Dunedin-born, London-based neurologist Christopher Shaw runs a clinic for patients with motor neurone disease, who, since there’s no cure, typically die within two years of diagnosis.
Shaw wants to experiment with gene therapy to mute their malfunctioning genes and extend their lives. He is about to launch a start-up to fund clinical trials – putting him in competition with one of the biggest, most chequered names in gene therapy, the University of Pennsylvania’s James Wilson.
Shaw was in Auckland last week to celebrate winning the 2019 Kea World Class New Zealander award. He spoke to Eloise Gibson about brain science, learning on the job at Whangarei Hospital, and the time he accidentally prompted the tabloid headline “FrankenBunny”.
[This interview has been condensed].
Newsroom: Congratulations on the award. You’re from Otago, right?
Chris Shaw: I was born in Dunedin and we lived the first six years of my life there, then we went to the States. My father was biochemist and he was a lecturer at Tufts (University, in Massachusetts). My mother brought her three boys back to New Zealand and we left him behind.
NR: Was he bad news?
CS: He was at the time, but he mellowed later in life and he wasn’t all bad.
I went to Otago medical school and I went up to Whangarei for my first year as a junior doctor. It was a very small hospital and the junior doctors were thrown immediately into what would now be done by very senior registrars or consultants. Some people freaked out and couldn’t do it because they were so frightened of the consequences but I was one of those people that loved it, I just strode in, read a bit about it and then would go in and do it. Fortunately, nobody died at my hand.
NR: How did you choose neurology?
CS: At the time, there were no treatments for most neurological disorders. There are still no treatments for most neurological disorders.
At the time, foolishly, I thought we were on the cusp of some extraordinary breakthroughs and that I would like to try to contribute to that.
NR: Has it panned out that way?
CS: Absolutely. It’s been moving so fast that it’s actually very hard to keep up, as has genetics.
NR: Did you foresee that you’d end up chasing genes?
CS: No. I started out working on multiple sclerosis. I wrote some papers and got them published and then I got a fellowship to Cambridge University. I was working there in a multiple sclerosis laboratory and I met this patient who had developed the early symptoms of motor neurone disease.
She described how she had spent all her life waiting for this to happen, because she had seen her mother die of it and she had an aunt and uncle who’d also died of it. So every time she tripped on the pavement or had trouble opening a door she’d think that was the beginning. And then of course it did happen.
And I thought, this is a terrible disease. At least most people don’t know how bad it’s going to get. She knows exactly how bad it’s going to get. And she knows she may well have passed this on to her children.
Then I saw another patient about a month later with a similar story, and they both turned out to have a mutation on a gene that been discovered the year before called SOD1.
I contacted the head of a research group in London and sent him DNA and in the end I collected some of the brain and spinal cord of one of these patients and we worked out the pathology.
I had a fellowship to come back to in New Zealand but it didn’t go very well because the head of clinical service wasn’t very interested in me coming. So I went back to London and this chap at Kings College said, “Would you like a job here?”. I’m still there 25 years later.
NR: You run a clinic at Kings College for motor neurone patients. It must be worse than being an oncologist, because, unlike cancer, you’ve got nothing to offer in terms of a cure…
CS: You’re seeing them waste away and die.
NR: How do you deal with it?
CS: I don’t know.
I thought it would get easier over time and it hasn’t, because the people seem to get younger and younger and I’m now seeing the children of people I looked after before come in for diagnosis and to die.
It’s one of the reasons I’ve thrown my lot in to try and do gene therapy, because I’ve lost faith in traditional pharma. I don’t believe there will be a revolution (from traditional pharmaceuticals) for this, but there is a revolution in gene therapy and it will be astonishing.
Ed: In 1999, gene therapy was almost derailed when a teenager, Jesse Gelsinger, died in a gene therapy trial at the University of Pennsylvania. The trial’s director James Wilson and others later determined the boy died after a severe immune reaction to the virus used to deliver the therapy, an adenovirus. Journalists and the FDA found troubling ethical lapses in how the trial was run, and the university paid Gelsinger’s family an undisclosed settlement. Wilson came back from infamy and today runs the university’s gene therapy programme.
NR: So you arrived at Kings College in 1995 and Jesse Gelsinger died in 1999. That wasn’t an auspicious start for gene therapy. What’s happened since, is there still a live risk?
CS: The risk is still there.
And Jim Wilson is still there.
Jim Wilson approached me, about four years ago, to start working on gene therapy for ALS (Amyotrophic lateral sclerosis, the most common form of motor neurone disease).
I understood we were set up to collaborate on the preclinical work with him but it didn’t work out. We parted ways and then he launched a company [start-up Passage Bio] with $115m Series A funding to develop some of the same therapies that we were going to do together. So that was a bit of a blow.
We just decided to compete with him. Obviously his is a bigger organisation. But we are smart and we are going to do things differently to him.
NR: But you would have been willing to work with him?
CS: Absolutely. He’s one of the best in the business.
NR: Jesse’s case was so tragic because he had a metabolic disorder, but he was not a terminal case until he went in the trial. Your patients…
CS: Are dying. Yes.
NR: So you’ll be trying to ensure your set-up is safe, but you’ll also have these patients who are saying please, please can you move quicker?
CS: They are a vulnerable population. And you need to be very careful not to exploit that. I am not going to be running the trials myself, using the drugs we’ve developed. I will outsource that to colleagues. Because obviously I’m trying to set up a spinoff company and there are commercial (conflict of interest) concerns with that.
I’m only doing it (starting the company) because it’s taken me an inordinate amount of time to raise the funds from philanthropic sources to even start to get the pre-clinical work done. We’ve raised $3.5million over two years to build the gene therapy team and we need $50 million. So at the moment I’m pitching to industry to get that investment.
NR: These are going to be expensive drugs then.
CS: That is partly true. There will be economies of scale that will transform the field and that will happen as we’re doing our trials.
NR: Motor neurone is a very sympathetic disease, and it seems to attract donations. You were the scientific adviser for a documentary [2013’s I Am Breathing], about the last months of sufferer Neil Platt] that was used to raise money for research. You’ve got all these donations flowing in, and in some cases they are from families who are fundraising because they want particular things done. How do you navigate that minefield?
CS: I don’t see it as a minefield. In all the time that I’ve been working in the field I’ve told people, ‘Nothing I do will help you. But what it might do is help other people, or help your children’.
Now, when we’re trying to do fundraising, we have a shorter timeline, but it’s still four-to-five years away and most of my patients will not be alive. And they know that. They are fundraising for the next generation.
It’s incredibly altruistic, these people in every trial. We’ve done 30 trials and only one (drug) has been successful, so that’s 300 or 400 patients who have gone into trials, none of whom have benefited. The challenge of coming to hospital every time, having blood taken, going into scanners…
NR: It must be exhausting, when you’re terminally ill.
CS: Very hard, and they’re getting more and more disabled. People are incredibly generous but it is their way of sticking two fingers up to the disease.
NR: Backtracking a bit, you were once involved in the second-ever trial to get approval to clone human embryos. Did your genetic discoveries about motor neurone disease come out of that?
CS: No. Nothing good came out of that.
NR: Bugger.
CS: Yeah, it all blew up in our faces. So we had a licence – actually, the first licence in the UK – to use human embryos to do nucleus transfer. It wasn’t me, it was Ian Wilmut.
NR: The guy who cloned Dolly the Sheep?
CS: Yeah, and he’s a remarkable man. I was just the vehicle for getting patient cells and we set up a collaboration with Woo Suk Hwang in South Korea, and we went over to visit him several times and we were greatly feted and driven round and we saw his extraordinary laboratories and his extraordinary science and then of course [it] was shown to be a fraud.
Ed: In 2006, a mammoth fraud investigation concluded Hwang had never cloned a human embryo as he’d claimed, though he had cloned his pet dog, Snuppy. The fallout dealt a serious blow to both Hwang’s reputation and the public’s trust in using embryo cloning for research.
NR: Oh! I read a big article about it but didn’t know you were involved.
CS: This was a bit of a crisis. It wasn’t our trial, and no cells were sent there, but it was a good place to start. The idea was just to make stem cells, that you could then turn to neurones and discover what was causing the disease. This was before (cell) re-programming really came of age (replacing embryo cloning).
People said “this is bad, stem cell research is bad”, and the Labour government brought in a white paper to shut down stem cell research in the UK And there was a big movement in the US that no federal funds were to be used for stem cell research at all.
I held a press conference to try to say, “Hey guys, it’s not that bad”, and I made a journalistic error, of not seeing the implications of what I’d said.
Because Hwang had been taking eggs from women in his laboratory, persuading them to undergo egg retrieval, so there were many layers of ethical corruption.
NR: What did you mis-speak about?
CS: I came back and said “Stem cell research isn’t bad, there are other options, obviously we can use cow eggs and rabbit eggs and there’s a wonderful woman in China who’s been doing this successfully and putting the nucleus of a human cell into a cow….”
NR: You got cow-human headlines?
CS: Exactly. The famous Sun headline was Mootant. FrankenBunny. There were others. It all exploded in my face and Ian (Wilmut) was very crafty because he kept a very low profile.
Ed: An academic article on the media reaction at the time says the Sun newspaper also ran a mock-up of ‘Simon Cow-ell’, a picture of the music producer holding a glass of champagne with a cow’s head superimposed over his own.
NR: He’d probably had enough of the media after Dolly.
CS: He was pretty roasted. There were lots of journalists he wouldn’t speak to, and he’s quite a curmudgeonly character anyway, although he’s a lovely guy, I actually adore him.
So then we had to suddenly try and turn the story around. I worked with the Science Media Centre in London…and basically choreographed a whole lot of interviews and TV and I went to Parliament and I met all sorts of committees to try to say “What we want to do is quite safe and these are the reasons we want to do it”. We got some public polling, we held some public meetings and I did lots of interviews and actually the legislation that came in was quite pro-stem cell research.
NR: But did it ultimately lead to your genetic discoveries?
CS: No. That was my circus. I got absolutely nothing out of it.
NR: But you assisted…
CS: Other people, yeah. One of my friends was on a treadmill in Los Angeles and I appeared on CNN and she fell off. It was quite a traumatic time and I was very pleased to drop all that and take a break from media.
And then Yamanaka saved us.
Ed: Shinya Yamanaka, a Japanese Nobel Prize-winning stem cell researcher, discovered that mature cells can be re-programmed, avoiding the need to clone human embryos for most medical research.
NR: Let’s talk about the search for a cure. You’ve found several genes that are linked to motor neurone disease.
CS: I think we’ve been either the first group or part of a collaboration in about 12 different ALS/motor neurone genes, which is about half of all the genes we know of.
NR: How much of the iceberg is that, do you think, out of all the genes involved in the disease?
CS: In families, we can identify the gene defect in about 70 percent of families now, and the same genes are present in 10-15 percent of people with sporadic disease as well, even though they have no family history whatsoever.
NR: So there’s still a large proportion of people for whom you don’t know the cause?
CS: Oh yes. We have a couple more genes we’re trying to track down at the moment.
NR: Tell me about the gene therapy you want to trial.
CS: We have produced mice with ALS that are used in laboratories around the world.
I thought, what do you do when you discover a gene, you knock it down (in a mouse) and see what happens when it’s missing, and when you find a mutant gene you express the mutant gene to see what it’s doing that’s behaving badly.
And gene therapy is pretty much doing that. It’s a bit more sophisticated, you have to deliver it to the right cells at the right time at the right dose, but that is pretty much the story – knocking it down or supplementing genes that are inefficient.
NR: So you’re getting a virus – AAV – and using it to manipulate these genes?
CS: There are some very specific genes, one that causes front temporal lobe dementia and we’re trying to bump that up [so it works better].
That’s our first target, and we’re trying to raise the money to put it in sheep.
Then we hope to start trials in patients with front temporal dementia. But I think there’s also a good case to use it for motor neurone. My friends in Belgium have taken an ALS (motor neurone) mouse and crossed it with a mouse that was over-expressing (the protein deficient in those with the faulty gene) and the mouse lived twice as long. The disease onset is unchanged, but they live longer. And that’s important, because our patients don’t have a choice about when they get diagnosed, we can’t start treating them two years before they know they have it. This could double the lifespan of mice, who knows what it could do in man.
NR: You’re trying to knock out genes that are doing unhelpful things?
CS: Yes. It’s trying to prevent the mutant protein being made so it doesn’t mis-fold and aggregate.
NR: Are you kind of un-clogging the neurones?
CS: Yes, obviously [a patient] has been making these mis-folded proteins for most of their life but your ability to clear them fails as we age, and our [brain’s] housekeeping abilities fade.
If you decrease the load for the housekeeping so there’s less mud around – for instance, your children leave home and they don’t make so much mess – you can get on top of it. And there’s pretty good evidence from mice that if you switch a mutant gene off there are a lot of cells that are not functioning but are still alive that come back to life, and that’s why motor function can improve in these mice. You’re bringing surviving motor neurones back into proper function.
NR: When do you hope to start clinical trials?
CS: 2021.
NR: What’s the company called?
CS: NeuroGeneus. Gene like G.E.N.E.
NR: Uh. Wow.
CS: I know. The company doesn’t exist at the moment. We’re in the process of negotiating with some big pharma and some biotech VCs to raise significant Series A funding, because it’s all about speed and momentum. We’ve got some serious commitment from serious players.
And we’re already running gene therapy trials with AAV (for other researchers).
NR: So my impression that gene therapy had gone quiet or halted was completely wrong?
CS: Yes, there are lots of trials. Sorry! The field has been bubbling along but there’s a real acceleration. It will change, and people will do things wrong, and hopefully nobody will die, but mistakes will be made. We are just going to be very certain that we’ve done everything right.
NR: You said earlier, before we got started, that you think more people will die in gene therapy trials, though obviously you’ll be trying to ensure it doesn’t happen in one of yours.
CS: Yes, and it’s going to be difficult. Yes, but that’s true for cancer, it’s true for every therapy that’s out there, even some of the multiple sclerosis drugs. Antibiotics killed people.
NR: Hopefully you will end up with this step-change in treatment you envisaged way back when you picked neurology.
CS: I do feel this is the last part of my career.
But it would be really nice to bring a therapy to some of the families, who’ve donated their DNA, their skin, their spinal fluid and sometimes their brains to make a difference. That we would then be able to turn around and say “yeah we nailed that gene and you helped us find it. And now we’ve dealt with it”.
