CASE NOTES 4. - GENETICS
RADIO 4
TUESDAY 27/04/04 2100-2130
PRESENTER: MARK PORTER
REPORTER: LESLEY HILTON
CONTRIBUTORS:
FRED KAVALIER
JOHN BURN
DIANE DONNAI
ADRIAN WILLIAMS
IMRAN KHAN
JANET HALL
TIM SPECTOR
PRODUCER: HELEN SHARP
NEWS CLIP
Scientists who've mapped out the entire human genetic code are speaking of a milestone in history. They now hope the information can be used to eliminate a range of diseases
PORTER
June 26th 2000 - scientists announce that they've finally cracked the code of life and identified the sequence of the three billion building blocks that make up human DNA, and the thousands of genes it contains.
The success of the Human Genome Project was hailed, at the time, as the greatest technological breakthrough in the history of mankind - a major step forward in the fight against disease that would lead to a much better understanding of illnesses, and a new breed of wonder drugs based on gene therapy. Even a cure for cancer.
It's early days for breakthroughs of this magnitude, but four years on, the unravelling of human DNA has already had profound implications for genetic testing - checking individuals to see if they carry genes that predispose them, or their families, to illnesses as diverse as arthritis, heart disease, breast cancer and muscular dystrophy.
So how useful is gene testing and can it really predict how or when you are likely to die?
BURN
There's a wonderful Dilbert cartoon which said: We've checked your DNA and we've decided you'll die in a freak stapler accident next week.
PORTER
And what about the implications of wider testing - could compulsory testing create an underclass who won't be able to get insurance, sickness cover or a mortgage to buy a home?
My guest today is geneticist Dr Fred Kavalier
Fred, I'm sitting here as every single one of my trillion or so cells contains DNA which in turn contains those 30 to 40,000 genes - half from my mother, half from my father - that turned me from a simple fertilised egg into what you see in front of you. How do they do that?
KAVALIER
Amazing isn't it. Well your father gave you half of his genes, your mother gave you half of her genes, they came together in the fertilised egg, the sperm and the egg came together and that double set of genes - half from your mum, half from you dad - made you into what you are today.
PORTER
Because I think most people tend to think of genes, don't they, as something that is responsible for the colour of your eyes or whether or not you're going to get a disease. But they actually do everything - they're the software that operates the human body.
KAVALIER
Well they do, they are a set of instructions - they do sort of tell the body what to do at various stages but I think it's important to remember that actually the genes are working throughout your whole life, they're not just when your eye colour is determined but later in life and even to the end of life your genes are working and telling your body some of the things it has to do.
PORTER
Now one of the other great mysteries is my parents had three more children after me and given that we've all come from the same basic genetic ingredients - my mum and dad's DNA - why aren't we identical clones - I've got two sisters, for instance, different sex, let alone they don't even look like me but they're a different sex.
KAVALIER
Well I suppose the first question is was somebody going to be a girl or was somebody going to be a boy. And your father's sperm determined that, some sperms carry the chromosome that makes you a girl, some carry the chromosome that makes you a boy. But then all the rest of the genes that decide other things about you - it's a bit like throwing some coloured beads up in the air - if your father's beads were all red and green and your mother's beads were all yellow and blue - when they came down they might have come down in all sorts of different combinations.
PORTER
Now genetically determined characteristics can be obviously passed on in different ways. There are three basic types of inheritance aren't there - can you give us some examples?
KAVALIER
Well the first one is something that we call dominant inheritance and what that really means is if one of the parents has a condition or carries a particular gene that there's a 50/50 chance they'll pass it on to a child. And an example of that might be well we have a condition called Huntingdon's Disease, we'll probably talk about later, some types of very rare cancers can be passed in this way. So if a parent has it half of the children, on average, will inherit it - that's what we call dominant. Then there's another sort called recessive - the parents are both fine and then all of a sudden a baby is born who's got something. And the reason for that is each parent has contributed a single dose of a gene and the disease only occurs if a baby has a double dose - a single dose from each of the parents.
PORTER
This is where we get two carriers coming together and having an effect.
KAVALIER
So two healthy parents come together, they'll be healthy for the whole of their lives but they have a child who's affected by a condition, for example, cystic fibrosis or cycle cell disease - a serious blood disease. And then the last sort is something to do with boys and girls - it's carried on what's called the x chromosome. And these conditions by and large affect boys but women and girls carry the conditions but don't have any effects from them themselves. So a mum who's a carrier might well have a boy who's got the condition. And an example of that is haemophilia.
PORTER
And colour blindness as well.
KAVALIER
Colour blindness, yes is on the same chromosome.
PORTER
Do we know what all the genes in our DNA do - I mean we're talking there about 30 to 40,000 genes have been "identified" - do we know what each of them does?
KAVALIER
We don't even know what they all are. I mean although we estimate there are 30 or 40,000 genes, they haven't all been found by any means, they're all tucked in amongst the big code that you talked about before. And we certainly don't know what most of them do. I mean I think it's fair to say we - what we don't know is much greater than what we do know about them.
PORTER
Thanks for now Fred.
Well one of the many advantages of identifying genes responsible for specific diseases is that it allows doctors to identify symptomless carriers of a disease - people who may not have significant problems themselves but, if they were to start a family with another carrier, could have a severely affected child.
Well sickle cell and thalassaemia are two such inherited blood disorders that can be carried as many as one in four people in some ethnic minorities in the UK. Lesley Hilton met two families who have used genetic testing to find out whether they carry the disorders and, if so, what the implications could be for their families.
HILTON
As the machine in this hospital laboratory tests blood samples for the genetic disorders sickle cell anaemia and thalassaemia, the patients wait anxiously for the results. But what exactly are these blood disorders and what problems do they cause? Dr Adrian Williams is a consultant haematologist at Bradford Royal Infirmary.
WILLIAMS
Sickle cell anaemia is a disease which is known for the pain it can cause. In normal people the haemoglobin - the pigment which makes the blood red - is carried in cells which circulate in the blood around the body and these cells are normally disc like in shape and flow through the blood vessels. But in sickle cell anaemia the red cells can adopt what's called a sickle shape and this blocks the blood flow to parts of the body and blocking the blood supply can cause very severe pain. Thalassaemia is a form of anaemia which unlike sickle cell anaemia where the haemoglobin is abnormal, in thalassaemia it's normal but reduced in quantity. In the most severe forms the anaemia is so severe that without blood transfusions the patient's life could not be sustained.
ACTUALITY
Would you like to have juice or chocolate? Juice? You want juice.
HILTON
Sickle cell anaemic is a blood disorder that affects mainly the Afro Caribbean population who have between a 1 in 4 to a 1 in 10 chance of carrying it. Beta thalassaemia is common among Asians, who have between a 1 in 10 and a 1 in 30 chance of carrying it, depending on where they come from. A person can carry the gene without becoming ill, for that to happen both parents must be carriers.
Imran Kahn comes from Pakistan. He didn't know if he was a carrier so when he married and decided to have a child he got himself tested. His wife did carry the thalassaemia gene, so there was a possibility that their child could have a problem.
KAHN
My wife she was thalassaemia positive but it wasn't dominant so because we got married and that was a family marriage so we thought it's better to have myself checked as well. If I'm also positive then that's going to affect our baby. This was the reason why we had this check up.
HILTON
Imran was negative but when his two-year-old daughter was tested she was found to have inherited the thalassaemia trait from her mother. Does that bother him?
KAHN
Well that didn't concern me because it wasn't in a dominant condition so she will be a carrier and she won't develop this thalassaemia. Obviously before getting married she will have her partner tested to see if he has thalassaemia or not.
ACTUALITY - COUNSELLING
Hello Mary, I'm Janet Hall, I'm the counsellor, the haemoglobinopathy counsellor.
HILTON
There are many avenues into testing. Patients can refer themselves or be referred by a GP, dentist or hospital.
Janet Hall counsels people with blood disorders at the Airedale Primary Care Trust in West Yorkshire. Her job is to support patients during and after the testing process.
HALL
Well both these conditions are life threatening, the long-term effects are awful. If people are screened then they are given the option of whether they want to carry on with the pregnancy or whether they want to have a termination. And if they do go ahead with the pregnancy then they are given the support that they actually need.
HILTON
Jane Thomas' partner and the father of her two young children comes from Bangladesh and is a thalassaemia carrier. She had both children tested at the age of six months, both children carry the gene. Did she have any problems getting them tested?
THOMAS
No it was great. I knew I needed to find out so I phoned up here - Janet Hall - and she was great, we arranged an appointment to have the blood tests done and went along to have that done and got the results. I knew a bit about it so ...lots of support, lots of notes sent to me, so I could read up about it and any help that I needed was given.
HILTON
It's quite common for people to only discover they have the gene for either of these disorders quite late in life, by which time it's too late to prevent it being passed onto their children. Janet Hall would like to see the testing process widened to pick up the problems much earlier.
HALL
Ideally pre-conceptually but on a wider scale I would be looking at screening children in schools, raising the profile, taking the stigma out of the disorder and educating people so that they understand it and that there isn't the stigma there.
PORTER
Lesley Hilton talking to genetic counsellor Janet Hall. You are listening to Case Notes, I'm Dr Mark Porter and I'm talking about genetic testing with my guest Dr Fred Kavalier.
Fred, what other diseases can we test for?
KAVALIER
Well genetic diseases tend to be rare, luckily I suppose because a lot of them are quite serious. We test a lot of babies who have serious problems soon after birth and discover they've got some kind of genetic disease, which has popped up for the first time in that family. And then there are quite a few genetic diseases which really tend to be chronic illnesses that go on throughout life - things like muscular dystrophy and Huntingdon's disease is another kind of neurological disease, which is a chronic illness but it does have a kind of downward course, so that people do get iller and iller with Huntingdon's disease.
PORTER
It's a particularly nasty disease this, isn't it, because your symptom free for most - the early part of your life and it doesn't strike until normally mid 40s and it's pretty - there's nothing we can do about it.
KAVALIER
No if you've got the gene for Huntingdon's disease there's no way to kind of undo that and the gene causes its effect usually later in life, in middle age and beyond.
PORTER
Which brings me on to the implications of testing "positive" if you like, presumably there are some conditions where you can find out if people are predisposed to a particular problem and maybe they can adapt their lifestyle. There are others where it might have implications for their family and you can counsel - do you counsel people, presumably give them advice before they start a family?
KAVALIER
Well if people want advice we're certainly happy to give it to them...
PORTER
...odds - they can say what are the chances?
KAVALIER
People want to know the odds, people want to know what's likely to happen but people also want to make decisions for themselves and we're very keen that people should make decisions for themselves.
PORTER
But what do you do - I'm going back to Huntingdon's disease - what do you do when you find that somebody is carrying a condition about which you can do nothing?
KAVALIER
Well if your dad say has Huntingdon's disease this is one of the conditions where there's a 50/50 chance that you might inherit it. The only way to find out if you've inherited it early on in your life is to have a test and it's really up to that person whether they want to have a test. So the first thing is do you want to find out - and as you rightly say this is a condition for which, at the moment, we don't really have any way of preventing it. So many people don't want to find out. But depending upon their personalities and their outlook on life some people do want to find out before it strikes.
PORTER
Well you don't have to have a particular concern to have a genetic test - a few minutes surfing the web revealed a number of American companies willing to analyse my genes. A few hundred dollars buys a test to find out if I'm particularly susceptible to osteoporosis, while a few thousand gets a full "executive" screen for hundreds of different diseases. But just how useful are these tests? Professor Tim Spector from St Thomas's Hospital in London is an expert in both genetics and osteoporosis and was consulted recently by a patient who wanted him to explain the results of a test she had booked over the net.
SPECTOR
I looked at this printout, which essentially had tested her for six genes out of our 30 odd thousand genes, have in some studies been shown to be related more to your risk of osteoporosis but that only looked at one small aspect of the genes, so what's called a snip, which is a very small fragment of the gene and not covering the whole gene. And they had these six snip results and they classed them as positive or negative and essentially three were up, two were down and one was in the middle. And so some of them suggested she had a high risk and some suggested she had a low risk. And they made a little story out for each one but didn't try and put the whole thing together. It did turn out there was a very good genetic test that she could have had done and that was asking whether her mother had had a fracture and she had.
PORTER
A little simpler than sending your cheek cells off to the States.
SPECTOR
And if your mother has a hip fracture basically you're a three fold increased risk.
PORTER
So she'd basically been wasting her time and money.
SPECTOR
On this instance she had, yes.
PORTER
You said in that instance it wasn't helpful to that particular lady. But are there instances where it can be useful?
SPECTOR
There are for diseases which are controlled more by a small number of genes - one gene or just a few genes. And these tend to be the rarer diseases, what we call Mendelian diseases, that run very strongly in families.
PORTER
Such as?
SPECTOR
Such as the rare forms of breast cancer which occur very early, and where the BRCA1 gene is useful. Certain early types of dementia where you get disease before the age of 50 and a lot of other neurological problems or problems in childhood knowing you're going to pass the gene on. So at the moment most of the tests that are being advertised for the general public tend to be commoner diseases, such as heart disease, obesity, diabetes, arthritis or osteoporosis. And we know that these diseases are caused by a large number of genes and very small little changes in the number of genes. And so the idea of having just a few tests that tells you exactly what your risk of getting it is, is really not credible at the moment. But that's not to say that in 10 years time we won't have tests where the same process is going on but you're getting a thousand of these tests done, whereas at the moment you're getting six for the same price and you'd get a much more accurate reflection of what your real risk is. But it's certainly not there at the moment.
PORTER
So they're not sensitive enough at the moment and we're only just touching on the tip of the iceberg. Tell me about these executive tests.
SPECTOR
There is a new type of test which gives us a glimpse of what's going to happen in the future and these are executive genetic tests. And they're being piloted in the US where for thousands of pounds where people are having say their health check ups they're offered an extra blood test and the DNA is extracted and their genes are tested for thousands of different genetic problems or diseases. And this can run from the way you handle drugs to the way - your addictive genes to your risks of heart disease, dementia etc. So far people have shown that the ones who are rich enough are quite willing to pay these extra thousands of pounds for this test that at the moment they can't do much with but will help exclude the fact they're carrying rare diseases as well. So as these go on I think we're going to see more and more of these sort of executive style tests and I think that's going to be an interesting trend on how we deal with that, with someone who comes to you with a telephone directory of all their genes and what possible implications it has. And whether people come along and say this is my prospective girlfriend would you please test her.
PORTER
There's an interesting thought! Professor Tim Spector talking to me at St Thomas's Hospital.
Fred, even if we do develop more specific tests, more accurate ways of predicting things looking at genes, it's a bit more complicated than that isn't it, I mean let's take the example of heart disease and high cholesterol levels - the high cholesterol level may be determined genetically, so that's nature that loads the gun, but it's the environment that pulls the trigger because it depends whether I smoke, whether I'm inactive, whether I'm diabetic, whether I'm lots of different things.
KAVALIER
Yes I think the complexity of diseases like heart disease is so enormous that simply looking at a couple of genes is never really going to tell us the true story. And in terms of what people are going to do with their lives, if you can keep your weight down, if you can exercise, if you can keep your blood pressure down - that may be more important than whatever your genes say.
PORTER
I suppose the bottom line is we should all be leading our lives as if we're predisposed to these conditions anyway.
KAVALIER
Well one way or another we do all get things and the healthier life you lead the less likely you are to get them.
PORTER
Now Tim mentioned the idea of using genetic testing to target drugs more efficiently, there's actually a pilot going on at the moment isn't there here in the UK.
KAVALIER
There's a lot of work going on in this because at the moment, for example, if you have high blood pressure, you go to see your doctor, and he says well let's try this, we'll try a beta blocker, we'll try an ACE inhibitor - one of the other drugs that's used for blood pressure. Sometimes it works, sometimes it doesn't work. We don't really understand why these things work in some people and not in others but there are undoubtedly genetic factors involved and if we can identify these genetic factors we may be able to do a simple test one day to say yes we'll use drug A for you because we know it will work, we know what your genes are like.
PORTER
Well thank you for now Fred.
SPECTOR
Tim also joked earlier about patients one day wanting him to assess the genes of future spouses, but a much closer possibility is the prospect of genetic testing as a routine part of medicals before getting insurance, or possibly even a job. John Burn is Professor of Clinical Genetics at the University of Newcastle and Diane Donnai Professor of Medical Genetics at the University of Manchester.
DONNAI
The Genetics of Insurance Committee was established in 1999 in response to a recommendation by the predecessor of the Human Genetics Commission and this was in order to try and make sure information coming from genetic tests was used fairly by the insurance industry in their underwriting. The only test to have gone through the system so far is the use of the Huntingdon's Disease test for life insurance.
PORTER
So if a family member tested positive for that presumably a life insurance company is going to withhold cover or weight the premiums considerably?
DONNAI
Well they have been doing that for many years on the basis of the family history of Huntingdon's Disease. Since the approval by GIC of the use of this test for life insurance, which is a very small number of people in the UK I would add, this means that half of the people, at least - those that were at risk but tested negative - they don't have their insurance premiums weighted at all, whereas those that do test positive well clearly they are likely to have their insurance - life insurance weighted. But people only have to declare the results of such tests if their application for life insurance is above £500,000.
PORTER
But surely, as you mentioned there, the insurance companies have been using family history to try and pick out people who might be at risk of long term disease - I'm thinking perhaps of, John, of breast cancer, I mean there's talk I gather that the BRCA1 and 2 - the genes that predispose to some types of breast cancer - are being considered in this role but surely an insurance company can ask you about your family history quite legitimately and if you have a very strong family history you could forgive them almost for assuming that you may well carry the gene and therefore weight the premiums accordingly?
BURN
Yes I mean the word accordingly is the key word there because it's actually very difficult to make accurate predictions about the life expectancy of someone on the basis of their family history, it's a very crude test. What we find is insurance companies often make rather arbitrary loadings, for example, they double the premium if you've got a family history. So it is a rather crude weapon. The other problem, of course, is that when we deal with Huntingdon's Disease it's a very exceptional circumstance where there's virtually nothing we can do to interrupt the progress of the disease. But if you've got a predictive test for a cancer condition you can obviously undergo surveillance to prevent that cancer. And so the future life expectancy is very different to what it would have been in the past in the more ignorant situation. In fact I had one lady who was refused insurance because she had a family history of bowl cancer, even though she'd had her colon completely removed, purely on the basis that she was at risk. So clearly it can be misused and it can be abused and it's very important that we ensure that people aren't put at a disadvantage.
PORTER
Diane, is there talk amongst the insurance industry of one day perhaps compulsorily screening people who are applying for insurance policies, if in 10, 15 years hence when we will have more accurate genetic testing, we'll understand much more about what the results mean?
DONNAI
One of the important criteria is the clinical relevance of any predictive test and we know that for things like Huntingdon's Disease if you're shown to carry the gene change you are very likely to develop the disease, if you're shown to carry one of the breast cancer mutations you have a high chance - I think John will correct me - but about 80% chance of developing the disease. Whereas if many of the other genes that have been talked about are variations that we all carry and so they're very unlikely to be highly predictive as single tests and actually what might happen is one thing that predisposes you, for example, to diabetes may, for example, protect you from other illnesses. So I think there's a long time to go before we've got any highly predictive tests for any of the common diseases in an individual person.
BURN
There's a wonderful Dilbert cartoon which said: We've checked your DNA and we've decided you'll die in a freak stapler accident next week. And I think the insurance industry, a couple of years ago, got into their head that this was going to sweep down on them, rather like the AIDS crisis, and cost them millions when people started taking out policies and selecting against them. As Di said, in fact almost none of the genetic tests will have sufficient predictive power and in any case in terms of life insurance if you find that you're at risk of something and you can prevent it by taking a tablet, for example to reduce your cholesterol, the likely is you're not going to just go and die to spite the insurance company, you're going to actually take measures to avoid dying. But the question of compulsory screening is an interesting one in that we already have one compulsory genetic test which is the form always asks you whether you're male or female and your weighting is actually changed depending on that observation because men die sooner than women. And so just as with family history collecting it may well be that we have to start looking not forwards - not only forwards at DNA testing, we need to look back at the information like sex and family history that's currently collected and how that's used because it actually isn't used terribly well in many cases.
PORTER
Fred - looking ahead - it seems that screening testing is going to be something of a double edged sword. On the one hand, as doctors, the more genetic information we have about our patients the better - we can advise them on lifestyle, possibly their risks of developing certain diseases, possibly tailor drugs to fit them. But on the other hand we've got to keep that information to ourselves haven't we?
KAVALIER
Well I don't think it's ever fair to have genetic information about people and keep it from them because the information belongs to them and I would shudder to think of the idea that doctors are collecting genetic information about people without people's knowledge.
PORTER
But you can imagine a day where we're testing genetic information, not so much the collecting of information, that's with the patient's consent, but it's the information that you find when you're doing that and whether the patient wants to know.
KAVALIER
Yes well I think before people start having these tests they have to think long and hard - do I want to know the answers because...
PORTER
And not just for the questions that are being asked.
KAVALIER
No, no, it's a partnership between the doctor, who's taking the blood, and the patient, who's giving the blood, and the patient really needs to know the ins and the outs of what this might mean.
PORTER
How popular do you think general screening might be? If I came up, for instance, with a test tomorrow that could test the British public for their predisposition to the hundred most common diseases in the UK, how many people do you think would come forward, do you think it would be popular?
KAVALIER
I don't think it would be popular. First of all it's going to be very expensive, although it'll get cheaper as time goes by. Secondly, I think it's going to be a very poor predictor of what really happens. If I tell you, for example, you're likely to get lung cancer but you're not a smoker then the test is probably wrong. So lots of the information that these tests give will not actually tell us what's going to happen.
PORTER
Going back to the way that we're using genetic testing at the moment in your day-to-day work - advising people who are worried that they might have a genetic problem, presumably because they've got a family history of it and I think that's something we haven't really mentioned - how important family history is, that's our main screen at the moment isn't it.
KAVALIER
Yes if you ask about someone's family history well sometimes genetic diseases pop out of the blue but quite often they're there in the background in the family and taking a careful family history - thinking about aunts, uncles, grandparents, cousins - often will give you good clues as to whether you're at risk of something genetic.
PORTER
Well let's take a common problem like thalassaemia or sickle cell anaemia - if somebody has cases of that in their family and there were worried - the implications for them when they started their own family how would they get to see somebody like you for advise?
KAVALIER
Mostly these things are pretty simple to get to the bottom of - things like thalassaemia and sickle cell, for example. They can go to their GPs, the GP may be able to sort that kind of thing out straightaway with a simple blood test. All GPs have access to local genetic centres which are organised around the country and the referral is easy.
PORTER
Well we're out of time, Dr Fred Kavalier, thank you very much. For useful contacts and addresses do check out the website, that's bbb.co.uk/radio4.
Next week's programme is all about heart attacks - I'll be finding out the latest on preventing heart disease using cholesterol lowering drugs - which are soon to be available without prescription. Why clot busting drugs mean time really is a matter of life and death in the modern management of a heart attack. And I'll be putting my own resuscitation skills under the spotlight.
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