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Chris Shaw. Photo/Clare de Lore/Listener

Top Kiwi scientist's quest to cure motor neurone disease

A cure for motor neurone disease is the holy grail of neuroscience and Chris Shaw is at the forefront of research that is bringing it closer.

Physicist Stephen Hawking, who died last year, lived with motor neurone disease (MND) for more than half a century. Not only was Hawking a scientific genius, he was also a medical freak. Few patients survive more than three years after being diagnosed with the muscle-wasting disease.

MND usually hits people over 40; most patients die within two to three years of diagnosis as swallowing, breathing and speaking become more difficult. In New Zealand, 400 people are living with the disease at any one time and, each year, 130 will die of it. There is no cure yet and, along with Parkinson’s disease, multiple sclerosis and Huntington’s disease, MND has caught the attention of some of the sharpest minds in neuroscience.

Chris Shaw has devoted his professional life to understanding the causes of, and seeking a treatment or cure for, the disease (also known as ALS – amyotrophic lateral sclerosis) and other neurodegenerative conditions. Shaw is a professor of neurology and neurogenetics at the Institute of Psychiatry, Psychology and Neuroscience at King’s College London, one of the world’s most prestigious research universities. Shaw and his wife, Pinar Bagci, an economist, have two teenage children and make frequent return visits to New Zealand where they first met and married.

Hawking at Princeton in 1979. Photo/Getty Images

One of three boys, Shaw moved with his family when he was six from Dunedin to Boston, where his father, Roger, worked as a biochemist. When his parents’ marriage ended, his mother, Helen, moved back to New Zealand with the boys and started carving out her own career in Christchurch. Helen Shaw rose through the ranks in education to become deputy director of health education for New Zealand, promoting sex and drug education in the 1970s. Chris Shaw trained in medicine and neurology in New Zealand before moving abroad and, despite the distance, remains close to his mother.

Shaw is chasing a dream for his patients – and for himself; his work is intellectually and emotionally demanding – all of whom die of the illness, most within a couple of years of coming under his care. Finally, there are breakthroughs, although Shaw is quick to point out that most people currently living with MND will not benefit. Future generations, however, can expect therapies and, possibly, a cure.

Most people know of motor neurone disease because of Stephen Hawking. Did you know him and how did he live so long?

He was, briefly, a patient in our clinic, but, really, when he came to see us, it was more that we were being interviewed by him. At Cambridge [where Shaw did his PhD], we were at the same college. We used to see him out and about on his own. He wasn’t ventilated then. He was able to operate his own wheelchair and go to the cinema and theatre. He kept progressing, but very slowly. He was an outlier’s outlier; he survived for 55 years of symptomatic disease. He had a high quality of life despite being incredibly disabled.

Shaw in his lab at King’s College London. Photo/Supplied

What’s the more usual decline?

Most patients lose a way to communicate, to touch, to care for themselves. You can’t feed yourself, you can’t wipe your bottom; there is such a loss of dignity.

You’ve said of your patients that “they give two fingers to the disease”.

Yes, and I think giving two fingers to the disease is very important for patients. If I asked them to give up a leg for me to further the research, they would offer me both. But sometimes they are also angry at us because we don’t have any really effective therapies. Sometimes you can turn that into a positive. There’s a lovely, giant Scottish rugby player, Doddie Weir, who has MND and has done a lot of fundraising. He’s also held our hands to the fire. He’s said to me, “Twenty years? What have you guys been doing?” You can start to make excuses, but actually he wants something really bold to happen.

Is that why you’ve narrowed your research?

Yes, for 10 of the past 25 years I have just focused on MND because it was getting too challenging to see so many people with this terrible disease. Every time you make a genetic diagnosis in a family, one person has the disease but many other people who are at risk have lots of worries and anxieties. Sometimes, they freak out and I’ll see them within 48 hours and give them a neurological WoF. Usually I can tell them, “It’s not there, that’s just muscle twitching and you’re fine.”

At 18, far right, with his mother, Helen, and brothers Michael and Douglas. Photo/Chris Shaw collection/Supplied

What is the familial risk of getting MND?

About 15%. If you count all the people who have got a family history, we can identify a gene defect in about 70% of those individuals who come forward. But the same genes are also present in people who have no family history at all – up to about 10-15%. More people with no family history have a gene defect that we know is causal than have a family history. And it’s because, in those families, not everybody who’s carried the gene defect actually develops the disease. We call that incomplete penetrance. So, there are lots of people very happily ignorant of the fact that they carry these potentially fatal gene defects.

What new research may benefit the next generation to be diagnosed with MND?

Because I’m also a consultant for [biotechnology companies] Biogen and AveXis, I get to go to these sort of secret meetings where they reveal unpublished data. There’s a particular gene mutation, SOD1, that’s super-aggressive. Everybody dies within 12 to 18 months, each month developing massive new disabilities. In a trial of an antisense oligonucleotide (ASO) drug targeting SOD1 involving eight people, four didn’t receive the active drug and they declined month to month, as we would predict, but the four people who had the ASO drug didn’t decline and some of them got better. There is video evidence of it.

What do you mean by “better”?

They went from not being able to walk up the garden path to walking up the garden path and walking up steps. It was incredibly moving; I had tears rolling down my cheeks. In the time since that meeting to now, two of my SOD1 patients have died because they’re not in the trial. It’s really hard, but revolutionary therapies are coming. A phase-III clinical trial is getting under way with about 60 people with the SOD1 gene mutation, so it will be a few years before this drug goes to market.

With wife Pinar Bagci outside 10 Downing St. Photo/Supplied

Even so, that’s encouraging news …

Going to market sounds wonderful – you think it’s going to be available to everybody, but these drugs are going to be extremely expensive.

Why so expensive?

The [cost of] manufacture for the ASO drug is absolutely trivial, but the drugs have been 10 or 15 years in development and the companies will have 99 failures for every one success, which people don’t really take into account. For a period, they will have patent protection, so other people can’t do a similar or identical drug. 

What was the most recent breakthrough for spinal muscular atrophy [an infantile disease of the motor neurons]?

This is a remarkable story – kids probably being cured for life from a single injection. It’s a recessive disorder, so both parents are perfectly healthy but they carry a deleted gene. The child gets two copies of the deleted gene and they don’t make any of this particular protein called, not surprisingly, the “survival of motor neuron” protein. Often, they are born a bit floppy, and then usually they never sit, crawl or stand. They often never talk because they’re ventilated before the age of acquiring speech. And they’re almost all dead by two years, unless you do ventilate them. It’s not a high quality of life, and they continue to decline over time. A colleague has been working for years to use a virus to deliver the gene that they’re missing. The motor neurons are able to soak this virus up and take on the gene. They ran a trial of 15 children, injecting them between the ages of one and seven months. Some of those kids are now running around and one of them is speaking three languages. They’ve now treated 120 kids and they don’t need to do the phase-III trial because the data is so astonishing.

And the cost?

Therein lies the rub. AveXis was bought by Novartis for US$8.7 billion [$13.7 billion]. The drug has been approved by the US Food and Drug Administration and launched at a price of US$2.1 million [$3.3 million] per injection [the most expensive drug in the world]. In the short term, the drug companies are trying to recover some of their costs but, in the longer term, these won’t be nearly as expensive; competition will drive down the cost.

Receiving a 2019 Kea World Class New Zealand Award at Auckland’s SkyCity. Photo/Chris Shaw collection/Supplied

You might have stayed in New Zealand but for a rather caustic exchange some years ago?

Yes. I came back to New Zealand and gave a lecture. Peter Gluckman was very positive and they were going to fund me with a fellowship to set up a lab. Then I went to see the head of clinical services, who’d been to my lecture, and he said, “We’re not really looking to recruit a smart-arse from Cambridge.” I didn’t want an anti-research sentiment about my work, so I took a post at King’s College in London and I have been there for 25 years.

So, you were lost to New Zealand because of tall-poppy syndrome?

Yes, but actually I’m immensely grateful to him because I would not have had the opportunities that I’ve had in the UK. I was interviewed a few years ago and I relayed that little story and the person concerned contacted me and said he felt terribly guilty.

Did he explain himself?

He said he was a bit of a prick in those days. I didn’t disagree, but I don’t resent anything. I have come back every year and spoken about my work and tried to encourage people here and I’ve employed a lot of Kiwis in my lab. I’ve had a wonderful career.

This article was first published in the October 19, 2019 issue of the New Zealand Listener.