out there yet because the field is still in a learning phase.
iPS is bringing a lot more people in because everyone can make iPS cells now. I think it will just become more competitive but the American way of just throwing very large sums of money at a problem is probably not going to work. However, it will probably attract a lot of people into Stem Cell Research. I also think that as there is a very tight funding climate here in the UK, a lot of people will be enticed to go somewhere where there is at least a perception of easier funding. So this is a negative thing I think for the UK especially when it is trying to compete with places like China which is expanding rapidly and the US which is pumping more and more money into this field. There are also countries like Spain, Sweden, Canada and Israel that are working well – but they have smaller research bases.
Rust: From my experience, hESC articles are published frequently from labs in the UK, Israel, Sweden, and Australia. The US still makes an impact (although much lower than could be the case) on research using the approved “Bush lines” and with state and private funding initiatives. I think this is clearly a result of permissive legislation and cultural attitudes.
Recognising the relative advantage that permissive legislation may give a country which is developing its biomedical research capabilities and reputation, some countries have made a targeted effort to develop and import hESC expertise. Examples of such efforts can be seen in Singapore (Singapore Stem Cell Consortium, Insititute of Medical Biology) and South Korea (Stem Cell Research Centre). These efforts have made an impact on international visibility and publication in international journals.
5. What technologies available are enabling further development in the field?
Paul Andrews: In the human ES cell arena – the advent of technology for feeder-free growth and expansion has dramatically altered our ability to perform larger experiments such as screening.
Induced pluripotent stem cells are beginning to allow the generation of patient and disease contextualised cells, which will be critical for research and drug discovery, and in the longer-term cell-based therapy.
Peter Andrews: Obviously the recent development of iPS technology will have a major impact. Other areas of technology which are crucial, but certainly offer roadblocks currently for human ES cell work include robust techniques for routine genetic manipulation. In the long run a significant problem is developing techniques for robust production of large numbers of human ES cells with both phenotypic and genetic fidelity.
McKenzie: Many scientists are searching for specific sub-populations of stem cells that ate ‘lineage restricted’ in that they have the ability to differentiate into a limited subset of terminally differentiated cells. If such cells retain their ability to divide, then they can be expanded without the need to go back to the original stem cell cultures. Such cells are often termed ‘progenitor cells’. At the moment, there is a keen desire for new technologies to allow the identification and isolation of such progenitor cells. Traditionally, progenitor cells have been isolated on the basis of the expression of specific cell surface markers, or by their capacity to retain specific fluorescent stains. However, the last few years have seen an increase in technologies such as Dielectrophoresis (DEP), which can allow specific sub populations of mammalian cells to be isolated, based on their overall character, rather than the presence or absence of specific cell surface proteins.
In a similar vein, spectroscopic techniques such as Raman or near-infrared spectroscopy are being applied to stem cell culture media to identify stem cell populations with defined characteristics. As the use of stem cells of all descriptions becomes more prevalent within the research community, we can expect existing technologies to be applied to stem cell challenges.
Minger: There are a lot of technologies that we need. I have just come back from California where we had a big review panel and saw ideas, such as enabling technologies, which we need. Certainly from a clinical perspective, there are a number of things we need in order to induce ES cells and iPS cells which can turn into very specific types of tissues and cells. Geron seem to have this protocol for making cells they can put into the spinal cord, but beyond that we are all making populations and we are all trying to derive protocols for being able to reproduce results day in day out and make relatively pure populations of the same kinds of cells. This is a big burning need because without it you can’t translate the research to the clinic, at the same time you need to be able to get rid of any undifferentiated ES cells that might still be in your cell preps because obviously if those cells are implanted they have the risk of becoming a tumour.
One of the things we need in terms of sorting and enrichment technology is a broader panel of cell surface markers that uniquely identifies individual cell populations – particularly if we are deriving those from ES cells. If you are working from blood for example or bone marrow, haematology specialists have a plethora of cell surface markers that they apply to different populations of bone marrow cells. You can isolate one in a million cells, but for us, and particularly if you are working on ES cells, you don’t have unique markers for neural stem cells, heart stem cells, liver stem cells and pancreas stem cells that you could use. If we had such cell surface markers even if you had a mixed population of cells you could pull out your pancreatic progenitor or your liver progenitor, for example, and from this mixture of cells expand those independently of all the other cells.
New surfaces to grow cells are another area where there aren’t any prevalent technologies out there at the moment – we’re still in the ‘gardening phase’. A lot of us are still trying to make synthetic substrates to grow the cells on and trying to move as much as possible away from biological and animal products into things that are more GMP. People are obviously working with different scaffolds and bio materials to see how cells interact with those because clearly if you are putting cells into the brain or heart you are probably fine to load them up in suspension. For some other types of tissue, such as cartilage, you want to create more of a tissue so there is a lot of work being done on scaffolds and substrates to grow the cells on and more of a focus on three dimensional constructs. Tissue engineering specialists moved into stem cells pretty rapidly.
It’s mostly trying to find the factors that seem to promote maintenance of cells in an undifferentiated state because we still don’t know what the signalling molecules are but we have some ideas. But more importantly, factors that stimulate cells to turn into other types of cells; that’s the other side that people are working on.
Rust: Currently, the clear answer is cellular reprogramming. This month, the journal Nature published two articles describing the conversion of embryonic fibroblasts to embryonic stem-like cells by nucleofected or transfected plasmid gene delivery systems in place of viral transduction3. Furthermore, the reprogramming genes (which are known to contribute to cancer development or progression), were either spliced out or un-induced without loss of pluripotency. This represents one step closer to the goal of cellular reprogramming without unintended genetic modifications. This follows on the heels of other groundbreaking work describing reprogramming with as little as one gene, and the generation of pluripotent lines derived from patients of 11 degenerative and developmental diseases4,5. These tools have very high value, not just for regenerative medicine, but also to drug discovery, toxicity screening, and the study of human development.
Another important technology is the development of simple and consistent methods for culturing pluripotent cells. Removing the difficulty and expense of culturing pluripotent cells will enable many more labs to adopt these research tools. Better culture methods will also enable more efficient genetic manipulation of pluripotent cells. This will broaden the usefulness of pluripotent cells to more applications.
6. Which areas of drug discovery will benefit most from further Stem Cell Research?
Paul Andrews: Probably the activities in the hit discovery area – once validated, differentiation protocols are established providing physiological cell assays platforms; in secondary screening; for toxicity screening both for developmental effects and on neuronal, cardiac and hepatocytes platforms allowing more relevant DMPK testing.
Peter Andrews: The pharmaceutical industry currently seems to focus on the use of specific differentiated cell types, such as hepatocytes or cardiomyocytes that are currently used in existing screens. The hope is that development of robust differentiation procedures from ES cells will permit production of large numbers of ‘standardised’ differentiated cells with uniform genotypes. In this way it would be possible to develop much more standardised assays. Clearly there is the possibility of pharmacogenetics, by acquiring ‘standardised’ cell types with specific genotypes. Much current effort is focused on the use of such cells for toxicology, which has obvious limitations but offers the prospect of being able to eliminate early from further development compounds that are likely to have significant unwanted toxicity. However, it seems to me that focusing on the cell types used in current assays, means ignoring the possibilities that might be opened up by a wholly new technology. Thus it seems to me that there are significant opportunities in drug discovery and lead compound optimisation by making use of the processes of differentiation of ES cells; by monitoring various pathways of differentiation that are dependent upon particular signalling mechanisms and following how specific compounds may perturb such processes.
McKenzie: Over the last decade, we have seen a step change in the drug discovery process where most, if not all large pharmaceutical companies are using mammalian cells as the basis of their primary screening regime. In the first instance, ‘non-specific’ mammalian cells have been employed. However, we are now seeing a movement towards the use of human cells which have a strong physiological relevance to the disease state under study. An example of this would be the use of human neuronal cells in a drug screen looking for neuroprotective agents that prevent the neuronal death seen in certain disease states. At present, it is not possible to obtain sufficient human neuronal cells to conduct a primary screening programme. We can anticipate that once we are able to robustly and cost-effectively produce sufficient human neurones, from a stem cell starting point, then the drug screening industry will use such cells as a matter of preference. Of course, the underlying belief here is that the use of physiologically relevant human cells within a screening programme is likely to produce safer medicines at the end of the process.
Minger: More and more big pharma companies are going to move towards stem cells in their screens rather than using rat cells or tumour lines. GSK in Shanghai are already doing this – it’s something they are very keen on and I think that might spread throughout GSK. Certainly with trying to discover new drug targets, part of the problem with the way big pharma has traditionally done this is they use a lot of reporter systems and that can predetermine what you want a drug to do – for example bind to a receptor or activate a kinase.
I think the unique thing about stem cells is they give you a chance to use the inherent biology of the cells rather than focusing on a defined predetermined target. You can use the biology that you see when you expose cells to different factors to guide that process plus having consistent genetics and a consistent quality of cells, which they don’t always have with tumour lines. Stem cells behave as normal primary cells but you can grow them week in and week out, you don’t have to constantly go back to embryos or tissues to get the cells so they give you a lot of consistency – particularly genetically. In terms of drug discovery, I think it will be very important and there is a big push to use human derived hepatocytes, human ES cells derived hepatocytes, for predictive toxicology because again that’s a really big problem. When a drug gets to a Phase III clinical trial and then fails, you are looking at several hundred million dollars down the drain and so particularly here in the UK we have formed a public-private partnership s called ‘stem cells for safer medicine’ and the idea is to fund research into developing technology that allow for differentiation of cells to hepatic cell fate and to determine how much analogous these cells really are compared to liver-derived hepatocytes.
Rust: There are two main areas where stem cell research is poised to make an impact in drug discovery. The first is as surrogates for animal studies of drug toxicity. An inexpensive in vitro system which faithfully models human tissues for drug screening has long been sought by the industry as a method of reducing the enormous expense of losing late-stage development compounds to unforeseen safety issues. Examples of this trend are the collaborations between Cellartis and both Pfizer and AstraZeneca to develop toxicity screening tools from hESC. I foresee that the rate of adoption of this technology will increase in the near future. Second is the use of pluripotent cells as models of developmental and degenerative disease. Although in its infancy, it is anticipated that in vitro models for progressive human diseases such as the muscular dystrophies or Alzheimer will accelerate discovery of novel therapies.
7. How will further application of Stem Cell Research affect the future of the pharmaceutical industry?
Paul Andrews: Difficult to say but iPS cells hold great hope in the area of personalised and disease focused medicine – not just for cell based therapies and regenerative medicine but also for testing drug combinations on cell models. In the future trans-differentiation (conversion of one differentiated cell type to another via an intermediate) might prove workable. Equally drugs to mobilise a patient’s endogenous population of tissue stem cells may prove viable in the future.
The views expressed in Paul Andrews’ answers are his own personal views and do not necessarily reflect those of The University of Dundee or ITI Life Sciences.
Peter Andrews: An important new prospect for the pharmaceutical industry is the development of disease models, making use of stem cells with specific disease associated genotypes. The development of new ES cell lines from embryos screened for specific disease genes is opening up new tools, for example, to address diseases such as muscular dystrophy and Huntington’s disease. Such cell lines can be used, for example, to screen for drugs that may ameliorate the disease. The new iPS technology will enable this approach to be much expanded as it will ultimately prove easier to derive new lines with specific disease associated genotypes.
McKenzie: This is related to Question 6. As stem cells become widely accepted as being the path to which safer medicines are developed, we will see the major pharmaceutical companies adopt the technology. It is not difficult to imagine that in ten years time, all areas of the drug discovery process involve stem cells in some shape or form. At the moment, there have been few attempts to conduct screening regimes using in-vitro generated organs or complex tissues, rather than cell monolayers growing in plastic dishes. As the ability to generate small-scale organ like structures, involving a range of different cell types emerges, we can imagine that the industry will move towards such complex systems as being ‘nearer to man’ and therefore likely to generate small molecules that are not only efficacious in-vitro, but have a lower tendency to fail in the clinic. Hence, the application of stem cells within the pharmaceutical industry will most likely increase over the coming years.
Minger: I think stem cells are going to revolutionise a lot of things and I think it will revolutionise medicine, but I would like to think it is going to revolutionise the drug development industry because again it gives you new tools. If we can make disease specific cell lines in particular and, on the one hand, you can use those cells to understand better on a cellular level how mutated genes and dysfunctional proteins corrupt the cell and try to model disease in a dish, we can get some good data and that then gives you a new target system for developing new therapies. Lets say if you see a mutant APP protein that causes a heritary form of Alzheimer’s disease, part of the reason why it begins to damage the cell is earlier association with a couple of other proteins. You can look for reagents that block that from happening so its gives a whole new set of targets that we haven’t had in human cells. I think that is particularly important with the kind of consistency that we just don’t have really anywhere else. I think it could revolutionise the drug industry but of course it really depends on how rapidly big pharma dives into this. In some companies like Pfizer, they seem to be more interested in the potential regenerative medicine side of it, but other companies I think are thinking about using the cells as screens and tools in their screens.
What I don’t know is whether or not you can, and I assume you probably can, automate this like they do with other cell types and I think that they would be challenged to automate production of human ES cells and iPS cells. It’s still fairly labour intensive at the moment. There are a lot of people that are trying to work towards making more kinds of automated handling systems that can deal with human ES cells.
Rust: I think the future of the pharmaceutical industry can be inferred from the current investments being made by large pharma. For example, the anticipated growth of the biologics industry is reflected in the investment by nearly every major pharma into its biologics discovery, development, and production capabilities. Likewise, we are seeing a burgeoning investment in applications of stem cells for either drug discovery applications or regenerative medicine. The prevailing attitude is that the greatest current value of hESC cells is in their use in toxicity screening. However, it is anticipated by many that hESC cell therapies will be forthcoming for particular diseases such as type 1 diabetes and heart disease. Tantalising pre-clinical results have been published by companies such as Novocell. Also on the horizon may be the possibilities that pluripotent cell models of disease will enable discovery of new therapies, and our understanding of pluripotency will enable new methods of stimulating tissue regeneration.
References (located in Will Rusts’ answers)
- Wadman, M. (2005) Nature 435:
- Amariglio, N. (2009) PLoS 6(2):221272
- Woltjen, K. (2009) Nature Mar 1. [Epub ahead of print]
- Kim, J.B., (2009) Cell 136(3):411
- Park, I-H. (2008) Cell 134(5):877