Genome Medicine

Bioinformatician Tim Hubbard on the ‘100,000 Genomes Project’, how to use genome data in diagnostics and treatment and what challenges the genome medicine is facing

videos | April 2, 2020

Genome medicine, the use of a whole genome of an individual in medical care, that was kind of a dream for many years. When we sequenced the human genome, it cost maybe three billion dollars: a very large amount of money, and it was actually impractical to sequence more than a few individuals. For many years we only sequenced other species like mouse or zebrafish which were important for doing investigation of models of human. But in around 2006 a new technology of sequencing came along, and it became clear that the price could drop dramatically and the time for sequencing a genome could drop as well. So now we’re at the point where a whole genome costs less than a thousand dollars and can take only around one day on one machine. So suddenly you go from a single genome to the ability to collect genomes around individuals at a price which fits with the kind of tests that you do in a healthcare system.

In the UK around 2009 the government, the House of Lords published a report on genomics in the Health Service and advised the government to start exploring whether this technology could be used to improve healthcare. In a couple of years there was a report from inside the government and this led to the ‘100,000 Genomes Project’ which was launched in 2012. An organization called Genomics England was created in 2013 to deliver that.

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So what does this really mean? What can you do with a whole genome in a health system? One thing you can’t do, we don’t really understand enough about a genome to be able to predict your future. It’s just not reliable at all. But if we know you’re ill with certain conditions, at the moment what happens inside the health system in the UK, if there’s a suspicion you have a genetic disease, there might be some individual tests that are carried out: we’ve had those for a number of years, sort of national structure of around 800 tests of individual genes. But if you don’t get a diagnosis from that (and the diagnostic rate from that is around 15-20%) then if you sequence the whole genome you can go and look for where there might be a problem across the rest of the genome. Now it’s cheap enough to do that. That becomes practical to integrate into a health system, and that’s what’s been happening over the last five years in the ‘100,000 Genomes Project’. For rare diseases, you compare the genomes of a person who is ill with their parents, and if they have a cancer, you compare the genome of the cancer with the normal genome.

From those individual analyses you can generate a report which can go back into the clinical system and guide doctors in terms of what drugs might be most appropriate. Or, in the case of a rare disease, really in many cases those patients have been investigated in the health system for many many years without a clear idea of exactly what’s wrong with them.

If you do sequence a whole genome you may get a very precise diagnostic of exactly what’s wrong, exactly which gene has been affected, and in some cases that may suggest a treatment which you as a doctor hadn’t considered at all.

For example, there is a girl who had seizures at age four and it wasn’t understood what was wrong. Then it turned out to be a gene that’s involved in glucose being transported into the brain: that means it’s not a brain defect, it’s an energy problem and she could be switched to a different diet where glucose is not what’s being transported. She hasn’t been cured but her condition has improved as a result of having better energy to the brain. So those are kind of unexpected results you get from when you didn’t have a diagnostics as a doctor and you end up with a precise molecular diagnosis about what’s wrong.

This project now is five years old, and it’s met its target of sequencing a hundred thousand genomes. Because of the statistics we’ve gathered around how this has helped in general, it’s been decided that the health service will start sequencing genomes forever in the health system as part of normal care, because before it was a special project to just essentially test if this will be a useful way of proceeding. So now we’re going to have what’s called the ‘genome medicine service’ across the UK. Here it goes in Hospital in Kings, they’re actually be the leading laboratory, one of the seven genome laboratory hubs, and this means in future people with rare disease and cancer will have the option of a whole genome deciphered clinically if that’s the most appropriate way of looking at to treat them.

Of course, the big advantage of a human genome is the genome doesn’t change during your lifetime, so you only have to sequence it once, and then you can go back and look at it for different conditions. So at the moment, we’re only sequencing people who are ill, but if you’ve got that genome, because you were ill once, if you come back with a different condition, we might look at that genome again for the other condition, we don’t have to sequence it again. That will probably become the general approach for using genome data.

There are other things we can do as well: for example, pharmacogenomics, about which is the best drug for you if you have a particular illness. At the moment there’s not much testing done: normally the doctor will give you the first drug and if it doesn’t work, they’ll give you another drug, and they’ll keep trying. But by looking at your genome you may be able to work out which is the best drug and which is the right dose for you immediately.

So we can probably improve healthcare by using genomics in a more systematic way. The next phase of this project in the genome medicine service is to sequence 500,000 human patients in the NHS over the next five years and with a possibility of sequencing 5 million over the next 5 years.

I’m part of Genomics England part-time from Kings, and I’ve been involved in setting up the project throughout the whole five years. There’s a side where the genomes are used directly to feed back to a patient, but one of the particular points about this is to try and also hold that data for research purposes. We’re not distributing the data because of privacy of the individual: we must keep patients confident that their data is being protected. But we can set things up so that researchers can come and work inside a secure computer environment and do analysis and help improve the treatments of the individuals as well because we don’t understand every individual. For some of those individuals, researchers looking at their genome will help interpret and find a better explanation of what’s wrong with them. This research side is part of the activity.

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Our understanding in genome medicine is basically very limited: we can’t predict what’s going to be wrong with you, we can’t even predict something like breast cancer very reliably. We know that one of the main risks are the BRCA1 or BRCA2 genes, but actually, we understand too little even about those two genes. And it’s only useful to test them if you have a family history of breast cancer: then it’s useful to test those genes, but if you don’t have a family history, it’s not reliable, it’s not predictive enough for a health system. So we would like to get better at interpretation, we’d like to get better at being able to run computer programs and interpret the differences in a person’s genome. At the moment we’re very very limited at that.

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Professor of Bioinformatics, King's College London
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