Professor Sir Stephen Holgate CBE

The early years – Macclesfield to London

Having been born and raised in Macclesfield, Stephen grew up not far from Manchester, one of the cities at the vanguard of the industrial revolution in Britain. In fact, his father worked as an auctioneer and valuer for the cotton mills in the North West.

Looking back on those years and his subsequent work on air pollution, Stephen believes the experiences of his early life made a subtle, but significant, impression on him. “In the 1950s, the air pollution was terrible,” he says. “People had to walk in front of buses with torches to stop them from going onto the pavements because the air quality was so bad.”

A career in medicine wasn’t the obvious choice for Stephen, but he had a strong interest in chemistry and biochemistry. No-one in his family, as far as he knew, had a background in the profession. It was a school careers advisor who suggested that he explore the subject at university.

No one I knew at my school had done medicine. It was an extraordinary moment for me because I’d never really thought about it before.

It was when he was preparing for his university interview that his mother then told him about a distant relative who was a medic. He later found out it was the great British medical doctor and politician at the turn of the 19th century, Christopher Addison, 1st Viscount Addison.

At 18, Stephen set off for London – his first ever trip to the capital. “In those days, people didn’t travel very much so this was a big eye-opener for me,” he says. “Going to a medical school like Charing Cross [which later became part of Imperial] was super. There were only 40 of us so we became a close-knit community.”

Mentorship

For Stephen, the medical school years were very influential on the development and trajectory of his career. The mentorship relationships he enjoyed at that time were central to that experience. “There were people of some seniority who had lived in the world we wanted to enter,” he recalls. “They held our hands and helped us through the difficult bits. There was one man in particular named Sir Ravinder ("Tiny") Maini, a consultant rheumatologist, who has mentored me over many years.”

Stephen later worked for Tiny Maini as a young house doctor at Charing Cross and West London Hospitals. In 1976, both men co-authored a paper together. Later Stephen also received strong support from Tiny Maini's research colleague, Sir Marc Feldmann. “Tiny and Marc weren’t in my area of respiratory medicine so they had no reason to work with me, but they wanted to help. Through that, I learnt how important mentorship is,” he says.

That strong belief in excellent mentorship has carried through his own career. To date, Stephen has supervised to completion 33 PhD and 28 MD students and has influenced the lives and careers of many others both in the UK and overseas.

In 1973, Stephen moved to the Royal Brompton Hospital where he worked with another charismatic person who would prove influential in his career. Dame Margaret Turner-Warwick, who was head of the Cardiothoracic Research Institute at the Brompton. In 1975, she encouraged him to go to Salisbury and Southampton General Hospital, with a new medical school, only four years old at the time.

Medical research career

Stephen says: “While I was a medical registrar in Salisbury, I met David Tyrrell CBE, Director of the Medical Research Centre Common Cold Unit. Eight years later, we developed the first PCR detection for human rhinoviruses that led to uncovering the sentinel role that this, and other respiratory viruses, play in driving asthma exacerbations in children and adults.” Many years later, in 2004, Stephen and two colleagues from the University of Southampton established a company called Synairgen to explore this further.

Together they developed inhaled interferon beta for restoring anti-viral protection in severe asthma and chronic obstructive pulmonary disease (COPD) cases but didn’t expect that a new respiratory illness to come out of China would require their expertise. “We set up the company in 2004 because we discovered that asthmatic people, and people with other lung diseases, had reduced capacity to defend their lungs against common respiratory viruses - including common cold viruses,” he says. “It proved to be a deficiency of a protein in the lung called interferon beta, and we patented that with the idea of developing a treatment for virus induced worsening of asthma and COPD. We completed a couple of successful trials and got a lot of safety data but then completely out of the blue, SARS-CoV-2 virus and COVID-19 came along.”

He continues: “For example, if a bat is infected by a SARS-type coronavirus, the virus has evolved very sophisticated ways of avoiding the interferon beta pathway. However, bats have a very high baseline production of interferon, that overwhelm the virus so that the bat can tolerate the virus without disease. But as soon as the coronavirus gets into humans, where there isn’t a high level of baseline interferon production, things get problematic with rapid spread of the virus leading to COVID-19. So, here was a green light going for us to say, ‘look, we have a drug that could actually replace what’s missing...’”

All of this led in 2020 to a successful Phase II Randomised Control Trial of inhaled interferon beta in hospitalised COVID-19 patients. The outcomes of Phase III trials, which have been in progress for several months now internationally and in the US, are expected in early 2022.

Air pollution work

Another important area of Stephen’s work relates to air pollution, and its role in causing and exacerbating asthma in patients. In 2013, nine year old Ella Adoo-Kissi-Debrah from Lewisham died of severe asthma. An inquest in 2014 reported that the cause of death was acute respiratory failure and severe asthma.

“I read about little Ella when I was returning from London to Southampton on the train,” he says. “In this article, Ella’s mother, Rosamund, described her daughter’s journey over the two-and-a-half-year period that she was suffering – 30 hospital admissions, five heart attacks, ICU ventilators, you name it. Ella’s story resonated with me because I had spent my career in asthma. There were two things that Rosamund was concerned about – asthma and the possible role of an environmental cause – and without having much evidence, she was convinced that Ella’s death was caused by something she was breathing in. So I got in contact with her lawyers to see how we could work together to shed light on why Ella had such catastrophic asthma.”

Over an 18-month period, Stephen, Rosamund, and her lawyers put a case together, with additional evidence, for the Attorney General. “In getting all the records out of the six hospitals Ella had been in, I noticed that there was a close link between her exposure to air pollution as measured by a DEFRA government monitor one mile from Ella’s house as well as local authority air pollutant monitors, and her catastrophic hospital admissions for asthma,” he says.

A second inquest happened in December 2020 and after ruling out other causes of her severe asthma attacks, the evidence convinced Philip Barlow, the coroner, that air pollution was not only the cause of Ella’s death but the cause of its progression and indeed, of her asthma in the first place. This was a ground-breaking and landmark case which led the coroner to issue a Prevention of Future Deaths report in April 2021. Ella was also the first person in the UK, and possibly in the world, to have air pollution listed as the cause of death on their death certificate.

The future

Stephen is not done yet. As UK Research and Innovation Clean Air Champion, and with COP26 having recently concluded in Glasgow, he has the wind in his sails. He says, “We have £42.5m worth of government research funding to better understand how air pollution harms human health. Among the lowest hanging fruit for cleaning up the fossil fuel carbon issue is sorting out air pollution. That involves connecting lots of different groups of people together to achieve various objectives; local authorities, central government, the motor industry, the construction industry, and so on.”

Stephen shares three tips for those in the early stages of their careers:

Always try and follow what you think is right. You want to be able to look back on your life and say, considering the circumstances, I did my best to follow what I believed was the right thing to do.
There’s no such thing as continued success, but there’s also no such thing as failure.
Get others involved!

Over the years, Stephen’s independent, pioneering, and caring spirit has caused his work to create paradigm shifts in the diagnosis and management of patients with lung diseases. But how would he like to be remembered?

I’d like to think that I put patients and people first. Honesty and truthfulness and sharing are the things my parents taught me. Ambition is great, money is great, cars are great, holidays are great, but putting people first and appreciating the importance of empathy when you’re making a decision, is what I’d like to be remembered for.