Sara Abdulla is a science and arts journalist who works for the leading international journal of science Nature as the editor of their free popular daily webzine: Nature Science Update
Will the human genome revolutionise medicine? A road atlas helps the motorist travel more quickly and efficiently, find shortcuts and avoid dead ends. But every journey is still shaped — still limited — by car and road technology, weather and traffic conditions and the driver's skills and stamina. The phenomenal technological, creative and collaborative achievement that is the human genome sequence is the 21st century human biologists' road atlas.
Though still being finessed, already it is hastening scientists explorations of the molecular scenery of health and disease immeasurably. Already it is leading them to rich, fertile terrain they would not have crossed otherwise. But, like road trips, the speed and success of these odysseys into the heartlands of human cell biology do still depend upon other technical and social factors — computing power, chemical synthesis, drug delivery, clinical trials, funding politics and fashion, to name but a few.
Plus, just as the reality of a country is more than even the most detailed map can express, so the human body is much, much more than its genetic recipe. The body's complex functions emerge from a mind-boggling interplay of parameters, so numerous and mutable as to be — possibly — indescribable except as a whole, rather than as a sum of parts.
Finally, the human genome sequence is in some ways a far from finished map: great stretches are sketched in, but not yet labelled. It will be some years before all these regions — the genetic equivalent of 'here be dragons' — will be usefully charted.
So, yes, like any map, the human genome sequence could change the medical landscape — by dint of the sheer weight of intellectual traffic set to thunder down the avenues it lays bare.
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Philip Ball is a science writer, and ex-Physics Editor at Nature magazine. He thinks the idea that there is 'a gene for every trait' is very misleading, and that biologists are still a long way off properly understanding the complex ways in which genes interact with each other and the environment.
Will the human genome project provide the information needed to find treatment for disease?
I think that really the genome project represents a beginning rather than an end point. It undoubtedly contains a tremendous amount of useful information, the only problem is that it's going to be a long time before we know how to understand and make use of that information. What has filtered through to the public consciousness is the idea that for every characteristic or trait or disease there is a single gene that controls or determines that outcome - we've even heard talk about 'the gene for homosexuality', 'the gene for intelligence', perhaps even 'the gene for criminality'. So a perception has developed that the genome project has provided something like a lookup table for all diseases, so that all one needs to do in order to develop a cure is to look in the genome for the gene responsible for that disease and then that will suggest a way in which the behaviour of the gene can be modified to develop a cure.
The problem is there are a few well known high profile diseases that do have a single gene basis, for example cystic fibrosis and haemophilia, but most single gene diseases are quite rare and most important diseases arise from the interaction between perhaps dozens of genes, in ways that we don't yet in many cases understand. I think this is illustrated by the fact that if we knock out the genes in the human genome one by one, we find that something like 40% of the genes can probably be knocked out individually without any discernible physiological response, at least in the short term - somehow when that happens the other genes are able to collaborate and conspire together to make up for the missing gene. This is an illustration of the way that genes act together, so that it's not always straightforward to predict what the consequences will be of knocking out or modifying a single gene.
Has the media therefore raised expectations too high?
There's a famous quote of Einstein that everything should be explained in terms that are as simple as possible but no simpler, and I think there's a danger in the case of genomics that things have gone slightly beyond that line, so that the public have received is this idea of genetic determinism and a linear idea of a single gene leading to a single end result. I think that that while that's partly a consequence of the understandable simplifications that the scientists are trying to make, I think it's probably also a bit of an outcome of our tendency to hope for a quick fix - if we can pin a particular disease on a single gene we feel we've nailed the problem, we know what to do, we can cure it. The natural desire to see that happen I think has encouraged people to want to interpret genetics in this way, the sad truth is that in very few cases is it really that simple.
Some have used the metaphor of the Book of Life to describe the human genome. Do you think this is a helpful way to think of it?
The scientists who've been working on genome sequences have understandably needed some kind of metaphor to try to convey what it is they are doing, what it is they are looking at. The one that they've hit on is to say once we've sequenced the whole of the human genome we've essentially read the Book of Life. To me that seems a little bit like saying that once we've read the English dictionary we have assimilated all the works of Shakespeare. In a sense it's true that if you work through the dictionary from cover to cover than you will in some sense have covered the works of Shakespeare - in fact not quite so because there are words in Shakespeare that won't appear in the English dictionary, and the same is true for the genome. But to me that's the sense in which the genome is the Book of Life and quite clearly we learn absolutely nothing about what happens in Hamlet or King Lear from reading the dictionary. So it seems to me to be a more accurate metaphor to talk about the genome as a dictionary. In fact it's even worse than that, because it's in this case a dictionary that's 95% meaningless junk where many of the words appear again and again, endlessly repeated over pages and pages, where the words are listed without their meaning being attached, where many of those words have no discernible meaning and where they are certainly not in alphabetical order.
How do genes work within a cell?
Some people think of a cell as a linear string of genes switching on and off one at a time. But with new genetic technologies it is now possible to obtain a snapshot of a cell and all the genes that are active at any one instant. This picture shows us just how complex the behaviour of the cell is, we find there are thousands of genes doing something or other at any one time. Making sense of that picture is a very big challenge, not least because often the genes that show up most prominently aren't necessarily the ones we are interested in, they're genes that have to be active in just about anything we do, they're so-called 'housekeeping genes'. But often the activity that we might be interested in is going on in one little corner of that snapshot. In general, interactions of the genes give rise to robust characteristics of the cell. In a sense the cell is designed in a similar way to the way engineers design systems to produce the same end result in a set of very different circumstances. The way genes do this is to operate together in networks, using principles very similar to those engineers use, principles such as feedback, back-up systems, error correction and so forth. It's the understanding of how these sorts of principles are used to provide the cell with its robustness that's really going to be needed in order to make sense of how genes give rise to the functions of life.
Scientists have been working to create a detailed picture of the human genome. Do you think this is the correct approach?
If I were to try to give a picture of the traditional idea that has developed amongst molecular biologists over the past decade or so of how genes work to control life, I'd again draw an analogy with Hamlet and trying to describe what goes on in the play. Instead of asking, 'What goes on in the cell?', we ask, 'What goes on in Hamlet?'. The traditional explanation would go something like, 'Well, two soldiers come on stage and they have a chat and then another one comes along and they talk some more and then a ghost appears and one of the soldiers says a bit like, "doesn't the ghost look a bit like the dead king?"', and so on. This step-by-step account isn't really what we're looking for. What we want to know in answer to the question, 'What goes on in Hamlet?' is, for example, 'Well, a young man struggles with his lack of resolve'. Those sorts of questions aren't necessarily the ones that can be answered by a blow-by-blow account, in fact sometimes that sort of account obscures those kind of answers. This is a leap that needs to be made in modes of thinking - it's really a different kind of answer that one is looking for, an account of the general characteristics of the cell that on the whole remain pretty much invariant despite what's thrown at it, how the broad themes emerge from the specific details.
What could geneticists learn from other fields of science?
Other fields of science can potentially offer some useful tools and concepts. For example, in physics the idea that one can find robust kinds of behaviour emerging from messy specifics is one that is quite standard. If you think of a glass of water, all those molecules are moving about in a crazy frenzy that is a completely different crazy frenzy from a different glass of water, yet both glasses will freeze to ice at 0 centigrade - that's a general property, something that emerges collectively from the way that water molecules interact with one another. We can expect to see at least some principles that are somewhat similar to this emerging from the interactions between genes. There are tools that have been developed within physics to handle big systems of many interacting components and to find out the modes of behaviour that emerge from those interactions. I think that it's likely that some of these tools may be useful in decoding what genetics really tells us about the way life works. There is some indication that this new way of thinking is already beginning to emerge within the biology community and that there is some recognition of the need to import ideas from other sciences. There are some molecular biologists who are trying to build models of the cell at the kind of systems level, I guess you could say, so that one tries to look at collections of genes and gene products and develop models of how they operate collectively to bring about some particular process. These models often involve quite sophisticated computational techniques or mathematical techniques and that is certainly one area in which physical scientists can contribute their expertise.
So, will the mapping of the genome transform medicine?
What the human genome gives us is a very useful medical database. If that doesn't sound quite as exciting as some of the claims that have been made for it, so be it. I think that even when we get to the stage where we understand what every single gene does - and we're very, very far from that stage - it will still simply be a database. Until we have a better understanding of the way that genes speak to one another, affect one another's behaviour and collectively act together we're going to be a long way from having a clear picture of how to attack very many genetically based diseases.
Professor Kay Davies - Professor of Human Anatomy and Genetics at the University of Oxford. Professor Davies is researching the genetics of muscular dystrophy and is developing solutions for gene therapy in this area.
How is knowledge of the human genome relevant to disease?
What you can do is use the genetic information to look at the disease process, because it gives you the tools and the information to ask the question 'what is the difference between the genes here in a particular disease cell versus a normal cell?'. And that tells you where to target treatment, because it tells you what the important differences are, and what the destructive differences are for a particular disorder.
How will this help for treatment of disease, for example from your own experience of research into muscular dystrophy?
Muscular dystrophy is a disease caused by a single gene deficiency. The most common forms of muscular dystrophy affects mainly boys - boys go into a wheelchair at 12 and usually die in their late teens or early 20s. The sort of treatment we're looking for is trying to replace the gene that's missing or trying to find ways of compensating for it. Replacing the gene itself requires a technique called gene therapy, where you disable a virus like the cold virus, you take the bits out that harm you when you have a normal cold and replace those with the human gene that's missing. Because viruses can infect muscle cells very easily you can then inject that virus into the muscle, the virus then produces the protein that's missing which then produces a good functional muscle. The difficulty is that you will have an immune response to the virus, just as you have an immune response to the cold virus and we have to find ways to suppress that immune reaction. In addition, because you have a lot of muscle in your body and all of your muscles are affected, we need to target all that muscle, both the heart muscle as well as the skeletal muscles in your arms and your legs. So it's still a big challenge, but there are a lot of developments in the field at the moment.
What do you think the overall impact of the human genome project will be?
The impact of the human genome project in medicine is really going to be diagnosis, prediction and treatment. The first thing is diagnosis - for example, you go into your GP surgery and you have a lump in your breast and the first thing for the diagnosis is to be able to take a sample of that tumour and identify exactly what sub-type it is of breast cancer. That will determine what sort of treatment you will have, what chemotherapy you might be put on or, more likely, which gene therapy protocol you will be exposed to: if your particular gene profile for your tumour is over-expression of gene A, they will try and down-regulate - make your cancer produce less of that - to make the tumour regress; if it's B, it will be a different gene therapy. The other thing that you could do within the clinic is determine whether you already have a predisposition to the disease. There are people in the population that are more susceptible to breast cancer than others, and that is partly genetic.
So you could do a genetic screen to determine which particular individuals had a susceptible allele - a marker in their genes - which made them more susceptible to an environmental insult. If you have a genetic predisposition then you can have continual screening. Now, that won't be an absolute answer, it will be 70%, 80% risk, but it gives you the opportunity of modifying your lifestyle, your diet, the way you live or being given drugs which might modify the clinical port. If you don't have a genetic predisposition, then you don't have to do that. This testing is particularly important for things like colon cancer - already there are individuals in families which have susceptibility to colon cancer that previously have had to go back to the clinic on a biannual basis and have an invasive investigation. Now they can have a gene test and half of those people can be told they're not at risk and therefore don't have to go through that process. That not only is good news for the family, it's good news for the NHS, because those resources can be used for something else.
Another advantage of gene therapy is that you can work very closely with the surgeons, and they're getting very much more skilled at directing things to very small areas of the body. So for example in heart disease it may be that the heart surgeon in collaboration with the gene therapist may be able to deliver a little capsule, which has got a gene factory in it, to a particular artery which would keep that artery clear. I think all sorts of applications of a combination of surgery and gene therapy are possible in the future.
Is the recent media coverage too much hype?
The media, I think, have improved in their presentations of the human genome project, but there is a fair amount of hype, there's an expectation that the treatments will be just round the corner. I think you have to remember that the first gene, which was for a blood disorder, was cloned in 1972 and we still can't cure that disease. Having said that, there are preliminary clinical trials for a particular type of treatment for that which does work spectacularly in two or three patients, which tells you we've made one step in a very important progress.
I think the impact of the human genome project on medicine is likely to be enormous, it's just that it'll take a little bit of time to get the results from the lab into the clinic. Even getting a diagnosis into every GP surgery is going to be expensive, it's going to require a lot of automated equipment, it's going to require a lot education of GPs, nurses and so on. So the impact on the 50 year scale is huge, in the 5-10 scale, simply because we have to implement it, is probably going to be relatively small. I think the media just have to get the time scale right, because otherwise people will think that it's going to happen tomorrow and it's not.
Couldn't genetic testing present problems, for example if people are put under pressure to find out if they have a predisposition for a disease?
There is an ethical problem in the human genome project being applied to diagnosis: some people will obviously want to know, they feel very proactive about their health and want to do all sorts of things; there will be others who don't want to know. I suspect personally that if it's something like diabetes most people will want to know because it is fairly simple and straightforward to make a lot of difference.
But if you had a very severe disorder, like Huntingdon's disease, which is an incurable neurodegenerative disorder, then you probably might not want to know. There's got to be very careful counselling here so that you're not forced to want to know. The danger then is that the insurance companies will demand to know and I think we have to educate these companies that those with incurable diseases are a small proportion of the population and we ought to be able to spread the load across that whole population. As long as if you refuse a test you're not allowed to take a million pounds insurance policy, it should work out alright.
What are the potential strains genetic testing could put on the NHS?
Genetic testing and bringing it in to the NHS is a major challenge, because you not only have got to deliver the test, you've got to be able to explain the answer of the test to the patient. I think what we have to remember with genetic testing is that it isn't something you can only go to your GP for. There will be companies, and there are already companies out there, internationally, that will put on their website 'we offer a test for breast cancer, Alzheimer's, and cystic fybrosis'. If you put a mouth swab, put a little cotton bud around your mouth, put it in this little tube, post it to us, we will give you back your genetic profile'.
I think the challenge for the NHS will be those people that decide they do want to know what their genetic make up is, and of course they're always optimistic so they'll put their sample in the post and they won't expect a negative answer back. If they get a negative answer they will be going to their GP and saying, 'Look, I've got an 80% risk of Alzheimer's, what are you going to do about it?'. So I think it's not just delivering what's already available in the NHS now, which is already a challenge, it's how are we going to meet the challenge of that sort of demand as well.
What is your opinion about pharmacogenetics and its potential in treatment of disease?
Pharmacogenetics is where you profile a particular patient group so that you understand better what sort of disease they have. For example, Alzheimer's disease is caused by several different faults, and you need to know exactly which type of Alzheimer's someone has in order to be able to get the treatment exactly tailored for that particular patient. Pharmacogenetics screens the patients first and determines whether they're group 1, 2 or 3 and then you can tailor the treatment. Now, the argument for pharmacogenetics is that if you target the right treatment to the right patient sub-group, then you're much more likely to see efficacy of that particular drug. But these sub-groups will have to be collected very carefully, because they're going to have to have high enough numbers in them to be statistically significant. You're also going to have to develop 3 drugs which potentially are going to be much more expensive to bring to the clinic - all of the optimisation which normally goes on in the drug companies is going to have to be done for each one of those, and the clinical trials are going to be carried out just as rigorously for each. So that is a note of caution of the sheer expense of introducing something like pharmacogenetics.
Dr Bruce Charlton - a clinical psychologist, whose interests include the nature of discoveries and breakthroughs in medicine. He thinks that genetics is eclipsing other important kinds of research in the biological sciences, and that the results of the Human Genome Project do not necessarily represent a significant medical breakthrough.
Could you explain the role of genetics in disease?
The role of genetics in disease is something that has to be established on a disease by disease basis, you can't really make a general statement about genetics as the cause of the disease. What's interesting though is that many of the most effective treatments of disease have not depended upon genetics, for example antibiotics, the use of steroid hormones and many other breakthroughs didn't depend on it.
Will the human genome project transform medicine?
When people claim that genetic research is somehow more fundamental than any other kind of biological research, it's a very arrogant kind of claim. There is a certain vaguely biological plausibility for it, but it's certainly not the most fundamental type of research in terms of medical progress. In any case, you're talking about a long term strategy, something that doesn't have immediate payoffs. If you're actually interested in getting treatments within the next decade or two, then you must have much more direct research projects which are actually trying to get breakthroughs in patients.
An example is the AIDS epidemic, a new kind of disease. The standard establishment view was that fundamental science in labs was going to provide the breakthrough in the treatment of AIDS. In fact AIDS is now a curable disease, using drugs that already existed when AIDS was first discovered, but using them in new ways and new combinations, so that a cure for AIDS was produced in as little as 10 years, under the pressure of the AIDS activists groups, not actually under the pressure of scientific researchers.
So is there too much focus on genetics at the moment?
I've got nothing whatsoever against genetics as an approach to biology, it's clearly a very valid and important approach. The problem is that it's coming to monopolise all resources, all prestige and all power within biology and medicine, therefore other approaches are not being pursued. One thing we do know from the history of medical innovation is that we don't know where the next breakthrough is going to come from, so it's vital to pursue as many different lines of research as possible.
How is research into genetics affecting pharmaceutical advance, finding treatment for disease?
It's not very well realised that almost every major drug that's used nowadays was actually originally designed and perhaps marketed for something quite different from what it's turned out to be used for. The most extreme example was aspirin, one of the oldest and simplest drugs in the pharmacopoeia, which in the 1980s was found to be the best drug for the prevention of heart attacks - a major breakthrough of the '80s was in a sense aspirin. Some people are saying that the major breakthrough of the next 10 years are the ace inhibitors, another drug which has been around for 20 years, used for the treatment of blood pressure and turns out to be fantastically good for preventing heart attacks.
Again and again it turns out that drugs that are already on the market are being used for new functions which are quite different. This happens because the human organism is so complex that we don't really know how it's going respond to an agent until we try it out on lots of different people in lots of circumstances. Another example: we expected the 1990s to be the decade in which human genetics and molecular biology was the great breakthrough in medicine. It didn't happen, it's been a tremendous disappointment.
What did actually happen in the 1990s is there were some new drugs, of which the most famous is Viagra, for impotence. How did the Viagra story happen? Here was a drug synthesised to be an anti-hypotensive agent for blood pressure, it ended up being used for the treatment of impotence and it wasn't even known that such a drug could exist. It happened by old fashioned ways of people closely observing patients. I don't think we've actually progressed to a point where we can drop that way of looking for innovations by close observation of patients and seeing how they react to drugs. And we're a long, long way away from the idea that we can get a gene sequence to predict exactly what effects modifications to the genes are going to have on the complex human organism.
What do you make of all the hype surrounding the human genome project?
The hype that surrounds the human genome project is essentially a form of advertising - it's to do with attracting funding into the area, it's not seriously to do with the science. It seems that sociologically people are forced to make claims about the medical importance of the kind of research they do in order to secure funding, they may even thoroughly resent having to make such claims, but certainly they do make them. They're simply playing a game and trying to present themselves in the most favourable light. So it shouldn't be taken seriously by anybody.
Is it difficult to defend yourself as a sceptic of the significance of genetic research?
The human genome project is an example of 'big science' in that it's very heavily funded and is run by extremely prestigious scientists in charge of large teams. These people have a great deal of influence within biology and medical research, with the result that their view carries a great deal of intrinsic weight. This means that anybody that disagrees with the claims that they make is put in the position of fighting against a very powerful establishment and is made to sound impertinent and implausible. In fact, such large claims as that the human genome project is going to have an immediate and powerful effect in improving medical treatment should be justified - they've not been justified and in fact they can't be justified by any normal criteria. Not to say they might, there's a small probability that things might work out like that, but none of the plausibility lies in that direction.
Dr Ian Dunham is a scientist working at the Sanger Centre, the UK wing of the Human Genome Project. Dr Dunham heads the team which sequenced Chromosome 22.
What work is done at the Sanger Centre?
The human genome project is a global 15 year initiative to discover essentially the complete set of genes that make up man. So what that means in practice is that we've tried to determine the order of our genetic material, the chemical bases A, T, C and G, along our chromosomes. What we've done at the Sanger Centre is to sequence those bases for about one third of the human genome, the rest of it is being done in an international consortium of labs around the world, the majority of which is actually in the US, but there's always contributions from labs in Germany, France, Japan and even China. The kind of techniques that we're using are we take human DNA, we put it into bacterial cells and then use a series of biochemical reactions to determine the sequence of the bases.
What are the results so far?
First of all, it's important to realise that we haven't completed the sequence yet, what we've done is to make what we call a "rough draft". That means that really we can be sure of about 99.9% of the sequence, but there are still gaps. What we can tell from that rough draft is that there's approximately 30,000 genes in the human genome. There may be slightly more, there may be slightly less, because when we get to the final stages we'll be able to see where we've made errors in the sequence, where we can join genes into one structure, or what was one gene was maybe 2 structures. So we've got a pretty good idea but not a complete accurate figure of the number of genes in the genome.
Fewer genes have been found than was originally predicted. Does this mean genetics is less important than is claimed?
The number of genes in the genome being estimated as around 30,000 was not that much of a surprise to people in the field - over the last 2 or 3 years it had become increasingly obvious that that was going to be around the right kind of number. When people talk say, "Does that mean that we're 'less genetic', or there is less genetic influence on our make up, well the number of genes doesn't actually matter that much - we know that we're genetic because if you look at traits that are passed through from generation to generation it's clear that you're receiving those traits from your mothers and father. What we need to do is explain how those 30,000 genes interact with each other to make up the complexity of the human body - there's obviously a lot of complexity there.
Is disease genetic?
There's a range of influences on human disease, from the diseases that are clearly entirely genetic - so for instance muscular dystrophy, cystic fibrosis - to diseases which are caused by infection - it would seem obvious that things like influenza, malaria, even AIDS are caused by infectious agents. Then somewhere in the middle there are a range of diseases that have influence from genes and from the environment. But it's clear that genes do play a role, so if we look at, say, juvenile onset diabetes, at least 50% of your contribution to getting diabetes actually comes from your genetic inheritance. I'd go on and say even something like the HIV infection has a genetic component as well, because there are certain people who have certain sets of genes who are less likely to become infected with the HIV agent than other people who don't have those sets of genes. So there's a clear range of possibilities between genetics and the environment.
What impact has the work sequencing the genome had on medicine?
I think knowing a complete set of genes that makes up a human being is extremely important for medicine in a number of different ways. Firstly it gives us the power to use DNA technology in diagnosis: diagnosis can be for genetic disease, it can also be for disease that involves genetic material, like cancer, so one can envisage that we will be able to look at sets of tumours and diagnose which ones are the best to have a particular type of treatment, using DNA technology.
Secondly, DNA technology is going to be important in discovering new drugs. We know that there's only about 480 targets for the drugs that are currently used in the pharmaceutical industry - clearly there are a lot more genes that we could target in the genome to try to develop drugs. That's going to be one of the major effects in the next 10 to 20 years. We can also look at how people are susceptible to particular diseases, so in diseases where a considerable component comes from genetics, like diabetes, like heart disease, we can look to see which genes are playing a role in giving that susceptibility and try to assess the risk that individuals have to particular diseases.
Finally, one thing that having the complete set of building blocks does is that it gives an incredible tool to study the biochemistry of disease, to study how disease works - whether it's genetic or whether it's infectious - and to try to pinpoint what molecules are involved to treat the disease, to develop new therapies, to develop new drugs. Knowing the complete set of genes is useful, but on a research level, because it provides with the set of instructions we need to go and study those more complex problems.
An example I've heard used is that you wouldn't go to a garage and expect somebody to start tinkering with your car without knowing what's going on inside. Having got this set of DNA instructions means that we actually have the information there to go on and study how humans work as a whole, and that's the level it's important. And you might not see the effect of that for some years down the road, so it might be a few years before you go into your GP and they start using genetic information directly at the GP surgery but I'm sure it will happen.
What do you think of the idea that the study of genetics might eclipse clinical research?
I think that although genetics is getting a lot of publicity at the moment there is a good reason for that, and that is because it provides you with these basic tools. These tools are going to be used everywhere - they are going to be used in clinical biochemistry, in clinical trials, they are going to be used in all sorts of clinical application when you want to know what is the base level of information in the individuals that you are looking at. So, for example, if you have a clinical trial of a particular drug you are going to want to know what is the genetic makeup of all the people who are involved in that clinical trial, because that will give you fundamental information as to how that trial is working. One thing that is important to mention is that the funding, both in the UK and in the US where the major amount of the genome project was done, was actually on top of what was already provided for biomedical research and clinical research as well. So it wasn't a question of taking away from pot, it was actually adding more money that really has benefited all areas of research.
What is your opinion of the recent media hype about the human genome project?
I actually think that that has been quite good, because it has brought genetics and the kind of information that is being produced by the genome project to public awareness. And if we are to use, as a society, that information in a positive way we need to discuss it as a society, and people have to be aware of what's going on. Even if there are some confusions that are caused by coverage in the media, it's better that those things come to light than that the issue is never raised. So I think media attention has always been good for the genome project.
Professor Jonathan Rees - a professor of Dermatology at the University of Edinburgh, he identified the 'red hair gene' and is an expert on skin cancer. Professor Rees thinks that the Human Genome Project is being hyped in such a way as to mean that the results that do come from it might be disappointing.
What do you think of the claims made about the impact the human genome project will have on medicine?
If you're going to look at the impact of genetics on medicine you have to take a much longer term view than I think has been done already. I like to think of it that genetics is a great way of doing biology, but biology isn't the same thing as clinical medicine. You've got to remember that medicine is far more promiscuous in terms of its intellectual origins and the discovery base of clinical medicine than many people believe. Medicine takes advances from engineering, from computing science, from material science, from medicinal chemistry. Genetics is part of that, but of course most of the claims for genetics on medicine have been made by people with very much a genetics background, rather than a background within clinical medicine. Most of the claims are made by people who don't see patients in clinics.
Generally, I think people confuse DNA and genes with therapy and most of the people who are most enthusiastic about genetics seems to know very little about therapy or the history of drug development. Goldstein and Brown, who won the Nobel Prize for the first major genetic discovery, have a very nice comment relating to the Magritte painting where they say if you look at DNA sequence 'ce n'est pas un medicament'. DNA is not a drug.
Do you consider the research that has been done into the human genome to be at all useful?
What's been seen over the last 20 years has been the ability to do genetics in human biology, whereas previous to that genetics was largely concerned with model organisms, fruit flies and maize and so on. So there's been great enthusiasm for that approach. But of course just because you can do experiments doesn't mean that they're going to lead to the results that are going to have a big health impact. I believe we need to think of what are the clinical problems we are trying to solve, rather than be tempted into doing perhaps second rate scientific problems just because they're now doable.
On the other hand, one of the ironies is I think amidst all the hype about the human genome project there have been genuine clinical advances, clinical genetic discoveries that have got forgotten about. In one sense people are so concerned about hitting the big disease targets - cardiovascular disease and cancer - they've forgotten that some of the basic research and human genome research has had direct practical implications already. For instance there are many rare skin diseases which are fairly devastating - we already know now how to prevent some of these diseases, and we certainly know how to predict who's going to get those diseases. Although numerically this may be only a fraction of the population, to those individuals those discoveries are very important.
Similarly, if you think about cancer of the colon, we're able to predict who will get cancer of the colon within certain families. Now, that doesn't account for the majority of people who get cancer of the colon, but again, within those families, perhaps 1 or 2% of the individuals, these are very important discoveries and have already moved into clinical practice.
Dr Alun McCarthy is the European Head of Drug Development Genetics at GlaxoSmithKline. Dr McCarthy is part of a team working on 'pharmacogenetics', a new kind of drug development in which drugs are tailored to individuals' genetic make-up, to reduce side effects.
What is pharmacogenetics?
Pharmacogenetics is looking at how genetic variation affects people's response to medicines. For example, if you take a hundred people with elevated blood pressure and give them the same medicine, some of them will respond very well and some won't. We now realise that quite a lot of that variability is due to the differences of the genetics of the proteins that are involved in controlling the blood pressure and in theory you can apply the science to any disease area. So what we're trying to do is understand what is the variation that affects that response and then get physicians to use that information to help them make therapeutic choices.
What are the implications for future drugs? If you think about how medicines are used at the moment, using the example of blood pressure, a physician will try probably a diuretic first, if that doesn't work they'll try maybe a betablocker or an ace inhibitor, the different classes that are available. With this better understanding, we can actually take the patient in front of the physician and say, well actually they are most likely to respond to this class. Instead of a patient having to go back to a doctor 3, 4 times, they just go a fewer number of times and get effective treatment sooner. So the drugs will still work to lower blood pressure, but we can get to effective treatment sooner. In addition, it's almost inevitable when you give a completely new chemical to people that there will be a percentage of people that will have side-effects. Again, there's quite a good understanding that some of the basis of these adverse reactions could be genetic variation - with pharmacogenetics we can also exclude a specific genetic group from treatment with a particular class of drug that would be likely to cause them side-effects.
What work are you doing at the moment in terms of pharmacogentics?
Here at GlaxoSmithKline we have one example which we're working on quite actively at the moment, particularly around adverse reactions. It's to do with treatments for HIV, many of which have side-effects associated with them. In fact, recently the treatment guidelines for HIV have shifted so that in fact people will be treated later on in the disease rather than earlier, because of the instance of adverse reactions. We're setting up quite a major study to see if we can understand the genetic basis for these adverse reactions, so we can perhaps understand what's going on: for some people who are not going to get those adverse reactions we can then bring the treatment forward in time; for people who are likely to suffer we now get to understand what's the basis of these adverse reactions and we can now design new treatments that won't have these problems. So that's an active programme, but like all these things it doesn't happen overnight, so it'll be a number of years before the populations are found, the study is carried out and the findings are made available. But we're starting now.
How do you respond the people who are sceptical of the significance of the human genome project?
Will the human genome project transform medicine? I think mapping of the genome is bound to revolutionise medicine. It will give us such huge insights and such tremendous tools for research that the impact will be absolutely enormous, I'm convinced of that. But it won't be very quickly, we won't see in 2 years time medicine completely transformed. The time frame for bringing pharmacogenetic changes to healthcare will be around 5 years and for 5 years onwards. In terms of the insights into new medicines, that will take longer because of the research, then the clinical testing, etc, that's actually more than 10 years from having a bright idea to having a medicine. So if we were having this discussion in 20 years time, we would look back and say, yes the genome project has completely transformed medicine. I think there are expectations for immediate translations into benefits and I think that's where people feel it hasn't delivered or it won't deliver.