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AT THE BENCH: John Hardy, PhD, on Unraveling the Genetics of Alzheimer's Disease and Attending the ‘Oscars of Science’

Hiscott, Rebecca

doi: 10.1097/01.NT.0000479861.67918.a3
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ARTICLE IN BRIEF

John Hardy, PhD, discusses his groundbreaking work unraveling the genetics of Alzheimer's disease, and what it was like to receive the 2016 Breakthrough Prize in Life Sciences at a lavish Oscars-style ceremony.

In November, John Hardy, PhD, head of the department of molecular neuroscience and chair of molecular biology of neurological disease at the University College London Institute of Neurology, was awarded the $3 million 2016 Breakthrough Prize in Life Sciences for his work investigating the genetic underpinnings of Alzheimer's disease (AD). His research led to the discovery in 1991 of the first genetic mutation associated with familial AD, in the gene encoding the amyloid precursor protein. Since then, he and his colleagues have identified additional genes associated with AD and other forms of dementia. Dr. Hardy spoke with Neurology Today about his prize-winning research and what it was like to receive the Breakthrough Prize in a lavish Oscars-style ceremony in the company of Hollywood celebrities and Silicon Valley entrepreneurs.

Dr. Hardy was just about to tuck in to breakfast at home — a bacon sandwich, he recalled — when he received a phone call from a colleague, the renowned movement disorders specialist Mahlon DeLong, MD. Dr. DeLong asked if he was sitting down. “I've got news which is going to change your life. You've won the Breakthrough Prize,” Dr. DeLong, a previous Breakthrough Prize winner and a member of the selection committee, told him.

After the call, Dr. Hardy and his partner abandoned their breakfast and headed to a restaurant a mile down the road for a proper champagne toast.

He needed no convincing that the award would be life-changing. The prize, founded in 2012 by Sergey Brin of Google, Anne Wojcicki of 23andMe, Jack Ma of Alibaba and his wife, Cathy Zhang, Internet entrepreneur Yuri Milner and his wife, Julia Milner, and Mark Zuckerberg of Facebook and his wife, Priscilla Chan, proffers large sums — in Dr. Hardy's case, $3 million of a total of $21.9 million awarded in 2015 — to physicists, mathematicians, and life scientists at the top of their fields, as well as one lucky high school student. The award was founded to give scientists the “rock star” treatment and the funding to match, Milner told the press when the prize was first announced.

Dr. Hardy soon found himself breakfasting with Zuckerberg, Brin, Wojicki, and his fellow Breakthrough Prize winners at Zuckerberg's California home, fielding questions about their research. “They don't need me to say it,” Dr. Hardy said, “but they were very smart people and they asked very interesting questions.”

The awards ceremony was no less exciting. It has been dubbed the “Oscars of science,” an elaborate soirée attended not only by top-tier scientists but by Silicon Valley entrepreneurs and Hollywood stars. The event was held at NASA's Ames Research Center in Mountain View, CA, emceed by comedian Seth MacFarlane, and included presentations by Russell Crowe and Hillary Swank and entertainment by musician Pharrell Williams.

“It was an astonishing event. It was great fun, but I was relieved when it was all over, too,” Dr. Hardy confessed. “Being in the public eye so much was stressful. Being in a tuxedo I found stressful.” The normally casual Dr. Hardy said he is excited to return for next year's award ceremony as a spectator. “It'll be nice to be a little further in the background.”

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EARLY INSPIRATION

Despite Dr. Hardy's aversion to the limelight, he is a household name in Alzheimer's research. He was elected a Fellow of the Royal Society in 2009 and holds the distinction of being the United Kingdom's most-cited researcher, and the fifth most-cited internationally. And with good reason: In 1991, Dr. Hardy and his colleagues discovered the first genetic mutation linked to familial Alzheimer's disease. This discovery of a mutation in the amyloid precursor protein (APP) gene that leads to the overproduction of amyloid paved the way for future research in AD genetics and the development of the first animal models of the disease.

Dr. Hardy always knew he wanted to work in neuroscience, but he became involved in Alzheimer's disease research by happenstance. He completed his BSc with honors at the University of Leeds in 1976 and received his PhD in 1981 from Imperial College London, where he studied dopamine and amino acid neuropathology. He was hired to do postdoctoral research at the MRC Neuropathogenesis Unit in Newcastle, where he worked with neuropathologists Elaine Perry, PhD, and Robert Perry, MD, who were among the first to describe the cholinergic deficit in AD.

“I was working on the pathology and the neurochemistry of Alzheimer's disease,” Dr. Hardy said, “and when you're looking at the pathology of the disease, of course you're looking at the end of the disease. You're looking at the car crash that has occurred after the disease has run its course.”

But in 1983, James F. Gusella, PhD, and his colleagues published an influential paper linking Huntington's disease to genetic mutations on chromosome 4. “I'm sure that many scientists felt the same way as I did,” Dr. Hardy said. “We suddenly realized that here was a way you could find the gene and understand how the disease started. When I saw that paper I thought, ‘This is the approach that might be useful to get to the beginning of the disease.’”

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THE FIRST ALZHEIMER'S GENE MUTATION

In 1985, Dr. Hardy accepted a position as an assistant professor of biochemistry at St. Mary's Hospital at Imperial College London under the leadership of Robert Williamson, PhD, then chair of St. Mary's Hospital Medical School. There, for the first time, Dr. Hardy began to study the genetics of Alzheimer's. His first hire was a postdoctoral student named Alison M. Goate, DPhil, with whom Dr. Hardy would share author credit on many papers, and who would forge a reputation as a renowned AD researcher in her own right.

That year, Dr. Hardy and Dr. Goate received a letter from a woman in Nottingham detailing her unique family history of Alzheimer's disease. Her father and four of his nine siblings, all in their mid-50s, had Alzheimer's, as did one of her three cousins, all siblings.

By then the gene on chromosome 21 that encodes the amyloid precursor protein had been described by Colin L. Masters, MD, and Konrad Beyreuther, PhD, and researchers were already aware of the link between amyloid pathology and Alzheimer's. So when Dr. Hardy and his colleagues collected blood samples from the entire family in Nottingham, they immediately set about sequencing the APP gene.

Their painstaking work — which, without the next-generation sequencing tools available today, took four years — revealed that all of the affected family members had inherited the same mutation in the APP gene from their grandfather. The mutation caused the overproduction of amyloid, and every person who inherited it eventually developed AD. They reported the finding in Nature in 1991.

“That mutation was the first known cause of Alzheimer's disease,” Dr. Hardy said. “The mutation told us that amyloid is in the pathology of the disease — we knew that already — but also that amyloid could cause the disease. That was the breakthrough.”

Continuing this line of investigation, “we then made other findings that supported the idea that in Alzheimer's disease, amyloid pathology came first, tau pathology came second, and cell loss and dementia came third,” he said. “Because of these genetic findings, we were able to put things in order.”

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TREM2 AND ALZHEIMER'S

Dr. Hardy migrated Stateside several years after the APP discovery. He accepted a position at University of South Florida in 1992, then moved to the Mayo Clinic in Jacksonville, FL, in 1996, and to the National Institutes on Aging in 2001. But he returned to the United Kingdom in 2007, taking up the chair of molecular biology of neurological disease at the University College London (UCL) Institute of Neurology, a title he still holds.

It was at UCL that Dr. Hardy and his colleagues made another milestone discovery: that a variant of the TREM2 gene is associated with an increased risk for late-onset AD. They reported the finding in the New England Journal of Medicine in 2012.

Dr. Hardy credits the finding to one of his researchers, Rita L. Guerreiro, PhD, who was looking at Turkish families with a recessive form of early-onset non-AD dementia. She identified three mutations in the TREM2 gene that appeared to cause the disease.

“To her surprise, when she looked at Alzheimer's cases in England, she found the same three mutations in a few cases, but not in any of the controls she sequenced,” Dr. Hardy said. “So we sequenced more and more Alzheimer's cases and controls, and through collaboration got a large data set, and realized that the same mutations that she had found in these rare recessive dementias from Turkey were predisposing people to Alzheimer's disease.” [To learn more, read the Neurology Today article, “New Genetic Variant Implicated in Alzheimer's Disease”: http://bit.ly/TREM2-AD].

The value of next-generation sequencing to this particular discovery, and to the field in general, cannot be overstated, Dr. Hardy said. It has accelerated the pace of gene discovery, and “I'm sure it will have more of an impact [in the future]. I think there are quite a few more rare genes still to find, and we're looking hard.”

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SPENDING THE WINDFALL

Dr. Hardy may be known for a few episodes of extravagance — with some prompting, he recalled a night out with a colleague, Karen Duff, PhD, that ended in a $1,000 American Express bill at a karaoke bar in Osaka — but he would hardly consider his tastes expensive. His only concrete plans for his Breakthrough Prize windfall involve donating a portion towards restoring the Institute of Neurology building at University College London.

As for the rest of the money, Dr. Hardy isn't sure how it will be spent. He is more interested in thinking about where the field of AD genetics will go, and where it should go. “Fundamentally, we need to get better treatments,” he stressed. “I hope we get amyloid treatments that work in the next couple of years, but that's a hope and not a certainty. We've still got some distance to go. The journey is not over yet.”

Even after decades in the field, Dr. Hardy remains captivated by this single-minded work. “You go to work in the morning, and there's a problem which you know is puzzling hundreds, thousands of people. And then during the day you see a piece of data, and suddenly you understand it, and you're the first person to understand it. That is a tremendous thrill. It's what you go into science for.”

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Dr. John Hardy, 2016 Breakthrough Prize Winner, Discusses His Work on the Genetics of Alzheimer's Disease

NEUROLOGY IN THE NEWS: In November, John Hardy, PhD, head of the department of molecular neuroscience and chair of molecular biology of neurological disease at the University College London Institute of Neurology, was awarded the 2016 Breakthrough Prize in Life Sciences for his work investigating the genetic underpinnings of Alzheimer's disease (AD), which led to the discovery of the first genetic mutation associated with familial AD. As part of the Neurology Today podcast series, Neurology in the News, Dr. Hardy spoke with us about his prize-winning research. Listen to the podcast at http://bit.ly/Hardy-podcast.

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LINK UP FOR MORE INFORMATION:

•. The New York Times, “Breakthrough Prizes Give Top Scientists the Rock Star Treatment”: http://bit.ly/NYT-breakthrough
•. More about the Breakthrough Prizes: http://breakthroughprize.org
•. More about Dr. Hardy's research: http://bit.ly/UCL-Hardy
© 2016 American Academy of Neurology