Christopher Shaw, MBChB, MD, tried hard not to be a doctor. Growing up in New Zealand, Dr. Shaw already had too many physicians in his family.
Instead, he studied political philosophy and dreamed of becoming a filmmaker. But he noticed that he struggled in his arts classes, whereas biology and chemistry clicked naturally. When he went to medical school, it wasn't such a perfect world either. Anatomy and biochemistry were too dry and boring.
He took a year off to drive trucks, work in bars, and figure out what he wanted to do. That, it turns out, was medicine.
“I went back to medical school and for the first time, I met a patient,” said Dr. Shaw, professor of neurology and neurogenetics at King's College London. “And from that first patient I interviewed, I realized what a privilege it was to get to know someone in such extraordinary detail. To hear about their life story and their innermost fears and ambitions and fears.”
This year, Dr. Shaw was awarded the AAN Sheila Essey Award for his research on how mutant genes might affect people with amyotrophic lateral sclerosis (ALS). He became interested in ALS during a neurology clinic while at Cambridge University (UK).
“Two women came into the clinic in the space of a month with familial ALS. They had spent much of their adult lives waiting for this disease to come,” he said. “I got to know them quite well, and really tried to understand what it was like to live under this cloud.”
At the same time the superoxide dismutase 1 (SOD1) gene had been discovered, and Dr. Shaw started collaborating with P. Nigel Leigh, MBBS, PhD, who won the Sheila Essey award in 2004.
The hope, Dr. Shaw said, was to advance our understanding of the disease through genetics and to use these discoveries to model ALS in order to develop more effective therapies. His current research focuses on the RNA processing proteins TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS), which had been detected within motor neurons. The role they play in neurodegeneration is unclear, he noted.
Dr. Shaw's research group showed that mutations in the gene encoding TDP-43 were pathogenic and that TDP-43 aggregation caused motor neuron degeneration. Motor neurons grown in the laboratory from patient skin cells replicate key pathological findings in ALS patients, he said.
While the disease itself is complex and frustrating to parse, working with patients who will live, and die, from ALS is both a challenge and a gift, Dr. Shaw said.
“It's such an unjust disease,” he said. “It's taught me a lot about life and about people. There's a saying that applies to a disease like ALS — it puts your hand close to the fire. You get to see what you're really made of.”
During his past 20 years of working with ALS patients, Dr. Shaw said he's changed the way he approaches his patients. “I listen to my patients more. I try to share information about ALS in response to what they tell me they want to know, and at their pace, rather than having this idea in my mind of what they need to know.
“Everyone is different and everyone absorbs information in a different way and at a different pace. There are some patients who want to have every last test and know how the disease will map out their life. Others are in denial. Both strategies can work, at least for a time.
“You also have to accept that your advice isn't absolute and isn't always right,” Dr. Shaw said. “You're working with the best information you have. How people recall that information is very individual — you can't force it on them.”
Dr. Shaw is optimistic about recent breakthroughs in genetic research, particularly TDP-43 and the newly discovered chromosome 9 open reading frame 72 (C9ORF72) expansion mutation. These mutations not only appear in familial cases but in patients with sporadic disease as well. The mutations are working at different levels in the same common pathway to inhibit the degradation of the toxic TDP-43 protein. The question is how to enhance the clearance of TDP-43 and prevent neurons from dying.
“We're moving on to the next generation of sequencing and I think that by 2015, we'll have identified most of the major ALS genes. That will be good news for families and a huge boost to research,” he said.
Next up, Dr. Shaw is helping to build a new research institute that will house 250 researchers studying a range of neurological disorders at King's College London, which is expected to open April 2013.
“We have a webcam linked up so I can see the construction from wherever I am in the world,” he said, laughing. “Unfortunately it doesn't have a speaker, so I can't give instructions!”
• Shaw CE. Capturing VCP: another molecular piece in the ALS jigsaw puzzle. Neuron
• Vance C, Rogelj B, Shaw CE, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science
• Sreedharan J, Blair IP, Shaw CE, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 2008;319(5870):1668–72. E-pub 2008 Feb 28.
• Shaw CE, Al-Chalabi A. Susceptibility genes in sporadic ALS: separating the wheat from the chaff by international collaboration. Neurology
• Vance C, Al-Chalabi A, Shaw CE, et al. Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2–21.3. Brain 2006;129(Pt 4):868–76. E-pub 2006 Feb 22.
• Ruddy DM, Parton MJ, Shaw CE, et al. Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q. Am J Hum Genet 2003;73(2):390–6. E-pub 2003 Jul 1.