Dieting meets DNA: Nutrition gets personal in new studies

Ushering nutritional science into the biotech age, UW–Madison researchers are exploring the complex interactions between food and genes to uncover new modes of disease prevention, drug development and, eventually, personalized diet advice tailored to one’s DNA.

Current science suggests that the genetic hand a person is dealt at birth influences predisposition toward a healthy life, but it does not commit them to it. Diet, among other environmental factors, has just as much to do with health as your genes do.

Teasing out the complex diet-gene interactions influencing life span, disease and overall well-being is at the heart of the marriage of nutrition and genetics known as nutrigenomics.

UW–Madison researchers are near the forefront of this burgeoning field, which promises to identify those lucky few able to eat high-fat, high-cholesterol diets and never gain a pound. But nutrigenomics also offers hope and cures for those on the other side of the bell curve — sufferers of food allergies, diabetes, obesity and genetic defects affecting nutrient use in the body.

But before the new science makes good on its promises, the field faces significant challenges, says associate professor of bioethics and medical history Linda Hogle. She says nutrigenomics researchers need to overcome the logistical and conceptual challenges inherent to multidisciplinary sciences.

“Geneticists, clinicians, public policy-makers, nutritionists, (genetic) test-makers, food-growers and distributors not only speak different languages but have very different perspectives on what the problem of health and nutrition is, and how to solve it,” says Hogle.

Also, researchers must grapple with the sheer complexity of diet-gene interactions. Because only a fraction of all genes are well-understood and even the simplest bit of food contains hundreds of unique chemicals, research techniques must evolve before a deep understanding of diet-gene interactions is reached.

Finding how diet-gene interactions differ among people may explain why everybody has unique diet needs. Professor of nutritional sciences Susan Smith explains that a nutrient’s function is essentially the same from person to person, but genetic variability and lifestyle choices lead to other subtle differences in how the body processes vitamins, fats and minerals. She says the required amount of a nutrient and how long it lasts in the body can vary, and certain kinds of diets can affect nutritional needs.

Genetic differences can also cause food-related diseases. For those with diabetes and obesity, a high-fat diet and an overactive gene known as SCD-1 may be the root of their problems.

The key gene?

James Ntambi, a professor of biochemistry and nutritional science, spent 15 years studying SCD-1 and the enzyme it produces. His research shows that the SCD enzyme has a profound effect on metabolism. Controlling its levels, Ntambi says, could be the key to a cure for diabetes and obesity.

Ntambi made headlines in 2002 when he created genetically modified mice lacking the SCD-1 gene. Without the enzyme to hinder their metabolism, these mice were resistant to weight gain and excess blood sugar levels, hallmarks of type II diabetes.

Ntambi also found that overweight people have particularly active SCD-1 genes, leading to slow metabolic rates. For humans with low levels of the enzyme, fat is burned off quickly. This could explain why some lucky overeaters can stay skinny their whole lives.

Ntambi says that by altering the levels of the SCD gene, a person’s metabolism could be fine-tuned, reducing the amount of fat deposited in his or her body and keeping glucose levels low.

Since 2002, Ntambi has refined his approach. Initially, the mice received a “global knock-out” of the SCD-1 gene, removing it from the DNA of every cell in their body. Today, Ntambi’s team is examining the role of the gene in individual organs and tissues, turning the gene “off” in certain areas while keeping it “on” in key locations. This is an essential step toward drug development.

According to Ntambi, overweight people have highly active SCD-1 genes localized in muscle and fat tissues. In the future, Ntambi believes doctors will be able to prescribe a drug to inhibit the production of the SCD enzyme in these areas, leading to weight loss.

However, Ntambi says cholesterol and certain other nutrients inherent to high-fat, high-carbohydrate diets fuel this gene’s activity, whereas polyunsaturated fats — classes of fats found in vegetable oils, fish and nuts — reduce SCD’s activity. These interactions among fats and the SCD gene mean any potential drug regimen would be complemented with a good old-fashioned diet — with a very high-tech twist.

Imagine it’s 2016. A man in his mid-40s complains of abdominal and joint pain, and his doctor believes a change in diet could help. The doctor collects a small blood sample and has the patient’s genome sequenced for about $1,000 (a run-of-the-mill procedure covered by his HMO).

After a screening process examining levels of gene activity, vitamins and minerals, the doctor scrutinizes the unique genetic map. Scanning through the patient’s 30,000 or so genes, the doctor finds the culprit: a single mutation, or genetic typo, located on the man’s HFE gene on the sixth chromosome.

The defect results in a disease called hemochromatosis, causing the patient to accumulate iron in his liver, causing the painful stomach cramps and arthritis he has been experiencing.

Fortunately, the iron overload is in its early stages and, apart from prescribing the man a phlebotomy (a procedure to remove excess iron), the doctor also provides the patient with a day-by-day, low-iron diet to combat his condition and give him a much-needed health boost, loaded with kidney and soybeans, wheat pasta and black tea (to reduce iron absorption). Kale, almonds and brown rice round out the diet plan, exclusively tailored to this patient’s distinctive genetic profile and designed specifically to meet his current nutritional needs.

Tailoring diet to genetics

The personalized, genetically determined diet is the most hotly anticipated aspect of nutrigenomics research. It heralds a shift in focus for nutritional sciences. Ntambi and professor of nutritional sciences David Eide agree that while diet advice was historically doled out to entire populations — think the food pyramid or an “apple-a-day” — modern nutritional science is becoming a lot more personal.

“By understanding how nutrients interact with genes, we can create individualized dietary recommendations. The way the things work right now, people say the general population should eat a low-fat or low-carbohydrate diet, but because of the differences in our genes, it may turn out what is good for you may not be good for me,” says Ntambi.

Ntambi envisions a time when a personalized diet can be prescribed based on a person’s genetics, lifestyle and health. However, uncovering new relationships among specific nutrients and genes is needed before this vision becomes reality. A community of nutritional scientists at UW–Madison is trying to do just that.

UW–Madison’s role

Smith studies vitamin A and its role in developing embryos and in adults. She also explores the interplay of nutrient status and alcohol consumption. Eide investigates human cell behavior in the presence of variable amounts of zinc, one of the most important minerals in a person’s diet. Still others, such as professor of nutritional sciences Roger Sunde, research lesser-known nutrients like selenium, a trace element required in small amounts in humans and all animals.

Sunde says essential nutrients are not the only ones that merit study. “For a nutrient like boron that people don’t think is required for humans, we may discover there is a protein that requires boron for expression, activity or function,” says Sunde. “That’s a critical missing piece in cancer or cardiovascular health. So the discovery phase of nutrigenomics is going to be vast.”

New modes of screening for nutrient levels and genetic profiling will also have to be developed. Already, Ntambi and biochemistry professor Allen Attie designed a test to monitor the levels of the SCD enzyme in humans. This is one of the first of many genetic bookmarks that could be screened for in the near future. And given the speed of nutrigenomics research, Eide says the genetically determined diet plan could arrive within a decade.

However, the success of the field is not guaranteed.

Already, startups piggy-backing on the hype surrounding nutrigenomics provide rudimentary genetic screening. Companies such as Sciona in Colorado and GeneLink in New Jersey offer direct-to-consumer personalized diet advice by screening genes for mutations linked to diseases. All it takes is a cheek swab, a detailed questionnaire and payment ranging from $100 to $1,000.

UW–Madison nutritional scientists unanimously agree it’s too early for these startups to offer individualized profiles because current science doesn’t back them up.

They’re not alone. In late July, the U.S. Government Accountability Office reported that the genetic testing offered by four such biotech firms is misleading, vague and based on scientifically dubious grounds.

In addition, Hogle says that some multidisciplinary sciences like pharmacogenomics, the study of drug-gene interactions, don’t necessary fulfill the promises they make or deliver on the hype they generate. She says nutrigenomics faces “challenges to understanding how best to bring the field to fruition in an appropriate way within broader social, public health and economic circumstances that exist, whether in the United States or poor countries.”

However, nutrigenomics is securing financial backing and organizational support from all directions. Ntambi says the National Institutes of Health has shown a lot of interest in furthering nutrigenomics, calling on scientists to submit new research proposals. Also, groups such as the Center of Excellence for Nutrigenomics at the University of California, Davis and the European Nutrigenomics Organization will help foster interdisciplinary debate, tackle ethical questions and address public policy issues.

Sunde says that UW–Madison’s investment in biotechnology and the highly anticipated Wisconsin Institutes of Discovery could position nutrigenomics research on campus quite well relative to other institutions. The Institutes of Discovery seek to fuel groundbreaking biological and medical research through widespread collaboration across disciplines on campus. It is funded by $150 million in equal donations from alumni John and Tashia Morgridge, the Wisconsin Alumni Research Foundation and the state of Wisconsin.

Eventually, Ntambi says he would like to see a nutrigenomics center open in the Midwest. Many researchers on campus would like one in UW–Madison, he adds.

Despite all the promise that nutrigenomics holds, any revolution in nutrition depends on the motivation of the dieter.

“Even with genetic dietary profiling, just like today’s nutrition, you’re still going to give people eating advice,” says Eide. “It’s still up to them whether they follow it or not.”

Moreover, Eide cautions that the general population shouldn’t be swept up in personalized diet plans.

“A lot of people are so concerned about micromanaging their nutrition that they lose sight of the big picture — that is they can enjoy food without scrutinizing every bit you take. Nutrition is not rocket science — it’s really easy, in my opinion, to eat a balanced diet, or at least know what one is and consume that,” says Eide. “But for a lot of people facing a disease condition, this is very important research.”