Perspectives

Profile Alvar Agusti: bringing systems biology to COPD “Some people think he’s a bit too wild, a bit too radical”, says Jørgen Vestbo. “He’s an unconventional thinker. When most of us start discussing things from a particular starting point he’ll often question the starting point as well.” Peter Sterk takes a similar view. “He thinks out of the box and ahead of the crowd. He’s a clinician who’s open to fundamental innovative developments that will change clinical practice dramatically in 5 or 10 years. He’s one of the frontrunners shaping that future.” Professors Vestbo and Sterk are both respiratory physicians, the former at the UK’s University of Manchester, the latter at the Academic Medical Centre of the University of Amsterdam in the Netherlands. So too is the “unconventional thinker” for whom they have a shared admiration. He’s Alvar Agusti, Professor of Medicine at the University of Barcelona, Director of the Respiratory Institute at its Hospital Clinic, and a firm believer that the future of medicine will be shaped by the insights of systems biology. Agusti had no ambition, as a child, to become a doctor. “What I really wanted was to be an astronaut”, he says. But reality dawned and 1979 found him qualifying in medicine from the University of Barcelona. Tellingly, while on a sabbatical in the USA at the University of Chicago in 1989, he heard that NASA was looking for physicians interested in going into space. “I sent my CV, but NASA never answered.” Back in the real world, Agusti sees his career in research as falling into several phases. Early on he was awarded a fellowship with a Barcelona professor who had recently returned from the USA and was launching a research programme on pulmonary gas exchange, which then became the focus of Agusti’s research for 10 years. This led to the description of a newly recognised condition now known as hepatopulmonary syndrome. When Agusti moved to Chicago he began studying peripheral tissue gas exchange. He returned to Spain in 1991, not to Barcelona but to Palma de Mallorca. There was no pulmonary service, so Agusti set about creating one. It went well; he stayed for 18 years during which time he set up a research group. “I applied what I had learned in Chicago to two clinical problems characterised by tissue hypoxia.” These were continuous hypoxia as in chronic obstructive pulmonary disease (COPD), and the intermittent hypoxia of sleep apnoea. “In my last 10 years what I discovered and became fascinated by were network analysis and systems biology.” It was during this decade that Agusti began to take a more questioning view of his specialty. These approaches, he believes, are the best way to understand and explore the complexity of biological systems—in his case, COPD. “Not www.thelancet.com Vol 390 September 2, 2017

everybody understands all the details, and they may not even see the potential of this approach”, he admits. “But the reception has been good, and I think as time goes by they will realise that to understand what I call multi-level network medicine is important.” Sterk is among those who wholeheartedly applaud Agusti’s interventions, particularly in respect of COPD: “We are working on a clinical problem that is very diverse with many biological mechanisms.” The diagnostic labels currently used are uninformative about patients’ conditions, he adds. “Alvar’s good at giving presentations in which he can explain himself”, says Vestbo. “He’s one of the best I know…He persuades a lot of people simply by being a good communicator.” Just to listen to Agusti, is to be swept along by his lucid explanations and simple but apt metaphors. “Think of a building with five floors”, he says as he embarks on an account of human biology in health and disease with all its multiple interactions between and within the various levels encompassing genes, proteins, cells, and organs along with their responses to the environment. He then launches into a second metaphor— this time using the flight of an aircraft to illustrate how the emergent properties of complex systems are dependent on the correct functioning of all their components. Health and disease are emergent properties of the workings of the body, he says. Medical science is traditionally good at the reductionist processes required to understand its various elements. “The challenge now is to integrate all this information.” Which is what he seeks to do through an emphasis on systems biology that although complex, “will help us to understand the clinical presentation [of disease] and identify molecular targets for new therapies”. As Agusti accepts, complexity can be overwhelming. But he argues that, conceptually at least, the task of integrating all sorts of available information and then formulating a plan of action is what doctors have always done. “What is the difference now?” he asks, rhetorically. “It is only the amount of information. It cannot be handled by a single human brain.” But not to worry; we have computers to share the burden. In a Series paper on COPD in this issue, Agusti writes of another concept he favours: the use of “endotyping” to categorise the subtypes of a condition according to its underlying pathophysiological mechanisms. Conventional disease taxonomy fails to reflect what we already know, he believes, never mind what we’re still learning. The future is a place that still exercises Agusti’s imagination—even though he’s never (yet) made it into space.

See Series page 980

Geoff Watts 927