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Nature v. Nurture Goes High Tech.

The human genome permits a closer look at the interaction between genes and the environment.

Think about your genes as a hand you've been dealt in a game of cards, suggests Patrick Stover, associate professor of nutritional sciences and the first chair of the Cornell Genomics Initiative's mammalian task force. "There's nothing you can do about the cards. Let's say perhaps that you have the genes that predispose you to colon cancer. As scientists learn to identify the function of genes and how the environment, especially nutrition, promotes or inhibits their activity, information can be tailored to individuals so that people can make the most of their own unique hand and play their cards in such a way as to lower their own disease risk and optimize their health."

Stover has been moving his research program in the area of nutritional genomics for the past three years. More than two decades of research have shown that nutrition is one of the strongest environmental influences in the regulation of gene expression, function, and stability. In the case of susceptibility to late-onset cancers like colon cancer, which typically occur after the age of 40, the genetic component of risk is about 30 percent. The balance--70 percent of the risk-comes from environmental factors, diet predominant among them. In fact, studies demonstrate that over one-third of all cancer deaths are attributable to diet.

While these percentages apply to the population as a whole, the picture changes as individual variation is taken into ac count. It is becoming ever more clear that one's genetic makeup strongly determines how her or his body uses the nutrients from food. Take folic acid, for example. While it is known that a deficiency in this common B-vitamin in the body can lead to birth defects in the head and spinal cord, it took genomics research to show that only 20 percent of the population is predisposed toward bearing a child with a folate-related birth defect that would benefit from nutrient supplementation.

"Yet overall there exists a striking dearth of definitive biological mechanistic data that ascribes specific roles for single nutrients in initiating or preventing disease at the molecular level," Stover says. Herein lies the future of nutrition, he says, whereby scientists can come to understand how genetic variation influences nutrient requirements and how nutrient requirements and genetics work together in dis ease onset, initiation, and progression.

Stover, a nutritional biochemist, is particularly interested in the relationship between folic acid metabolism and disease. It has already been shown, he points out, that if you make a mouse model of colon cancer and change the methylation status of DNA (which can be done through diet since DNA methylation is an end product of folate), you can reduce the risk of colon cancer in that mouse from 100 percent to 2 percent.

To examine further the role of folate and carcinogenesis, Stover needs access toa multidisciplinary team of other scientists, including computer scientists to do genomics data analysis, nutritional scientists who know the biochemistry of the metabolic pathway, and pathologists who can look at disease. They are all available here because of the CGI.

Federal funding organizations are only too well aware that it takes a team to work in the new life sciences. "With the advent of the Human Genome Project, the National Institutes of Health and the National Cancer Institute realize that individual investigators working on narrow problems cannot reap the whole benefit of any given research area," Stover says.

To facilitate building collaborations that can attract multi-investigator grants to study the interrelationships between human nutrition and genetic variation in health and disease, the Division of Nutritional Sciences is establishing the Cornell Institute for Nutritional Genomics. Stover is the proposed director, and Cutberto Garza, professor of nutritional sciences, is the proposed associate director.

"What is happening in genomics is going to be the key to solving the problems we're faced with in nutritional sciences," says Garza, who also chairs the Food and Nutrition Board of the National Academy of Sciences Institute of Medicine--the principal science policy board for nutrition issues in the United States--and serves as a liaison from it to a broader National Academy of Sciences committee on biotechnology. "It has all the hallmarks of a true revolution."

In addition to supporting collaboration among on-campus researchers, the Institute for Nutritional Genomics will facilitate joint projects with outstanding scientists around the country. One of the first of those is with Gene Renchick, an internationally recognized mouse geneticist who directs the Oak Ridge National Laboratories. As the site of the earliest radiation experiments, Oak Ridge National Laboratories has a long history of studying the genetic mutations occurring in mice.

To support the division's work in nutritional genomics, three new faculty members are being recruited through an inter disciplinary search committee of faculty participating in the CGI. They'll join the five division members currently working in the area of nutritional genomics.

Because the mouse is the next mammal whose genome will be sequenced, a mouse geneticist is on the top of the hiring list. This person will have expertise in genetics and developmental biology and a particular interest in problems that have a genetic and metabolic component. The second position is for a mouse biologist with an expertise in genetic manipulation and genome-related technologies who is interested in studying metabolism in disease and developing mouse models. The third is a human genetic epidemiologist, whose work will be the bridge between the other mammalian specialists and the role of genetics and nutrition in human health and disease.

"As these positions are filled within the next couple of years, we'll have a critical mass of individuals interested in human nutrition from a genomics point of view that will be unrivaled anywhere else in the country," says Jere Haas, the Nancy Schlegel Meinig Professor of Maternal and Child Nutrition and director of the Division of Nutritional Sciences.

The task of the Cornell Institute for Nutritional Genomics is to generate information that will advance the study of genetics and nutritional sciences. For example, Patrick Stover points out, it is now universally accepted that the long-term health maintenance and optimal dietary and pharmacological management of late onset diabetes, hypertension, obesity, and cardiovascular disease must be tailored to individuals on the basis of their specific genomes. In addition, the institute will coordinate research that will lead to the individualization of the universal recommended dietary allowance. At present these requirements are based on an average for a population where 95 percent of the population doesn't suffer a deficiency, explains Haas.

"Through understanding the human genome we can look at an individual's genetic makeup and say that for a person with these particular genes they'll need to have more of this vitamin and less of this mineral to function optimally," Haas says. Up until now, dietary recommendations for the general population have been the only option for a public health approach. "Genomics will revolutionize the field of public health nutrition toward better targeted, even individually tailored, interventions to prevent nutrition-related diseases and promote a healthy lifestyle," predicts Haas.

Deeper Insight into Why We Are Who We Are

Not only is data from the Human Genome Project taking nutritional sciences to a new level, it promises better tools to investigate human development as well.

"In the study of human development the question has often come down to which is more powerful, nature or nurture--how much of what we turn out to be is determined by our genetic makeup and how much is determined by our experience," says Steven Robertson. Robertson, a professor of human development whose research and teaching emphasize the interaction between biological and psychological factors, compares the debate to a modern day paraphrasing of the old philosophical argument that pits John Locke's position that we are just a blank slate--tabula rasa--upon which the world in scribes itself through the experiences of the five senses against Rene Descartes' view that we come into the world with categories of knowledge.

"The advances in genomics," Robertson says, "have put at our disposal the methods and ability to address this issue in a direct and powerful way." Modern science has shown that human development emerges as the interaction of those two things, but it has always been difficult to measure what comes from nature. The data from the human genome puts researchers closer to being able to do just that. Robertson offers three examples.

The first shows how the study of genetically based diseases points to more fruitful ways of viewing how humans develop. The insights come from researchers examining Williams syndrome, which is caused by a submicroscopic deletion on chromosome 7. Children with this disorder are mentally retarded and show extreme disorders in spatial cognition yet at the same time are remarkably fluent with language and with processing information gained by looking at other people's faces.

In the past, investigators have thought that the behavior of these children proved that there are separate modules in the mind for language and for spatial reasoning--since the children are good at one but not the other--and that capabilities were set because of the chromosomal anomaly. But in following the early development of children with Williams, researchers are seeing a more complex picture, one in which the deficits these children suffer are caused not simply by damage to a part of their brain but by the interplay of this genetic flaw and their experiences.

"The work that's being done with this disorder shows that studying the development of individuals with genetic disorders can give us insight into the nature of development as a whole," Robertson points out, "because it demonstrates how the genetic makeup and the experience work together to produce the phenotype, the observable characteristics."

Robertson's second example sheds light on the common notion that a single gene might be responsible for a single behavior. He cites the first study to show that a gene directly influences whether or not a mouse mother nurtures her offspring. In this study researchers who created "knock out" mice by inactivating a gene called fosB found, to their surprise, that offspring from these mothers were born healthy but then inexplicably died. They did follow-up studies to see if turning off the gene resulted in a physiological or anatomic defect that would result in poor nurturing--perhaps abnormal mammary glands that didn't produce enough milk or damage to the olfactory system that would

prevent the mice from recognizing their young through smell. But they found nothing.

They had known all along that the fosB gene played a critical role in controlling the expression of other genes--it is an immediate responder to stimulation. "It seems, then, that when this gene is turned off, mouse mothering behavior of all kinds doesn't occur," Robertson says. "It's not that they found the gene for maternal behavior-no more than turning the ignition key alone causes all of the complex and coordinated functioning of an automobile. But in both cases if the gene and the key are not turned on, nothing else follows."

The third example that shows the potential for genomics studies to help us understand human development has to do with new findings regarding one of the most disruptive disorders affecting children: attention deficit hyperactivity disorder (ADHD).

For half a century the drugs that have been effective in treating hyperactivity have been those that stimulate the receptors for the neurotransmitter dopamine. Genomics research has revealed that ADHD-linked variations exist in the noncoding regions surrounding the gene for the dopamine transporter and in the coding region of the gene for one of the dopamine receptors. The variation in the transporter gene has also been seen in monkeys, the animal model for studying the condition.

"If it's shown that these variations lead to a dopamine transporter that is too efficient and a dopamine receptor that is less sensitive, they may contribute to a dopamine deficit that drugs like Ritalin partly correct," Robertson says. If so, then we will be closer to understanding the biological risk for ADHD."

Without a doubt, genomics research not only raises new issues, but it offers new ways to tackle them, too. The intersection of nutrition and human development positions the College of Human Ecology to make important contributions to the field.

Emia Oppenheim: Doing and teaching science

Joe Wilensky

WHEN EMIA OPPENHEIM graduated from Cornell in 1993 with a bachelor's degree in nutritional sciences, she didn't know she'd be coming back.

Oppenheim, a Washington, D.C., native, first headed to the University of Virginia to become a registered dietitian. She was subsequently offered a research opportunity at England's Sheffield University, where she completed a master's degree in molecular immunology.

"I really enjoyed the research," she says. "I decided to combine my two loves, nutrition and research, and go for a doctoral degree in nutritional biochemistry."

That brought Oppenheim back to Cornell, where she became a graduate student in the fall of 1996. She has been working in Patrick Stover's lab and expects to complete her degree this spring.

Oppenheim has been investigating the connection between iron and folate (folic acid) metabolism. "There have been associations for decades now between iron deficiency and changes in folate metabolism," she explains. "But they've all been clinical, and there has been no evidence of an underlying biochemical mechanism."

While working in Stover's lab, Oppenheim found several possible links between the two. She says they discovered that a particular folate-dependent enzyme, cytoplasmic serine hydroxymethyltransferase (cSHMT), plays an important role in regulating folate metabolism, "acting almost like a traffic light," she says. As research progresses, Oppenheim and Stover hope to understand the related implications on nutrition and what we eat.

"I really enjoy teaching, and that has been clear throughout my doctoral experience as a teaching assistant in the lab and as a mentor," Oppenheim says. "I'd love to be in a position where I'd be teaching health practitioners about nutritional biochemistry and the impact nutrition has on people's health, both normal health and disease states. A fundamental understanding of biochemistry helps you understand why good nutrition is so important."
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Publication:Human Ecology
Geographic Code:1USA
Date:Mar 22, 2001
Previous Article:Genomics: The Frontier Within.
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