by Kirk, Edwin;
Other such scores have been less successful, so far at least. A group from Germany and the UK used data from the UK Biobank including 306,473 people aged 40–73 to develop a risk score for stroke. They succeeded: using their model, the people in the top third for risk had a 35 per cent higher risk for stroke than those in the bottom third. That sounds pretty good — until you consider that they also found that by asking four simple questions about lifestyle factors, they could do rather better: people who had zero or one healthy lifestyle factors20 had a 66 per cent higher risk of stroke than those with three or four. In even worse news for the risk score, the lifestyle benefits applied to everyone equally, regardless of their genetic profile. Conclusion: it’s best to just advise everyone to lead a healthy lifestyle. The genetic test, based on superb underlying data and being scientifically as robust as you could hope for … doesn’t add a great deal to decision-making about how to live your life in order to reduce the chance of stroke.
[20 We’re not talking about needing to be a vegan triathlete here. The factors they considered were: no current smoking, healthy diet, body mass index < 30, and moderate physical activity two or more times weekly. If you’re a (current) non-smoker and not obese, your score is two already.]
That doesn’t mean that scores like this won’t be used by someone — if not for medical reasons, then to make money. There are a variety of companies that will test your DNA and give you detailed advice about lifestyle and diet based on the results. If you come from the same genetic background as the people who were studied to develop the scores (i.e. mostly European), the results might even be scientifically valid, more or less. They just aren’t terribly meaningful for an individual. Before you pay for such a test, consider that there is really no prospect of receiving a report that says, ‘It’s fine for you to smoke, avoid exercise, and eat a diet that’s full of sugar and saturated fats and low on vegetables.’ A test result that says your body might not tolerate alcohol very well is not nearly as definitive as having a few drinks to see what happens21 … and so on.
[21 In the name of science, of course.]
A possible exception to the ‘this stuff isn’t all that useful’ rule is testing to see how well your body handles medications. There are quite a few genes involved in the metabolism of drugs, and these vary between people — some of us make a version of an enzyme that works only sluggishly and struggles to keep up, whereas others have a highly efficient version that works particularly well. Knowing about these genes might be important. For example, if your body processes a drug fast, you’ll probably need a higher dose than other people, or you’ll never have enough of that drug in your body to do you any good. On the other hand, if you’re a slow metaboliser, the drug might build up in your body and poison you, so you need a lower dose than usual. Most of us either don’t have these variations, or won’t ever need the medications for which this matters — but without either having a test or suffering the consequences, there’s no way of knowing.
Most of the companies that offer to test your DNA for complex conditions confine themselves to telling you your granny probably came from Eastern Europe,22 and that you should eat more fruit and vegetables. At worst, some of them will also suggest you might benefit from specific dietary supplements … that, by sheer coincidence, they are in a position to sell you. Mostly, though, as long as you don’t take it too seriously, this kind of ‘recreational genomics’ is relatively harmless, and might even be helpful. If being told that you have a higher than average chance of developing type 2 diabetes leads you to eat better and do more exercise, that can only be a good thing.
[22 If she’s around, you could also find this out by asking her. But if there are gaps in the information available to you, this kind of testing is getting really quite good, although it’s better for some populations than others. It will be no surprise to you at this point to learn that being of mainly European ancestry is an advantage, in terms of the likely detail and accuracy of the test results.]
There’s always someone willing to take things further, of course. Stephen Hsu is one such person. Hsu started out as a theoretical physicist, and is evidently very good at it — he is Professor of Physics at Michigan State University. Unusually for a physicist, he has branched out into genetics. Hsu hasn’t confined himself to studying height or heart disease — he has a keen interest in the genetics of intelligence, and, as we saw earlier in this chapter, has done some work looking for genetic variation that might predict intelligence. He is co-founder of a company called Genomic Prediction, which offers pre-implantation genetic testing with a difference.
As we saw in chapters 6 and 8, PGT has so far been used for situations where the outcome is very clearly defined — mainly in selecting an embryo that does not have particular genetic conditions that are known to be in the family, or chromosomal abnormalities. Genomic Prediction offers this type of single-gene and chromosomal testing, like many other companies. Unlike anyone else, they also offer testing for polygenic risk scores. Specifically, they’ll test your embryos and provide a risk score for diabetes (insulin-dependent and non-insulin-dependent), heart attack, high blood pressure and high cholesterol, various types of cancer, and short stature. There have been questions raised about how reliably they can assess risks for most of these. The published research on which the test apparently rests reports an ‘area under the curve’, a measure of test accuracy, for these conditions that sits in a range of 0.58–0.71. On this scale, a score of 1 would be a perfectly accurate test, and 0.5 a coin toss. A score in the range of 0.6–0.7 is definitely better than a coin toss, but not so good that it would be very surprising if an individual who was scored as being likely to have a heart attack didn’t, and vice versa.
Set that technical question aside for a moment, however, and let’s assume the test is very good at making these predictions. Is this useful information? If you were choosing between two embryos, equal in all other respects, but one was likely to have a heart attack some time during her life … is that really a basis for making that choice?
To put that into some kind of context, one in three people23 over the age of 45 has high blood pressure. One in 11 over the age of 45 has diabetes. Two in five have high cholesterol. Thyroid problems are less common — perhaps one in 200 people, mainly women, is on treatment for thyroid-hormone deficiency. Heart attack and stroke cause about a quarter of all deaths. Half of us will develop cancer at some time in our lives, and three in ten will die of cancer.
[23 These are Australian numbers, but figures are similar in other developed countries. In the developing world, other causes of death, including malnutrition and infectious diseases, are more common, reducing the proportion of deaths from vascular disease and cancer, and nutritional differences make diabetes and high cholesterol proportionally less common.]
So, you’re sitting in a clinic room and your fertility specialist has presented you with the results of the PGT on the four embryos from your latest cycle of IVF. Two of the embryos have major chromosomal abnormalities that would likely mean that those embryos would be miscarried if they were implanted. If not, and they somehow made it to full term and were born alive, they would be expected to have severe disabilities and short lives. Most people in this situation would think it best not to choose those embryos.
At the other end of the spectrum, though, the report says that one of the remaining two embryos is likely (not certain) to have high blood pressure, and the other, high cholesterol. Both of these are treatable problems that affect a large proportion of the population. Is this really useful information in considering whether to implant an embryo? Think about all the things this result doesn’t tell you about this baby. A third of all great artists will develop high blood pressure.24 Forty per cent of all great scientists will have high cholesterol. Thyroid disease, although fairly common, isn’t in the same league as those others. But it’s very easy to treat. A tablet once a day, a blood test now and then to check the
treatment is working as it should. Not a huge burden.
[24 Perhaps I should declare at this point that I am on treatment for high blood pressure that needed a combination of two different drugs to bring it under control. I may not be an entirely neutral observer in this instance.]
Okay, but heart attacks are bad news, right? So maybe that would be a different kind of result?
Well … maybe. Remember that, already, there are things your potential child could do about their risk of heart attack. This genetic profile represents only one set of inputs into the overall risk, which will be modified by lifestyle — choosing not to smoke, eating well, exercising — and also medical interventions. At present, the latter are mainly limited to keeping an eye on blood pressure and cholesterol (and other blood lipids) and using treatments to bring them into the healthy range if needed. It’s quite possible that there will be other options available long before today’s embryo becomes a 45-year-old with a heart attack.
Nonetheless, you might take the view that it’s best for your child not to have to worry about all this stuff, or at least not more than most people. You might feel the same way about a risk of cancer, too. Mind you, if you add cancer to heart disease, you’re talking about more than half of all deaths. If this test were a perfect predictor of possible serious health problems, you may not have that many embryos left to choose from. Is there someone in your family who has had one of these problems? Do you think it would have been better, for them and for the world, if your grandmother who had colon cancer, your father who has heart disease, or your cousin with diabetes had never been born?
Of course, there is a counter argument to this. Imagine you have two embryos and must choose one. One has a high risk of stroke, the other does not. Otherwise, the two score about the same for the various risks covered by the test. Either might turn out to be a wonderful person, gifted in some way, a boon to humanity. Or, perhaps, either might live a perfectly ordinary life but be happy, loving, and loved. Either might have a terrible health problem — say, severe psychiatric disease — not covered by the test that’s available to you. With your lack of knowledge of everything else about this potential person, why not choose the one that is unlikely to have a stroke? Perhaps, in 65 years, that person will be starting a long and happy retirement, whereas the other would have just suffered a devastating stroke, permanently losing the ability to speak and to use one side of her body; her retirement would be spent dependent, in a nursing home. You may be long dead by then, but at least you had the chance to watch your child growing into adulthood without worrying about that particular future event. Worth it? Do you want to have this test?
It’s possible to push things still further. Genomic Prediction make it very clear that they do not test for intelligence. But what if a similar company could tell you which embryo was likely to be the smartest? What if they could test for homosexuality? There is good evidence that, although there isn’t a ‘gay gene’, there is a strong genetic basis to sexual orientation, and it’s complex — like height, and blood cholesterol, and high blood pressure. There’s every reason to think that one day it might be possible to score embryos for ‘likelihood to be gay’. If you could test your embryos for this, would you? Should you?
The balance between what we can do in medicine, what it is useful to do, and what we should do is not an easy one to manage. There are lots of ways we get it wrong. It seems to me that even a perfect test for common, more-or-less treatable conditions is likely to do more harm than good, for most people. It also seems to me that, based on what we know about it, this particular test is too far from perfect to make it an attractive proposition just yet, even if you think the concept is good. But there is room for the test to improve … and we’d better decide what we think about it, because this particular genie is already well and truly out of its bottle.
Speaking of mythical creatures: there’s magic of another kind, just around the corner.
10
A spoonful of mannose-6-phosphate
Physicians of the Utmost Fame
Were called at once; but when they came
They answered, as they took their Fees,
‘There is no Cure for this Disease.’
HILAIRE BELLOC
Jesse Gelsinger died on 17 September 1999, just a few months after his 18th birthday. Gelsinger had a rare genetic condition that affected his body’s ability to safely dispose of excess nitrogen. He had been a volunteer in a clinical trial that aimed to see whether a virus, which had been modified to carry a normal version of a gene called OTC into the cells of the liver, could safely be given to humans. Sadly, the answer was that it could not — Gelsinger’s body reacted in an unexpected and extreme way. Over the course of four days, his organs progressively failed, and, despite all efforts, he could not be saved.
The clinical trial in question was one of the early attempts to perform gene therapy — a treatment designed to directly replace a gene that is faulty or missing, by inserting a working copy into the DNA of the person affected by the condition. There are formidable technical challenges that stand in the way of gene therapy, and there were some known risks from trying it. But nobody had really thought that a research subject might die in this way. Jesse Gelsinger’s death was a shock to the whole field, and it seemed to many of us in genetics that the very idea of gene therapy might have died with him.
*
At the public announcement of the completion of the Human Genome Project in 2000, both US president Bill Clinton and British prime minister Tony Blair spoke of the ideal that our new understanding of the genome would lead directly to treatments for medical conditions. Both mentioned cancer; Blair also referred to the treatment of hereditary diseases. Over the years that have followed, there has been quite a bit of criticism of the field’s failure to produce cures — a recent newspaper article asked, ‘Was the Human Genome Project a Dud?’, and concluded that yes, it was. Fortunately, this is far from the truth — as we’ve seen, the HGP has unquestionably delivered for people affected by genetic conditions and their families, in all sorts of ways. Treatments for cancers have, in fact, been developed based on knowledge gained from the HGP. By sequencing the genome of a cancer and comparing it with the genome of the same person’s healthy tissues, it is increasingly possible to recognise the specific genetic damage that has driven the development of the cancer. There are many treatments — existing and in development — that work directly to counteract the effects of those changes.
But as for cures for genetic conditions … well, that was always asking for a lot.
The reason it’s hard to cure a genetic condition is that the problem lies so deep within. The cell nucleus is a walled fortress, protected against changes for the very reason that change is dangerous; damage to DNA can kill cells, and those that survive risk becoming cancerous. The idea of gene therapy is generally to replace something that’s missing, but, for many genetic conditions, ‘something missing’ isn’t the problem. Sometimes, the faulty gene is overactive, so the problem is too much rather than too little. Sometimes, the faulty gene causes the cell to make a toxic substance, such as an abnormal protein that builds up inside the cell and poisons it. And sometimes, even if the problem is ‘something missing’, it’s in the form of ‘something missing at a particular time’, such as in the early weeks after conception. If that’s the case, replacing the gene in an adult, or even in a newborn baby, may mean that you are acting far too late to make a difference.
Even if you can get a working copy of a faulty gene inside the nucleus, and then get it inserted into the cell’s genome, and then get it to turn on and function normally — there are risks. It’s hard to control where the new DNA goes; if you’re unlucky, it might wind up somewhere you don’t want it, and cause other problems. Most gene therapy relies on using a modified virus, since there are some types of virus that have already solved the problem of getting their DNA into the cell’s nucleus — that�
��s part of how they hijack the cell’s machinery to make new viruses. But that means you have to engineer the virus in a way that stops it doing harm, without stopping it from doing the job you need it to do.
So, long before there were successful gene therapies — and as we shall see, there are finally some successful gene therapies — people turned to other approaches to try to treat genetic disease. For instance: if it’s hard to change the DNA inside a cell, why not swap out the cell itself, replacing it with a healthy cell?
*
I know it’s just coincidence. Still, sometimes I see several people with the same very rare condition in a short period of time, and it feels like there must be something in the water — or like the world is out to get me. In the space of a six-week period, I once saw two children whose families were presented with a deadly dilemma.
Both boys were toddlers, and their stories were strikingly similar. A series of seemingly minor problems had led them to see a range of health professionals. They had both needed hernia repairs. They had frequent colds, chest infections, and ear infections. After they turned one, they were slow to learn to walk, which eventually led to them seeing paediatricians. Each of those paediatricians ordered a screening test on urine, and that led to a devastating diagnosis.
Ethan and Angelo both had Hurler syndrome, a condition that affects the lysosome. If mitochondria are the cell’s powerplants, the lysosomes are its recycling centres — structures that contain a set of enzymes that break down materials in the cell that have passed their use-by date. There are 40-odd different enzymes inside the lysosome, each with a different recycling task. One might recycle the aluminium cans of the cell, another its scrap paper, and so on. If you’re born with a deficiency of the paper recycler, loads of used paper are still being delivered to the lysosome by the cell, but nothing happens to it; there’s nowhere for it to go, and it can’t be processed. If you put a tissue sample from someone in this situation under the electron microscope, you can see the lysosomes transformed from small balls, scattered through the cell, into large blobs that grow over time until they can fill the cell completely.