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By Linda Bren
Many of us try to make the most of what nature has provided. We buy clothes that enhance the shape of our bodies. We pick colors that go with our skin tones. We choose hairstyles that flatter us based on the shape of our faces. So why not choose medicine to improve health based on our genetic makeup?
Researchers worldwide are hoping to make this medical possibility a reality one day. And they're making strides by studying the way the body's cells work using powerful technologies and sciences known as genomics, proteomics, and metabolomics. Genomics is the study of all the genes, proteomics is the study of all the proteins, and metabolomics is the study of all the molecules derived from metabolism (metabolites) in a living organism.
"New biological understanding to help us to combat disease will come from knowledge of genes, proteins and metabolites," says Yvonne Dragan, Ph.D., a research biologist and director of the Division of Systems Toxicology within the Food and Drug Administration's National Center for Toxicological Research (NCTR). The FDA, academic and medical institutions, and pharmaceutical companies are all working to learn more about these cellular components, which can lead to more effective treatments for people based on their genetic structures and acquired differences.
"The long-term goal is to be able to personalize medicine," says Dragan. "Metabolomics is one of many tools to help do that."
Metabolomics, genomics, proteomics, and other "-omics" grew out of the Human Genome Project, a massive research effort that began in the mid-1990s and culminated in 2003 with a complete mapping of all the genes in the human body.
Scientists believe there are 30,000 to 40,000 genes in the human body. A gene is a piece of deoxyribonucleic acid (DNA). About 99.9 percent of the DNA sequence is identical in all people, according to the National Human Genome Research Institute (NHGRI). But the 0.1 percent difference is critical because it represents the genetic variations that determine a person's risk for getting a disease, how mild or severe the disease will be, and how he or she will respond to a treatment.
While genomics researchers are searching for variations in genes that cause disease, and proteomics researchers are seeking out abnormal protein patterns, metabolomic researchers are mining for abnormal metabolite patterns.
Metabolites are generated through metabolism--all the chemical reactions within the body that create and use energy, handle foods and other substances, and regulate our internal environment. Digesting food, eliminating waste, regulating body heat, and even breathing are all involved in the body's metabolism.
Experts believe there are at least 3,000 metabolites that are essential for normal growth and development (primary metabolites) and thousands more unidentified ones that are not essential for growth and development (secondary metabolites) but may help fight off infection and other forms of stress on the body.
Scientists are especially interested in certain very small metabolites, known as low-molecular-weight metabolites. These include amino acids, sugars, carbohydrates, and lipids, and they can provide important clues about a person's health.
By studying the changes and concentrations of these small metabolites within the body's cells, scientists can find unique patterns, or profiles. These profiles change when the body is fighting a disease, reacting to a drug, or responding to another form of stress. The NHGRI defines metabolomics as the evaluation of tissues and body fluids, such as urine, blood, plasma, saliva, and cerebrospinal fluid, for metabolite changes that may result from bodily responses.
Researchers conduct metabolomic studies using predominantly two methods: nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR can rapidly identify and quantify hundreds of metabolites in a sample of body fluid. MS complements NMR in that it can display, quantify, and generate profiles of thousands of metabolites with more sensitivity than NMR. The profiles are then run through powerful computers that process, store, and generate data in a form for scientists to visualize and interpret.
Some scientists prefer an older term, "metabonomics," instead of metabolomics. They make a distinction between the two terms, using the older term to refer more broadly to the underlying principles or rules that govern the production of metabolites. But they don't all agree on the difference, and the two terms are often used interchangeably. In general, metabolomics is the term more commonly used.
Researchers are both optimistic and cautious about predicting the potential of metabolomics. "The field of metabolomics is still in its infancy," says Richard Beger, Ph.D., biophysicist and director of the NCTR's Center for Metabolomics. But in comparison to using proteomics or other -omic technologies, "metabolomics is cheaper and faster," he says. And the sample for metabolomic analysis is obtained through a relatively noninvasive procedure.
Beger sees metabolomics as a likely first screening tool for disease because metabolites are found in body fluids, which are easy to collect and prepare for testing. "A fluid sample can be tested within 10 to 15 minutes," he says. Then any abnormal results can be confirmed with genomics or proteomics tests, which require special cellular samples to be prepared.
"Metabolomics is a relatively new field and I'm very careful about not being overly speculative," says Christopher Newgard, Ph.D., director of the Sarah W. Stedman Nutrition and Metabolism Center at Duke University in Durham, N.C. But Newgard is excited about the potential of metabolomics to provide information about a person's traits and characteristics (chemical phenotype), and the presence or absence of disease. "What you're actually doing is getting a profile of the chemical phenotype of the person or the organism that you're studying," he says. "What is it about that individual's ... genetic program that translates into how ... he or she actually ... feels at this moment?" Metabolomics has that immediacy, he says, as opposed to genomics, which involves predictions of the course of a disease or the outcome of treatment.
Metabolomics researchers believe the field has enormous potential to improve human health in a number of ways:
The FDA approves drugs based on their safety and effectiveness in clinical trials. But sometimes, after a drug is on the market, it causes rare but bad reactions (adverse events) in some people that were not seen in clinical trials. One of these common adverse events is injury to the liver, but other organs such as the skin, heart, kidneys, and brain may be affected.
Liver injury brought on by a drug is the leading cause of acute liver failure in the United States and is the most frequent reason a new drug is removed from the market, says John Senior, M.D., associate director for science in the Office of Pharmacoepidemiology and Statistical Science within the FDA's Center for Drug Evaluation and Research (CDER). Part of the problem, says Senior, is that clinical trials are controlled studies of a specific group of patients who have been screened and who meet stringent criteria to be included in the study. Once approved, a drug is given to a much larger, more diverse population. "You find a problem that pops up after making the drug more available--problems you never had in controlled clinical trials."
Researchers within the NCTR and CDER are using metabolomics, integrated with proteomics and genomics, to try to find out what makes certain people especially susceptible to liver damage from a drug, while most patients are not harmed by it.
"By looking at metabolite pattern differences in urine and blood, we can find out in what measurable way people are different," says Senior. "The value is not only being able to understand the mechanisms by which injury is caused, but to be able to develop tests to detect individual metabolic differences in response to a drug and to predict who shouldn't take a particular drug."
"Early identification of susceptible people would avoid removing approved drugs from use because of rare but serious adverse effects," adds Senior. "If you knew who was at risk, you could safely give the drug to others who could benefit from it."
Other applications of metabolomics lie in the drug discovery and development process. To find new drugs to treat people, potential compounds are first tested on animals. Animals and humans may show consistent changes in metabolism in response to a disease or to the effects of drugs, says Beger. Although there are genetic differences between species, many metabolites are very similar, he says. For example, the fat, cholesterol, and glucose metabolites in a rat and in a human are the same, "so we can translate our results a lot easier between species."
"The technology shows tremendous impact early on in drug discovery," says Donald Robertson, Ph.D., a toxicologist and director of the Metabonomics Evaluation Group at Pfizer Global Research and Development in Ann Arbor, Mich. "The goal is to move the safety evaluation earlier into the discovery process." Using metabolomics, says Robertson, "we can show toxicity at an early stage in drug development and in a less invasive way, so fewer animals are needed for research."
"One of the big concerns is keeping drug development costs down early on, which is a benefit for everyone," adds Robertson. The Tufts Center for the Study of Drug Development reports that on average, a new drug costs $802 million to develop, with most of that cost going toward failed drugs. And, according to the Pharmaceutical Research and Manufacturers of America, of every 5,000 drugs screened, only five make it into testing in clinical trials. Only one of these five drugs eventually gets approved for marketing, yet all of them cost millions of dollars to develop.
Metabolomics can help weed out drugs that are unsafe early on, says Robertson. "The earlier they fail, the less expensive it is."
Knowing who might have a bad reaction to a drug would also help researchers design clinical trials better, says Senior. The trials could include only people most likely to benefit from the drug based on their metabolic profile, and could exclude those for whom the drug would be toxic or ineffective.
In addition to helping develop safer drugs more quickly and at less cost, scientists predict that metabolomics will lead to developing noninvasive screening tests for more diseases. Some individual metabolites are already being used as indicators, or biomarkers, of disease. For example, high levels of the metabolite cholesterol in the blood indicate an increased risk of heart disease, and high levels of the metabolite glucose in the urine signal a risk of diabetes.
When a person goes to a doctor, lab tests are done to check for a limited number of biomarkers, says Dragan. "With metabolomics, you could look at a broader range of potential problems--a whole lot more than just the half dozen things that we currently look at."
Researchers at the Imperial College of Science, Technology and Medicine in London were able to diagnose heart disease and its severity with metabolomics. They evaluated the metabolites in plasma to identify people whose major coronary arteries had narrowed, indicating a risk of heart disease. The scientists see their technique as a rapid, noninvasive screening test to diagnose blocked arteries, "allowing diagnosis to be made simply and cheaply on the basis of a single blood sample," writes lead researcher Joanne Brindle in the December 2002 issue of Nature Medicine. Such a test might replace the current standard test, angiography, an invasive procedure in which a catheter is inserted into the groin and threaded through the body up to the arteries.
At Duke University Medical Center, researchers are looking for metabolic biomarkers for breast cancer, says Newgard. By identifying metabolic profiles of malignant vs. nonaggressive breast tumors, they are hoping to be able to detect the presence of malignant tumors at an early stage when they are most treatable.
"The application of metabolomics can run the gamut of every sort of health care situation that you can imagine," says Newgard, including weight loss. Newgard and his research team are charting the metabolic changes that occur in people who lose weight using eight different weight-loss methods, ranging from the Atkins diet, to weight-loss drugs, to stomach-stapling surgery.
How will this work help people lose weight? "In the most optimistic sense," says Newgard, "you can imagine that in the future when an obese person wants to lose weight, a first step in the process would be to get that individual's baseline metabolic profile." Then based on a person's metabolic condition and information gained from studying weight-loss interventions, scientists might be able to predict and recommend the particular weight-loss method most likely to work for the person. "That is the ultimate possibility," says Newgard.
"Another strength of metabolomics is to follow an individual over time," says Dragan. Research is moving toward using metabolomics to monitor disease, she says, by looking at different stages of the same disease across time in an individual or within a group of people, such as in clinical trials.
"You can monitor healthy people, too," says Dragan, to catch diseases early. "If somebody has a disease, the metabolite patterns look different than if they don't have that disease."
Metabolomics and other -omic technologies are likely to have a dramatic impact on the FDA's regulatory mission over the coming decade, says Dragan. "We know that in the future companies will be submitting data for new products based on metabolomic studies." The agency must seek new ways to evaluate the performance and safety of drugs and diagnostic tests that employ metabolomic technologies. And FDA scientists must gain the knowledge to be able to specify standards and procedures for the performance of metabolomic studies and for the submission of data.
In anticipation of this regulatory responsibility, FDA scientists at the NCTR are conducting basic research to better understand the technologies and science of metabolomics and their use in product development and evaluation. They also are collaborating with medical institutions and drug companies that are doing metabolomic research on nonproprietary agents.
"Through this collaboration, the FDA can leverage its limited research dollars to be able to extend its expertise," says Dragan. "Both sides are learning how to apply the technology. It's a way that we can work together in order to bring the best science to the problem at hand."
Although the potential benefits of metabolomics are great, so are the challenges to using the science to advance public health. One of these challenges is determining the significance of metabolomic changes. "Finding changes in metabolite profiles is not a problem," says Beger. "It's figuring out what these changes mean."
Researchers must distinguish between changes caused by a drug or by some other influence, such as diet. "Diet plays a large role in metabolizing drugs," says Beger. "Humans can eat thousands of different small molecules at any one sitting," says Beger, "which can affect the way a drug is metabolized."
Robertson sees metabolomics as "a molecular way to do what physicians have done for thousands of years," which is to diagnose patients based on a combination of symptoms that indicate a disease. If a patient has a rash and fever, for example, a rash by itself may not be enough of a clue, says Robertson, "but combine that with a fever and other symptoms, then it's an indicator."
"We do the same thing at a molecular level. The challenge is to identify molecules or patterns of molecules, out of tens of thousands of metabolites, that are specific enough to use as biological markers."
The complexity of the technology required to do metabolomic studies is another challenge, says Newgard. "I think there is a perception by some that you buy one of these sophisticated mass spectrometer instruments and you start squirting stuff into it and it gives you the data--and it's not like that at all. It's actually fairly hard analytical chemistry, and it takes rigor and dedication."
"Perhaps the greatest challenge is that our ability to generate masses of data far outstrips our capacity to understand it," says Robertson. Every sample of fluid analyzed requires measuring hundreds of substances, and all of these measurements produce data.
The data will also present regulatory challenges for the FDA. As drug and device makers incorporate metabolomics into their research, development, and testing of products, the agency must be prepared to evaluate the large quantities of data that these companies will submit to support clinical trials and product approvals.
The Center for Metabolomics at the FDA's National Center for Toxicological Research
www.fda.gov/nctr/science/centers/metabolomics/
Metabolomics Society
www.metabolomicssociety.org