UCL Prize Lecture in Clinical Science

Written by guest blogger, Marianne Neary, MBPhD student

Yesterday  a group of UCL MB PhD students met Professor Jeffrey Friedman for afternoon tea in the Wilkins Terrace restaurant.  We were granted the honour of a private audience before his UCL Prize Lecture in Clinical Science.

In 1994 Professor Friedman, and his colleagues at the Rockefeller in New York, made a landmark discovery which armed obesity researchers with a new weapon in the battle against widening waistlines and burgeoning bum-prints.

It saw the dawn of obesity genetics as Professor Friedman and his team identified the ‘obese’ (ob) gene in mice and humans. This gene codes for a hormone he later named leptin.

The word ‘leptin’ is derived from the Greek word for thin (‘leptos’), since replacement of the hormone in leptin-deficient mice reduced their body weight back to normal.

Leptin is produced by fat cells in proportion to how full they are. This relays the energy status of the body to the brain. Leptin also has powerful effects on reproduction, metabolism, other endocrine systems and immune function.

Professor Friedman began his science career at the Rensselaer Polytechnic Institute, and in 1977 he received his M.D. from Albany Medical College of Union University. He worked as a doctor at the Albany Medical Center Hospital for two years before going to the Rockefeller to do a Ph.D. in the lab of James E. Darnell Jr.. It is here, at the Rockefeller, that he has remained ever since, continuing his work in obesity research.

After humbly discussing our own research projects with Professor Friedman, it was with great anticipation that we all piled into the basement of the old hospital at UCL to hear about his work. The lecture was packed – some attending as an annual ritual and some, like myself, hoping to learn the secret of weight loss.

Professor Friedman asked the audience: “Why are people obese?”. He discussed commonly held opinions such as “a lack of willpower” and “lifestyle choices”, before putting forth his own view that obesity is a manifestation of our genetic heritage. In other words, we wear the genes we are born with.

Studies in identical and non-identical twins (sharing all and half their genes respectively) show that weight is more heritable than height, schizophrenia and heart disease.

Very rarely, obesity can be underpinned by a mutation in a single gene. In these cases, such as humans lacking leptin, massive weight loss is achieved by hormonal replacement.

Most of our genetic susceptibility boils down to multiple variations in many genes. A significant number of these occur in the leptin pathways in the brain, including the leptin receptor, α-melanocyte stimulating hormone and melanocortin 4 receptor.

You could almost hear the disappointment when Professor Friedman explained that weight-loss cannot simply be achieved by giving escalating doses of leptin. In obesity, the fat cells are already pumping out copious amounts of leptin such that the brain is overwhelmed with the hormone and a state of leptin-resistance is induced.

However, Professor Friedman’s studies have shown that replacing leptin in dieters (whose leptin levels normally plummet in response to fat reduction) does help maintain the weight-loss.

Professor Friedman’s laboratory has focussed on elucidating the mechanisms of leptin resistance and the pathways in the brain responsible for translating leptin signals into eating behaviour. He hopes that understanding this will help them to tap into eating behaviour artificially.

Eating is a complex, motivational behaviour, and so tracking down the important cortical pathways is no easy task.

Professor Friedman’s lab has employed some new techniques. They bred mice that express a sodium channel which activates neurons when a light is shone in a particular region of the brain and, similarly, radiowaves can be used to activate neurons via nanoparticles.

“They should eat only once a day, and walk for as long as possible” wrote Hippocrates around 400 BC. Dietary advice does not seem to have progressed very far from this, but the work of Professor Friedman adds a glimmer of hope to the 70-95% of dieters who fail.

Professor Friedman has been the recipient of numerous prestigious awards including, the Gairdner Foundation International Award and the Passano Foundation Award. Of course, none is more prestigious than the UCL Clinical Prize Lecture, which, now in its fifteenth year, has hosted some of the most eminent scientists in the world.