Prof Jim Lupski - Genome sequencing

Kat - Now it's time to hear more from the Genetics Society Spring Meeting. First, here's Professor Jim Lupski from Baylor College of Medicine in Houston, Texas - who was one of the team that sequenced the genome of Nobel Prize-winner James Watson. He explains how new techniques, including whole genome sequencing, are shedding light on rare genetic diseases, including one that affects him - Charcot Marie Tooth disease.

Jim - One of the examples which I talked about is the Beery twins - and the family has no problem with their name being used - where the family struggled for many years with the children having all kinds of problems related to their condition. And finally, it was the mother who read a lot in the literature and she convinced neurologists to try them on a little bit of L-dopa which you use to try to bypass the dopaminergic system when there's some abnormality there. And they were remarkably improved overnight when they got that L-dopa.

But years later, there continued to remain problems as they grew, though not as bad as before. So, there was a question whether too much of the medicine was being given, or too little of the medicine, what was going on and we went and sequenced the genome and to our surprise, they had a very rare form of this disease where in fact, they had a mutation in one of the vitamin cofactors required for that enzyme to work. But it's also required for other enzymes in a different neurotransmitter pathway.

So, when we gave them a little bit of the compound that bypassed the other serotonergic pathway, they really were improved dramatically and it really helped the family a lot. And so, I would say it's interesting because the twin girl who couldn't participate in athletics before the genome sequence and the treatment, now had become a champion runner and also, very good at the trampoline and she broke her arm on the trampoline. So, now that we were treating her, she broke her arm. Is that a physician-caused problem? I don't know.

Kat - And that's great, finding the two hits rather than just the one pathway. Do you think that that's going to be common in some of these complex diseases?

Jim - That's a very good question and as I tried to point out when we put this into the clinic, we were quite surprised to find that almost 1 in 20 individuals had two different genes where the mutations seem to be playing a role in their susceptibility to those clinical conditions they had. And that can make it look very complex and difficult for the physician to make a diagnosis based on what they observe clinically because actually, it's a mixture of two different things. So, I think that's another place where we could not have anticipated that before introducing it clinically that this would occur, but it will change our thinking a little bit.

Kat - And you've got your own personal experience of having your genome sequenced. Can you tell me a bit about that?

Jim - It was a very interesting experience because I had studied this disease, Charcot-Marie-Tooth neuropathy, and although we had found the cause of that disease and novel mutational mechanisms, after 25 years, I still didn't know what my disease was due to. So, we tried to see if genomic sequencing could find that and sure enough, we did find that. But you know, sequencing your own genome and what are the potential ramifications, that's just never been done before.

Kat - Because you could find all sorts of things in there.

Jim - Yes and we did, okay, and that's certainly when everybody's started talking about incidental findings. We found [a variation] in the literature, reported in a 9-year-old who was in a persistent vegetative state, but I didn't have a persistent vegetative state, okay. And in fact, as we investigated that further, the database was wrong. There are other incidental findings that also, the analysis misinterpreted what that was. We did not find any other cancer susceptibility or other incidental findings that had to be medically actionable. So, yeah, it was a little scary at first because we didn't know what we were going to find. But being scared won't stop you from moving forward. Look, about moving forward, we know where to focus studies of my own disease. So, we made the mutations in animal models now and we're starting to study it there.

Kat - So, I guess is there a possibility you might go from the genetic study of your own personal disease to finding a treatment in the lab for your own disease and then hopefully other people too?

Jim - Potentially, okay. In the meantime, there's a lot to be said for knowing the molecular diagnosis, both in terms of truly, that was the first time we could truly, truly say this is a recessive gene and recessive mutation. We had it there in the genome. We watched it go between parents and grandparents and the children. So, I think knowing a diagnosis in and of itself can be extremely helpful in the family. Even if the family says, "Well, I know I have the disease" or "I know I don't have it" but actually, from the clinician perspective, it could be useful also.

Kat - And just to look into the future, where do you think we'll be with gene sequencing in 10 years or even just in 5 years?

Jim - To me, it was almost a surreal experience sequencing Jim Watson's genome and then looking at the variation and sitting in a room and trying to explain to him what some of this might mean. Well of course, we didn't know what we were doing and just also to think that that man was involved here in this country in helping to elucidate the structure of DNA. And in his lifetime, he never thought somebody would be talking to him about his own genome and what the variation might be. That was 5 years ago and now, we've already heard the announcement of 100,000 genomes in the UK. With the disruptive technology, the internet, the computer, the cell phone, it's really hard to know what will happen and how fast it will happen. I do think that the information may very much empower the patient even more in their own healthcare. That's what I would hope then.

Kat - That was Professor Jim Lupski from Baylor College of Medicine.