Research Professor at Sorbonne University and Director Emeritus at INSERM
Opportunity is the oyster of life - open it and look inside!
John Chapman is a Research Professor at Sorbonne University (Faculty of Medicine Pitié-Salpetriere) and Director Emeritus at INSERM. He sat down with us to recall the trials and triumphs of a decorated career in basic and clinical research and teaching, as well as to map out the ongoing evolution of research in cardiovascular disease.
From the river to the sea
John Chapman’s story starts in England’s northwest— on The Wirral, a pensinsula between the River Mersey and the River Dee, where the researcher grew up. It was here, at 11 years of age, that John began his studies at a grammar school and quickly found he was especially taken by both biology and chemistry. After winning a prize for biology for his successful dissection of the nerves of a rat, and conducting a controlled explosion of yellow phosphorous in chemistry, he realized: “I could have a bit of fun here.”
Thus, having settled on an academic pathway at the interface of science and medicine, John went on to undertake his bachelor’s degree by the seaside in Aberdeen, Scotland. In between school, social activities, and plenty of fish soup to accompany him through it all, he made time for short research programs, such as a government program at the Torrey Institute for Marine Biology.
The senior lecturer responsible for this project was very interested in lipids—or fats as we know them. In researching how fish metabolize fat, it was discovered that there were particles that carried fat in their plasma, so-called lipoproteins. At the time—the early 1970s—not much was known about the topic, so this work fascinated the young scholar. As JC recalls, “Physicians in the US were just learning that there was a link between certain circulating lipoproteins that transported fats and cholesterol, that we called “LDL” (low-density lipoproteins), and heart attacks and strokes in human beings. That was the very beginning.”
Joining America’s cutting edge
Next, John was awarded a Wellcome Trust research fellowship at the Middlesex Hospital Medical School in London to study lipoproteins and their link to cardiovascular disease. As part of the project, he benefited from a collaboration with the Regents’ Park Zoo, which enabled him to compare the way an array of animal species transported fats. It was through this work that John and his collaborators showed that HDL, or what we call “good cholesterol,” predominated across the animal kingdom. It was when they got to humans and higher apes that “nasty” LDL was seen to predominate. When levels of LDL are elevated, i.e. as in hypercholesterolemia, then these particles can enter the arterial wall, depositing cholesterol, a major driver of the formation of atherosclerotic plaques. It is the rupture of such plaques, particularly in the coronary circulation, with ensuing clot formation, which underlies heart attack.
“There was such a contrast at that point between what we observed in a wide spectrum of animal species and what we found in human beings.” Says JC. “Humans were primarily using LDL to transport cholesterol, and experiencing all of the downsides that came with it.”
Also in the 1970s, a major clinical study took place in the US in which a pharmacological agent successfully reduced LDL cholesterol and related cardiovascular events. It used a non-absorbable resin that bound cholesterol in the gut, in this way increasing cholesterol excretion and loss from the body. The trial was called Mr. Fit, and it put researchers around the world on the track of LDL as a possible target to decrease cardiovascular disease. “The other critical component,” JC notes, “is that cardiovascular disease exploded in the 1970s, and it’s never stopped. One American dies about every 30 seconds from cardiovascular disease—mainly heart attack. It’s the largest killer worldwide.”
Harnessing the momentum of these exciting discoveries (and the growing need for them), John soon emigrated to San Francisco to pursue his studies at the Cardiovascular Research Institute. He arrived to find that his workspace at the University of California Medical Center was on the 13th floor, looking directly onto the Golden Gate Bridge: “A better place to work you couldn’t find.”
JC was in San Francisco on a fellowship awarded by The National Institute of Health, once again to work on lipoproteins, and this time with a very strong, clinically oriented research team. With this buzzing research environment and a hippie-era Californian lifestyle to enjoy (his next-door neighbors were Crosby, Stills, Nash and Young), John remembers this chapter as “heaven.”
“I learnt an awful lot,” he enthuses, “it was at the cutting edge.” John had found himself at the forefront of the research and understanding of cardiovascular disease of that time.
There came another important discovery towards the end of the 1970s, called the LDL receptor, made by Mike Brown and Joseph Goldstein in Dallas, for which they later received the Nobel Prize. The LDL receptor is responsible for picking up LDL particles, mainly in the liver, and breaking them down to eliminate the cholesterol. If a person naturally has many LDL receptors, they are in good form, but when someone’s LDL receptor gene is in some way defective, and their receptor activity subnormal, they are at high cardiovascular risk. This inherited condition (1 in 200-250 persons) is known as familial hypercholesterolemia (FH). Knowledge of the cumulative exposure of the arterial wall to LDL in FH has brought us to a key realization: “we can just about predict the age when you’re going to be highly susceptible to a cardiovascular event. That’s how far we’ve come.”
To France and beyond
Also in San Francisco, John met a French researcher working in the same lab, and on the same topic of LDL. The researcher already knew that he himself had this genetic disease, with very high levels of LDL. Like JC, he realized there was a lot of work to do to get this information to the public and foster broader, meaningful understanding.
Through John’s newfound friend, the Director of the French National Institute for Health and Medical Research in Paris expressed an interest in his work, and wondered if he would be willing to travel over to give presentations. His decision was easy: “I love France; I spoke a bit of French. Why not!”
John spent the next five years between Paris and San Francisco as a fellow with INSERM. After creating an INSERM unit in association with Professor Jean-Luc de Gennes at Pitie-Salpetriere, he became affiliated with Sorbonne University and began teaching, too. From this joint lab, he worked on trying to understand why LDL enter the arterial wall and why they elicit atherosclerotic plaque formation. He was also able to study and identify patients with genetic disorders leading to premature cardiovascular disease.
The turn of the millennium brought new milestones. Already a research director by this stage, in 2000 John was elected President of the French Atherosclerosis Society. In 2009, he became the President of the European Atherosclerosis Society. This leadership led to a very important development: the creation of a Task Force with the European Society of Cardiology (ESC) in 2009 to establish evidence-based guideline recommendations for clinicians on how to diagnose lipid abnormalities (ie. dyslipidemias) associated with premature cardiovascular disease, and how to treat such patients. Up until this time, there was little information available to cardiologists and other clinicians in terms of the pharmacological, dietary and lifestyle approaches that could diagnose disorders related to fat metabolism and treat patients concerned. With Professor Vahanian, President of ESC, they gathered 30 people from all over Europe—cardiologists, endocrinologists, internists, nephrologists, dieticians, pharmacologists, basic researchers—experts in all the areas implicated in atherosclerotic cardiovascular disease— to create the first clinical guidelines (2011) for the diagnosis and treatment of premature cardiovascular disease, highlighting the management of lipids.
This two-year project was preceded and accompanied by the pharmaceutical industry’s sudden and enormous investment in the development of statins and other lipid lowering drugs. Indeed, the prevention of cardiovascular disease associated with atherosclerosis (ie. ASCVD), and a more coherent approach to treatment, was the consequence of a large, successful 1994 clinical intervention trial, titled ‘4S’, involving a statin.
At the same time, there had been a major increase in publications on all aspects of cardiovascular disease. “ASCVD, its diagnosis, prevention and potential clinical complications are now recognized as a speciality in many medical centers,” notes JC. The high citation rates of the 2011 guidelines, and of their major updates in 2016 and 2020, demonstrate the importance of these recommendations in real world medicine.
From genetic analysis to today’s challenges
The next breakthrough, which brings us to the present day, has been the development of genetic analysis of large cohorts and indeed of patients themselves, particularly in FH. According to John, these analyses are “totally transforming the field.”
“Not only are we now able to identify patients at high genetically-determined risk, we can also determine genetic scores for lower and higher risk, and we are beginning to identify those who will respond to therapy and those that might not.”
Importantly, clinicians can now screen the children and other family members of a parent with FH for a defective LDL receptor gene. And John believes genetic analysis will only continue to grow.
Genetic analysis in large cohorts such as the UK BioBank has recently enabled experts to determine which lipoprotein particles are causal in ASCVD; consequently, development of novel, innovative therapeutics to these new lipid risk factors is ongoing. As of today, there are three identified causal particles: LDL, a lipoprotein called Lipoprotein (a), and the newly emerged third atherogenic particle, “remnants”.
The very first sophisticated therapeutics which target Lipoprotein (a) and remnants are being tested in major cardiovascular outcome trials today, and involve impressive drug innovation. The focus however will always be on upregulating the LDL receptor to eliminate LDL: “When we do this, we decrease cardiovascular risk, morbidity, and mortality, so we save lives at all ages and in both men and women. It’s very important.”
As for the next steps in cardiovascular research and treatment, John is quick to highlight the importance of managing both the genetic disorders on the one hand, and lifestyle aspects on the other. In the US, where JC has been working recently, one in three citizens is obese, and one in six is diabetic. Lifestyle and diet are therefore especially important. And diabetes is associated with a major increase in cardiovascular risk, in part due to diabetic dyslipidemia with elevated atherogenic lipoprotein levels, mainly involving LDL and remnants. Considered together then, there is a critical need for dual awareness of lifestyle conditions and family history, and thus for education.
A major gap in current cardiovascular healthcare lies in women’s medicine, an overlooked area in which the LDL receptor once again plays an important role, particularly as LDL receptor levels fall in the menopausal and post-menopausal stages of a woman’s life. Consequently, LDL levels rise progressively in women with age, exposing them to greater cardiovascular risk.
“Networking is absolutely critical.”
As for advice for young people interested in working in his field, John places emphasis on education and networking with colleagues.
“I’ve always felt exceedingly strongly about education. About sharing information, about encouraging students and young people to come into the field, and about mentoring them as they develop. That is why we have now created two non-profit educational websites in lipids, lipoproteins and cardiovascular disease with wide outreach, “PCSK9 Forum” and “Triglyceride Forum”.”
In addition, he advises young people to seize the opportunities presented to them and to recognize the value of networking. “Networking is absolutely critical,” he notes, “and when opportunities occur, you need to think about them seriously. Opportunity is the oyster of life - open it and look inside!”
To conclude our conversation, in which John has looked back on decades of achievement, movement and transformation, and looked ahead to the challenges and developments that await us, the esteemed researcher has one final message: “Aim high.”