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Researchers look beyond genetics to help doctors predict disease
By LILA GUTERMAN

The human genome has yet to live up to its hype. Its decoding a few years 
ago was supposed to have been the dawn of the age of personalized 
medicine. It was going to usher in a new era of health for everyone. But 
it turned out that health is affected by a lot more than genes.

Of course, scientists already knew that. They knew that the environment 
and life experiences have a huge impact on disease. So, quietly, some 
researchers toiled at making sense of such complex connections.

One of those researchers was Jeremy K. Nicholson.

"Environment, generally speaking," he says, "is much more important to 
whether you're going to live a long time."

Instead of looking at genes, Mr. Nicholson, a professor of biological 
chemistry at Imperial College London, checks out metabolites: the 
molecules that arise when the body processes materials such as food, 
drugs, or pollutants. Starting in the early 1980s, he and others showed 
that metabolites differ in predictable ways between people who are sick 
and those who are well.

Today Mr. Nicholson is a leader in a growing field called metabolomics. 
Its investigators have shown that metabolites can distinguish people who 
have cancer, diabetes, or other illnesses from those who do not. 
Metabolomics has caught the eye, and the pocketbook, of the pharmaceutical 
industry. The field may eventually help medicine to reach that elusive 
goal of personalized healthcare, predicting whether a healthy person will 
get sick and whether a drug will work for one person but not for another.

Bringing a new field to life in academe is far from easy. When one does 
rise, it is often because of a few researchers who shrug off indifference 
and even hostility from colleagues, journals, and grant-making agencies. 
Mr. Nicholson's experience with metabolomics is no exception.

'Fishing With Hand Grenades'

In retrospect, the concept behind the field seems obvious. Doctors have 
long used single metabolites such as glucose and cholesterol to identify 
diseases like diabetes and heart disease. Metabolomics simply extends this 
idea: Measure all of the body's metabolites at once and find one or a few 
that differentiate between disease and health.

Some have criticized such broad approaches as being mere fishing 
expeditions.

"Yes, it's fishing," responds Ian D. Wilson, a senior principal scientist 
at the pharmaceutical company AstraZeneca, who has collaborated with Mr. 
Nicholson. "But we're fishing with hand grenades, so we will find 
everything that's there to be found."

In the past few years, the number of papers published in the field has 
increased rapidly. But in the early days, it was lonely work.

"Nobody really gave a toss about it," says Mr. Nicholson. "I used to give 
lectures at conferences, and people would say, 'Why do you need this? You 
can do everything by genetics.'"

He recalls the curt response in the late 1980s from the editors of Nature 
to a manuscript he sent: They rejected it within a few days of receiving 
it. Despite his annoyance at the time, he now thinks the rejection may 
have been a boon. Had the paper appeared in the well-read journal, he 
says, many other scientists may have started research in the area and he 
may not have been able to compete.

"The stealth approach, enforced by the ignorance of others, worked 
enormously to my benefit," Mr. Nicholson says.

It was only after 2000, when the limitations of genomic research became 
clear, that others started paying more attention. "It suddenly got easier 
to get money," he recalls. Today his laboratory has grown to 70 
researchers supported by millions of dollars in grants from government 
agencies and companies.

Finding New Links

Over the years, Mr. Nicholson has developed many techniques to read and 
interpret metabolic data. He has linked metabolic profiles to 
characteristics such as heart disease, kidney damage, and the body's 
response to numerous toxins. For instance, he published in Nature in 2006 
that by using metabolites, he can predict (in rats, at least) which 
individuals will develop liver damage after taking acetaminophen, the 
active ingredient in Tylenol.

Last month Mr. Nicholson and a multinational group of collaborators 
reported that a few metabolic molecules are linked to high blood pressure, 
an important risk factor for heart disease. The group measured metabolites 
in urine samples from 4,630 people. In their paper, published in Nature, 
the scientists noted that one of those metabolites was formate, a molecule 
that is common in the body. No one had ever linked it to disease before, 
according to Mr. Nicholson.

Perhaps, he says, a new drug could be devised that would lower the 
concentration of formate. His group has already begun planning how to test 
that idea.

Using the same data, his team has also found metabolites that correspond 
to obesity. "That's our next Nature paper, hopefully," he says.

Obstacles Large and Small

Metabolomics requires exquisitely sensitive instruments to detect minute 
quantities of chemicals in urine, blood, saliva, or other fluids. Many of 
the achievements of the field have been to develop technologies and figure 
out ways to show the difference between "a humongous amount of data in 
condition A versus a humongous amount of data in condition B," says Ian A. 
Blair, a professor of pharmacology and chemistry at the University of 
Pennsylvania.

Researchers still squabble over which are the best techniques, and the 
field remains limited by high start-up costs because of the expense of the 
instruments. The complexity of the work can also slow it down: With 
hundreds or even thousands of compounds in each sample, researchers must 
devise ways to pull out the information on the important molecules.

A group at the University of Alberta hoped to help that process when it 
announced last year the completion of the Human Metabolome Project, which 
listed 2,500 metabolites and the spectra that 400 of the molecules produce 
on various instruments. Though some scientists say the database is useful, 
others have groused about the metabolites it left out.

There is even some conflict, much of it tongue-in-cheek, about the field's 
name. Though the field at large seems to have adopted "metabolomics," Mr. 
Nicholson and his collaborators replace the "l" with an "n" and use the 
name "metabonomics." Mr. Nicholson explains that the difference is subtle: 
Metabolomics focuses on the measurement of all metabolic mol ecules, while 
metabonomics focuses on the change in metabolic profile caused by a 
stressor like disease.

Others downplay the distinction. "I never understood what a metabonite 
was," says one scientist. Another jokes, "The 'n' stands for Nicholson."

Into the Future

Much of the field's early work focused on animals, but researchers have 
begun doing human research. No results have made their way to the doctor's 
office yet. When asked which diseases might best suit the metabolomic 
approach, Mr. Wilson, of AstraZeneca, says the jury is out but that the 
approach's potential has been obvious for "every disease area that's been 
looked at."

Oliver Fiehn, an associate professor of molecular and cellular biology at 
the University of California at Davis, has begun to study whether 
metabolites can differentiate between people who benefit from taking 
certain pharmaceuticals and those who do not.

Scientists are also beginning to ask when people develop illnesses. 
"People's risk factors change as they get older," Mr. Nicholson says. He 
has begun to study samples taken from long-term studies of thousands of 
people, in hopes of finding metabolites that signal when a person moved 
from health to disease.

Others are using a similar approach. At Brigham and Women's Hospital, in 
Boston, Bruce S. Kristal has sorted out metabolites that differ between 
normal rats and those fed a very-low-calorie diet, which tend to live much 
longer and suffer much less disease.

His group is looking at those metabolites in the blood of people enrolled 
in long-term studies, and seeing if the molecules correlate with breast 
cancer, diabetes, and other disorders. Mr. Kristal, a senior 
neuroscientist in the department of neurosurgery, hopes to use them to 
predict, years in advance, who will get sick, so that those people can 
either get treated, change their lifestyle, or get followed closely by 
their doctors.

Should his and others' research pan out, Mr. Nicholson will have 
demonstrated what he has insisted on for nearly 30 years: Genes are not 
everything.