Do these genes make me look fat?

October 1, 1999

When Nobel chemist John Walker joined the Dunn Unit in Cambridge, several nutritionists left. But his work could lead to a cure for obesity. Steve Farrar reports.

Not so long ago Sir John Walker spent several hours a day sitting in a Cambridge maternity hospital waiting for placentas. While anxious parents awaited the birth of their child, the future Nobel laureate's attention was focused on the afterbirth. If he was lucky, he would not have to wait too long for a nurse to hand him the bloody flesh. There was really no alternative - the samples he needed could only come from this source.

Time and again the precious human tissue, packed in ice, was taken straight to Cambridge's world-renowned laboratory of molecular biology. There, Sir John would set about the fresh placenta in a bid to extract pristine examples of the microscopic power houses that provide life-giving energy to living organisms - the mitochondria.

It was possibly the most unglamorous pursuit that Sir John had undertaken, but he knew that the potential rewards were huge. He had embarked on a quest to unravel what was going on at the most fundamental level deep inside these tiny bodies.

His colleagues told him he was crazy to even contemplate being able to get at the truth. "People said it might damage my career because it seemed almost impossible," he recalls. "But Fred Sanger (the only double Nobel laureate in chemistry, also at the LMB) told me to get on with it."

All that hanging around paid off when Sir John was finally able to gaze at the structure of one of the most important molecular constructions that nature has yet invented - the enzyme ATP synthase that creates the currency of life, the chemical ATP.

This molecular wonder is embedded many times over in the membrane of mitochondria yet its complexities remained a mystery.

Sir John spent eight years trying to grow crystals from the enzyme and then get x-ray images of them. What emerged was a microscopic collection of 16 proteins that worked like a factory assembly line to convert the energy found in food into a form that could be used everywhere in the human body.

The achievement, which won him the 1997 Nobel prize for chemistry, is now helping usher in a new approach to understanding one of the most central aspects of life - the link between food and people's metabolism.

The post-genomic era is dawning. Scientists estimate that the first draft of the human genome, the three-billion-letter DNA sequence that describes how to construct and operate a human, is less than a year away.

In the next few weeks, scientists at the Sanger Centre near Cambridge expect to announce that the first sequence of an entire human chromosome, number 22, has been completed. It is a milestone of sorts, a sign that this project is nearing its end. And then the real work will begin.

To take advantage of the information stored in our DNA, scientists will have to isolate 80,000 genes encoded in its 23 chromosomes and work out what they do. From disease to personality, our species' past history and hints about its future, the post-genomic era will be one of startling advances and corresponding ethical dilemmas.

One area of scientific endeavour that will be influenced by this project is nutrition. It is an essential part of what Sir John likes to call the post-genomic challenge - how do our genes influence the way we take the energy stored in food and convert it into forms that our bodies can use? Understanding the molecular roots of nutrition, including ATP synthase, is central to this - which may be why George Radda, the Medical Research Council's chief executive, announced last year that the Dunn Human Nutrition Unit in Cambridge had a new director - Sir John Walker.

Scientists at the Dunn have been investigating how nutrition impacts on humanity for 60 years, trying to get to grips with such pressing questions as the roots of obesity and how diet can affect health.

Sir John's appointment was not exactly welcomed by some of the institute's more prominent scientists. There were fears that a man whose research was so rooted at the molecular level would effectively end the centre's commitment to nutritional research. Even when Sheila Bingham, world authority on links between diet and cancer, was made his deputy, the doubts remained.

Sure enough, there has been an exodus of highly respected nutritionists from the unit. "Nobody likes being the subject of personal attacks. What hurt me most was that nobody asked me what I was going to do within the Dunn," Sir John says.

On the one hand, the Dunn will continue to conduct projects such as large-scale epidemiological studies to identify cancers that are influenced by food components. But at the other extreme, it will set up a group to take the new DNA information produced by the human genome project and link this directly with Sir John's molecular work. The ideas that may emerge from this cross-fertilisation will make or break the institute.

From the Dunn's new Cambridge building, opened last month next door to Walker's old haunt, the laboratory of molecular biology, the 58-year-old director will oversee operations from a well-fitted office.

The first members of his team of experts have begun to assemble. He has 50 people - he is aiming for more than double that.

"I have been given an opportunity to promote an area of important research that I think has been somewhat neglected," Sir John says. "In the past, nutrition research has been much more interested in food and fibre than in genes and molecules. This is an attempt to really change the way that we think about nutrition research - to understand the fundamental mechanisms and then take this (understanding) right up to food."

When molecular and genetic processes go wrong, the impact on human health can be great. But this new level of understanding may throw up new ways of dealing with such failures - intervention on a molecular level.

While Sir John's ATP synthase is a product not of the human genome proper but of the mitochondria, which carry their own DNA, the interaction between the two is critical.

If the ATP synthase gets out of balance with a similar molecular machine that converts the energy in food merely to heat - most frequently found in brown fat - the result could be obesity.

"Maybe this is why some people can shovel food away and never put on an ounce of weight," Sir John suggests.

If this is the case and genes intimately linked with the two different types of molecular machine are isolated, they could present science with a possible genetic target to tackle obesity. A mouth-watering prospect.

There are other exciting possibilities. It seems that mitochondrial DNA mutates ten times faster than the DNA in a cell nucleus. Each time it does so, it is increasingly likely to break down and it appears it has no way of repairing itself. This could be one of the root causes of ageing. As you get older, more of your cells' power houses shut down.

"This probably lies at the root of elderly people having less energy. Perhaps ageing could be looked at as a mitochondrial disease," Walker suggests.

At the very least, this knowledge might help develop specific diets that avoid the chemicals that accelerate this process.

Scientists yet to be recruited to the Dunn will take a leading role in using genomic information and molecular investigations to get a better grip on nutrition - ATP synthase and mitochondria are only part of the picture. The results, ranging from informed dietary advice to new therapies, will be nothing short of a revolution. And Sir John will be there at the birth - the molecular midwife, perhaps.

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