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Dead Famous DNA - Q&A with Dr Stephen Kingsmore
Category: News ReleaseWhat does your job entail?
It’s a new way of practicing medicine which uses genome information as part of a doctor’s routine workup. Up until now doctors have practiced medicine, blinded to the information in the human genome. Our fundamental change is to have that information at the physician’s fingertips. When he/she sees an individual patient who has a problem, that information is available to him/her to help guide his approach to that patient.
How were you approached to appear on the series, and what were you asked to do?
There are several of us who are – I’m not sure what you’d call us – but we love to tinker with new technology. I have a friend, Professor Stefan Schuster (Professor of Biochemistry and Molecular Biology, Pennyslvania State University) who is kind of legendary for the weird stuff he does with genomes. He called us up because he had been decoding these dead famous folk, and he really wanted some people who could apply the medical overlay to what he was finding. So he got in contact with us, and of course, who’s going to say no to such an amazing project?
What was it you were asked to do?
We were asked to take the DNA sequences, and pretend that it was a live person who we were looking at, and say what we found that would be relevant to the person’s health.
Did you know whose DNA you were apparently working on?
Yes we did. That’s a critical part of how we examine a genome. A genome in the absence of a patient and knowledge of what’s going on in that patient’s life is sort of like a map without a destination. What we’re always looking for are things in the genome that are related to the aspects of that person’s illness or family history or things like that.
How confident were you about the provenance of the sample? That you were dealing with Elvis himself?
That’s a good question. Our task was to provide an interpretation, and certainly we were students of Elvis’ medical history, to guide us in terms of what we were looking for. But it’s a very good point, this is sort of an autopsy sample, if you will, and we were pretty much dependent on others in terms of was this an authentic sample or not. One good example that I’ve been reading about in the press is about Richard III, whose remains were found in a Leicester car park. A fairly spirited debate about whether or not it is the King has taken place. That’s a very different situation for our day-to-day medical one where we have a live patient who provides a blood sample when phlebotomy is done. We have bar-coded information attached to the samples. There, the chain of custody is much clearer.
As a scientist, is it your role to be concerned about how these samples have been obtained, or is it your role just to examine what’s put in front of you?
We operate in a children’s hospital, so we always have to worry about the ethical and moral implications of what we do. So truthfully, we’re more like physicians than scientists. In the case of somebody who’s dead, their human subject’s protections have gone away, so it’s a very different case. There, it’s much more about the family, and respect for their wishes. But under the law, at least in the United States, a dead person doesn’t have rights, at least as a human being. It’s something that’s interesting from an ethical standpoint, because there isn’t much guidance.
Can you explain, as simply as possible, what the process was of the work that you carried out on the sample?
Sure. A disc drive arrives at our facility – we actually get these every week from all over the planet – that has somebody’s genome sequenced on it. And we transfer that into a small supercomputer that we have in our facility, and we take these tiny fragments of DNA sequence, and we have to turn that into a massive jigsaw puzzle where we have to figure out where in the normal human genome sequence those pieces are derived from. You fill all the jigsaw pieces in the right spots, and then you have to scan that information and say, “Where are there DNA letter-changes from what we call normal?” Having done that – and in you or I there are about 5 million letter changes from what we call a “normal” genome – in a sample such as Elvis, it’s a very different proposition, because the DNA is fragmentary, it’s not a complete sequence. Really, this is at the edges of what’s technologically possible.
Then we have to take each of the DNA code changes and apply a pipeline of steps that start to add medical information for each. Does this change a protein? If it changes a protein, is it going to be deleterious to the protein’s function? Has it ever been seen before? Is it rare? Is it common? Is there any literature about this variation? Has it been associated with a disease? So we add all of that together, and then it’s spat out into an interface where a human being can actually look at this and start to draw interpretations and conclusions.
Normally, we would then take that information into a confirmatory phase, where we would confirm it using a different method, then we would normally sign that out as a record that goes into a patient’s chart. In this case, we took the findings – we did not do confirmatory steps – and we were able to send those back to the documentary team.
What did you discover?
We discovered quite a lot of stuff. One particular finding was kind of thorny. That was a variant that is associated with a kind of cardiomyopathy. We know that Elvis had a strong family history of heart failure, and we know that he died suddenly, and at autopsy his heart was indeed thickened, which is another word for cardiomyopathy of a particular type. So this was a very good fit with Elvis’ clinical picture. There had been so much speculation about cause of death, and so much ill spoken of his lifestyle, and we had this intriguing finding that possibly Elvis actually had a medical illness, and all of the stuff about how he killed himself with his lifestyle might have been very unfair. On top of that, we had the issue that this variant could well have been passed on to some of his children, so did we have a moral obligation to suggest to them that they ought to go and see a cardiologist?
What are the potential benefits of looking at history through the prism of genetic profiling?
We deal with kids who have a medical problem. These children-patients always come to us with genomes that are largely inherited from ancestors, so in that sense, what’s gone before is very important. You and I don’t have any say in what our genome is composed of. So we’re always thinking about what went before. One of the amazing things about the human genome that we’re only finding out is that our genome isn’t entirely derived from our parents. That there are two types of genome changes that occur prior to birth – one when the lucky sperm or egg is being formed, and the second early in embryonic development, and both of these are actually quite common. So we’re having to rewrite the textbooks a bit.
Is legislation keeping up with developments, in terms of the law being up-to-date on the relevant issues?
In the US we’re very fortunate that a law was put in place called the Genetic Information Nondiscrimination Act (GINA). It’s not perfect, but GINA does mean that for 95% of situations, you can’t be discriminated against for things which are in your genome. For example, you can’t be denied healthcare coverage. Now it’s not perfect – there are loopholes. You can be denied life insurance. But in terms of employment or healthcare coverage, you cannot. There are areas that are very interesting.
Foetuses don’t have any standing under the law in the US. They do in Ireland and countries who signed the American Convention on Human Rights. The US did not, and they’re not considered human beings until the head pops out from mummy. So we have this weird disconnect, where independent human life starts at around 20 weeks after fertilization, in terms of that being a child who, were they in the outside world, would have rights and would have life. But we can now examine that foetus’ genome, and the foetus has absolutely no say in the matter, and under the law has no standing, in terms of the consequences of those findings.
We’re working in a kids’ hospital, and we’re committed to the idea of children’s healthcare, which for us starts at conception, but in general society, this is a huge omission. We just haven’t figured it out yet. In the US this is all tremendously politicised, because there are also – I wouldn’t call it equally valid, but very valid concerns about a woman’s right over her body versus a foetus’ rights over their body. It’s not easy to see how we can come up with a new set of rules as concerns a foetus’ rights over their genomic information.
What are the ethical implications of being able to discover someone’s complete genomes, both for them and their family and descendants?
It’s not an area I’m an expert about, but here in the States, whenever we get federal funding to do research related to genomes, we always have to put in an ELSI component – Ethical, Legal and Social Implications. We have a centre for Bioethics here in our hospital, and the guy in charge of that – John Lantos - deals with those issues on our behalf.
In the US we have a tapestry of opinions, with very different ideas about genome information across the country. There is no one size fits all. Each family and each individual has their own take on “am I comfortable knowing my genome? What would I like to know and not like to know? Would I let my children know? Should I ask my children’s permission have my genome interpreted.” It’s a very complex issue.