Attacking the asthma problem

By Emily Leighton, MA'13
Drs. Stephen Holgate and Malcolm Sears work on different continents, but the renowned researchers are united in a common goal – to better understand and treat asthma.
An estimated 235 million people suffer from the disease worldwide, according to the World Health Organization. And in Canada, asthma attacks are responsible for the largest number of childhood hospitalizations and lost days of productive work.
Drs. Holgate and Sears have transformed approaches to the treatment and management of asthma, and on November 10, they will receive the 2016 J. Allyn Taylor International Prize in Medicine from Robarts Research Institute.

Origins and outcomes – Dr. Malcolm Sears
Losing two young patients to asthma early in his career put the disease in perspective for Dr. Malcolm Sears.
A physician at an asthma clinic in New Zealand, he became increasingly concerned with the prevalence of severe asthma cases. He soon discovered that other colleagues were facing similar concerns.
“I realized we were seeing an epidemic of severe asthma and deaths across the country,” he said. “I became involved in an Asthma Task Force, exploring the reasons why we were seeing such severe asthma cases and an increasing number of deaths, especially in young people.”
This was the start of a distinguished research career studying the epidemiology and natural history of asthma with a focus on its frequency, risk factors and characteristics in large populations.
As an emerging researcher in New Zealand, Dr. Sears joined the Dunedin Multidisciplinary Health and Development Research Study – a longitudinal study that enabled him to follow participants from age nine into adulthood.
He continues to be involved with this decades-long project which will be checking in with participants, now 45 years old, in 2017.
In 1990, Dr. Sears published a landmark study in The Lancet showing that regular use of short-acting bronchodilators, a commonly prescribed asthma treatment, was related to an increased risk of asthma attack and death. By comparing prescribed or regular use (considered to be four times daily) with treatment on an as-needed basis only, the study conclusively showed the current standard approach at the time was making asthma worse for sufferers.
The shocking results weren’t easily accepted by the medical community. “It’s always troubling when a treatment we are recommending with the best intentions is questioned,” he said. “The study was quite controversial at the time. But what followed was a move away from regular use of short-acting bronchodilators.”
Dr. Sears moved to Canada in 1990  – arriving at McMaster University to direct the Firestone Institute for Respiratory Health. He helped establish and currently leads the Canadian Healthy Infant Longitudinal Development (CHILD) Study, a national birth cohort study involving over 3,500 Canadian infants and their families. The CHILD Study explores how genetics and early childhood environmental exposures impact the development of asthma, allergies and other chronic childhood diseases.
A significant difference between this and the Dunedin study is the availability of early life data. The CHILD Study provides critically important information on the earliest stages of growth and development, starting in pregnancy and focusing on the early years.
“We know that permanent damage is already done at age eight or nine,” explained Dr. Sears. “The most important things that happen in setting a child’s course for allergies and asthma occur during the critical years between the womb and age five.”
Dr. Sears and his collaborators are now starting to analyze data from the first two and three years of life. “It takes a long time to collect the data. There are hundreds of thousands of samples of blood, urine, nose swabs and stool sitting in our freezers waiting to be analyzed,” said Dr. Sears. “This is where it gets really exciting.”
After more than forty years in the field, Dr. Sears is continuing to make a difference in the lives of asthma sufferers. “What motivates me is that asthma is a very troublesome and common disorder,” he said. “We’ve got to get to the bottom of why it occurs. My vision for the long term is to see children grow up without allergy and asthma.”

Biology and environment – Dr. Stephen Holgate
Dr. Stephen Holgate, a professor at the University of Southampton, shares a similar vision, and is worried by the growing numbers of asthma sufferers around the world.
“The prevalence of the disease is increasing quite dramatically, especially in those low and middle income countries adopting aspects of the Western lifestyle,” he said.  
Dr. Holgate’s research is poised at the intersection between basic science, clinical application and business, focusing on the mechanisms of asthma, as well as the development of new treatments.
When he entered the field in the 1970s, very little was understood about the disease. “At that time the knowledge of what drove the asthmatic process was very primitive,” he said.
The UK researcher set out to understand the biology driving asthma and allergy. Concentrating on the human disease, Dr. Holgate gradually started to uncover a number of exciting avenues, including the response of the bronchial tubes during asthma attacks, the role and regulation of mast cells in causing over-reactive airways when exposed to common allergens, and the significance of airway inflammation.
“Much of my research has been focused on trying to uncover different causative pathways involved in the disease,” he explained.
As Dr. Holgate’s research continued to examine questions around the mechanisms of asthma, it became apparent that there was an underlying genetic cause to the changing shape and muscle content (remodeling) of the bronchial tubes. With his collaborators in Boston, he uncovered the first novel asthma gene involved in the airway remodeling process – ADAM33.
His current research is focused on blocking ADAM33 to prevent the increase in smooth muscle that causes bronchospasm on exposure to a wide range of environmental stimuli.
In addition to this work, Dr. Holgate recently developed inhaled beta-interferon to block asthma worsening after viral infection stemming from the common cold. “This novel approach was licensed and is now in phase 2 clinical trials,” said Grace Parraga, PhD, a Robarts scientist and member of the Taylor Prize committee. “It has the potential to transform life for asthma patients and significantly decrease asthma attacks and deaths.”
Dr. Holgate isn’t stopping there – he is also looking at asthma in relation to air pollution. This year, he launched a report with the Royal Colleges of Physicians and Paediatrics and Child Health highlighting the damage effect of air pollution across the lifespan and with a focus on young children and pregnant women.
“This is generating a lot of interest for future generations and what we should be doing for our environment,” he said. "It is 60 years since the UK introduced a Clean Air Act in relation to coal burning; the time has now come for new legistlation, but this time focused on emissions from vehicles."
In looking to the future, Dr. Holgate is optimistic about the potential for multidisciplinary collaborations.
“The future of asthma and chronic disease research is going toward the digitization of biology – harnessing ‘big data’ and applying approaches that have been successful in the physical sciences,” he said. “It’s going to be a wonderful revolution.”

Recognition for asthma research
As co-recipients of the 2016 J. Allyn Taylor International Prize in Medicine, Drs. Holgate and Sears are pleased that their work, and that of their collaborators, is being recognized.
“My whole career has been built with the help of people all over the world,” said Dr. Holgate. “They were the energy,  the discovery and the imagination. I owe all of them a huge debt of gratitude.”
Dr. Sears agrees. “Working with other colleagues has been a tremendous inspiration,” he said.  “And I’m delighted to be sharing this award with Stephen, it’s a great honour.”
The Robarts community is looking forward to presenting Drs. Holgate and Sears with the Prize at the Leaders in Innovation Dinner on November 10.
During their visit, Drs. Holgate and Sears will also spend the day at Robarts and take part in the Taylor Symposium and Public Forum. Members of the public are invited to attend the Public Forum, a free event, to learn about advances in chronic lung disease from local and international researchers. Visit www.robarts.ca/public-forum for more information and to register.