Eating According to Your Genome

The emerging field of nutrigenomics is starting to yield some DNA-based diet tips, says nutrition scientist Jose Ordovas.
By Emily Singer

If you knew that you were especially susceptible to heart disease when you gained weight, would it increase your motivation to diet? How much would you be willing to pay to find out if you are one of the lucky people who can eat as much fat as you want and not have an increased risk of heart disease? Such tests are the goal of nutrigenomics, which seeks to identify the links between nutrition and disease based on an individual's genome.

While the field is still too young to offer personal dietary advice for the average consumer, research has uncovered links among genes, diet, and heart disease. Jose Ordovas, director of the Nutrition and Genomics Laboratory at Tufts University, has spent years studying the link between metabolism of dietary fats and risk of cardiovascular disease. After analyzing data from the Framingham Heart Study, a large-scale study that has traced the health of some 5,000 people since 1948, his team has found that certain genetic variants can protect people from diet-induced cardiovascular disease--or put them at increased risk. Ordovas spoke with Technology Review about his research and the future of the field.

TR: Why is nutrigenomics important?

JO: Everybody knows that some people can smoke and live a long life or eat little and still gain weight. But we don't know in advance who these people are. If we did know, these people could be educated to try to avoid the health concerns that could hit later in life. [Nutrigenomics] offers the potential to understand the relationship between food and our health on an individual level.

TR: You have found a striking link between genetic variations in a gene known as apolipoprotein E, or APOE, and risk factors for heart disease, but only under certain dietary conditions.

JO: People with a certain variation, known as APOE e4, are born with a predisposition to heart disease. For these people, a high-fat diet, smoking, or a high BMI [body-mass index] is very bad. For example, they have higher blood glucose levels, a risk factor for heart disease, but only if they have a body-mass index over 30, which is considered obese.

But these people also respond much better to a low-fat, low-cholesterol diet. So they are the ones who should really follow dietary guidelines. If you want to select people for behavior modification, these are the people to start with.

TR: Can people get tested for their APOE variant?

JO: That's a tricky situation. If you have the APOE e4 variant, you're at increased risk for heart disease, which you can do something about. But you also have a higher risk for dementia, which we don't know if you can do anything about. So there are legal and ethical issues associated with testing.

TR: One of the current nutrition debates is over the benefits of omega-3 fatty acids--different studies have produced conflicting results regarding omega-3's ability to protect against heart disease. Can nutrigenomics help sort this out?

JO: We have found that some people are more susceptible to the negative effects of omega-6 [a related fatty acid] than others. Those with a certain variant in the apolipoprotein A, or APOA, gene show a rise in triglycerides, a risk factor for cardiovascular disease, when they eat a diet high in omega-6. In these cases, the protective effect of omega-3 may be overwhelmed by overconsumption of omega-6.

This allele is much more common in Asia, and those who have it are more susceptible to the effect of omega-6 consumption. That may explain the rising rates of cardiovascular disease in Asian populations.

TR: What are the major hurdles in identifying how our genes affect our body's response to food?

JO: There are so many combinations of genes and environmental factors, you need huge populations to study. Most studies in the field are underpowered. We've done studies with 5,000 people, but that's just not enough. We need to do studies on the order of 100,000 people to take into account all the different factors.

We also need better statistical tools. Currently, we are borrowing analysis tools from situations that are much simpler, such as Medelian genetics, where a single gene leads to a certain phenotype. But applying those methods to huge networks of interactions is just not feasible.

TR: Is the nutrigenomics community using new genetic tools, such as the large gene chips that can detect 500,000 genetic variations in a single experiment?

JO: Yes, those chips do help to accumulate data. But because we need to run thousands of subjects, the cost is still prohibitive.

TR: A few consumer nutrigenomics tests are already on the market. What do you think of them?

JO: These tests may point people in the right direction, but they are not by far a final answer. Their worth also depends on the feedback the consumer gets. If the test is accompanied by prudent recommendations on diet and does not make snake-oil promises, then they probably don't have much potential to harm. And they may even have some benefit. One study found that people who took the test and went to a dietician did better than people who just went to a dietician. I think it's the placebo effect. People will pay better attention because they feel they are getting advice that is just for them.

Copyright Technology Review 2007.

Original Article

Diabetes breakthrough

Toronto scientists cure disease in mice
 
Tom Blackwell
National Post
Friday, December 15, 2006

In a discovery that has stunned even those behind it, scientists at a Toronto hospital say they have proof the body's nervous system helps trigger diabetes, opening the door to a potential near-cure of the disease that affects millions of Canadians.

Diabetic mice became healthy virtually overnight after researchers injected a substance to counteract the effect of malfunctioning pain neurons in the pancreas.

"I couldn't believe it," said Dr. Michael Salter, a pain expert at the Hospital for Sick Children and one of the scientists. "Mice with diabetes suddenly didn't have diabetes any more."

The researchers caution they have yet to confirm their findings in people, but say they expect results from human studies within a year or so. Any treatment that may emerge to help at least some patients would likely be years away from hitting the market.

But the excitement of the team from Sick Kids, whose work is being published today in the journal Cell, is almost palpable.

"I've never seen anything like it," said Dr. Hans Michael Dosch, an immunologist at the hospital and a leader of the studies. "In my career, this is unique."

Their conclusions upset conventional wisdom that Type 1 diabetes, the most serious form of the illness that typically first appears in childhood, was solely caused by auto-immune responses -- the body's immune system turning on itself.

They also conclude that there are far more similarities than previously thought between Type 1 and Type 2 diabetes, and that nerves likely play a role in other chronic inflammatory conditions, such as asthma and Crohn's disease.

The "paradigm-changing" study opens "a novel, exciting door to address one of the diseases with large societal impact," said Dr. Christian Stohler, a leading U.S. pain specialist and dean of dentistry at the University of Maryland, who has reviewed the work.

"The treatment and diagnosis of neuropathic diseases is poised to take a dramatic leap forward because of the impressive research."

About two million Canadians suffer from diabetes, 10% of them with Type 1, contributing to 41,000 deaths a year.

Insulin replacement therapy is the only treatment of Type 1, and cannot prevent many of the side effects, from heart attacks to kidney failure.

In Type 1 diabetes, the pancreas does not produce enough insulin to shift glucose into the cells that need it. In Type 2 diabetes, the insulin that is produced is not used effectively -- something called insulin resistance -- also resulting in poor absorption of glucose.

The problems stem partly from inflammation -- and eventual death -- of insulin-producing islet cells in the pancreas.

Dr. Dosch had concluded in a 1999 paper that there were surprising similarities between diabetes and multiple sclerosis, a central nervous system disease. His interest was also piqued by the presence around the insulin-producing islets of an "enormous" number of nerves, pain neurons primarily used to signal the brain that tissue has been damaged.

Suspecting a link between the nerves and diabetes, he and Dr. Salter used an old experimental trick -- injecting capsaicin, the active ingredient in hot chili peppers, to kill the pancreatic sensory nerves in mice that had an equivalent of Type 1 diabetes.

"Then we had the biggest shock of our lives," Dr. Dosch said. Almost immediately, the islets began producing insulin normally "It was a shock ? really out of left field, because nothing in the literature was saying anything about this."

It turns out the nerves secrete neuropeptides that are instrumental in the proper functioning of the islets. Further study by the team, which also involved the University of Calgary and the Jackson Laboratory in Maine, found that the nerves in diabetic mice were releasing too little of the neuropeptides, resulting in a "vicious cycle" of stress on the islets.

So next they injected the neuropeptide "substance P" in the pancreases of diabetic mice, a demanding task given the tiny size of the rodent organs. The results were dramatic.

The islet inflammation cleared up and the diabetes was gone. Some have remained in that state for as long as four months, with just one injection.

They also discovered that their treatments curbed the insulin resistance that is the hallmark of Type 2 diabetes, and that insulin resistance is a major factor in Type 1 diabetes, suggesting the two illnesses are quite similar.

While pain scientists have been receptive to the research, immunologists have voiced skepticism at the idea of the nervous system playing such a major role in the disease. Editors of Cell put the Toronto researchers through vigorous review to prove the validity of their conclusions, though an editorial in the publication gives a positive review of the work.

"It will no doubt cause a great deal of consternation," said Dr. Salter about his paper.

The researchers are now setting out to confirm that the connection between sensory nerves and diabetes holds true in humans. If it does, they will see if their treatments have the same effects on people as they did on mice.

Nothing is for sure, but "there is a great deal of promise," Dr. Salter said.

© National Post 2006

Cancer-Killing Invention Also Harvests Stem Cells

by Lois H. Gresh

Associate Professor Michael King of the University of Rochester Biomedical Engineering Department has invented a device that filters the blood for cancer and stem cells.  When he captures cancer cells, he kills them.  When he captures stem cells, he harvests them for later use in tissue engineering, bone marrow transplants, and other applications that treat human disease and improve health.  With Nichola Charles, Jared Kanofsky, and Jane L. Liesveld of the University of Rochester, King wrote about his discoveries in "Using Protein-Functionalized Microchannels for Stem Cell Separation," Paper No. ICNMM2006-96228, Proceedings of the ASME, June 2006.  King’s team includes scientists at StemCapture, Inc., a Rochester company that bought the University patent for King’s technique in November 2005 to build the cancer-killing and stem cell-harvesting devices.  The technique can be used in vivo, meaning a device is inserted in the body, or in vitro, in which case the device resides outside of the body – either way, the device kills cancer cells and captures stem cells, which grow into blood cells, bone, cartilage, and fat.

When King was working at the University of Pennsylvania from 1999 to 2001, one of his labmates discovered that bone marrow stem cells stick to adhesive proteins called selectins more strongly than other cells -- including blood cells -- stick to selectins.  When King came to the University of Rochester in early 2002, he started studying the adhesion of blood cells to the vascular wall, the inner lining of the blood vessels.  During inflammation, the vascular wall presents surface selectins that adhere specifically to white blood cells.  These selectins cause the white blood cells to roll slowly along the vascular wall, seeking signals that tell them to crawl out of the bloodstream.  This is how white blood cells migrate to bacterial infections and tissue injuries.  King set out to find a way to duplicate this natural process.

First, he noted that the selectins form bonds with the white blood cells within fractions of a second, then immediately release the cells back into the bloodstream.  He also realized that selectin is the adhesive mechanism by which bone marrow stem cells leave the bloodstream and find their way back into bone marrow.  This is how bone marrow transplantation works.  Finally, he learned that when a cancer cell breaks free of a primary tumor and enters circulation, it flow through the bloodstream to a remote organ, then leaves the bloodstream and forms a secondary tumor.  This is how cancer spreads.  He put these facts together with one more, very important fact:  the selectins grab onto a specific carbohydrate on the surfaces of white blood cells, stem cells, and cancer cells.  Associate Professor King decided to capture stem and cancer cells before the selectins release them.

Harvesting Stem Cells

Because bone marrow stem cells stick to selectin surfaces more strongly than other cells, King’s group coated a slender plastic tube with selectin.  They then did a series of lab experiments, both in vitro and in vivo using rats, with this selectin-coated tube to filter the bloodstream for stem cells.  It worked, and the King Lab discovered that they could attract a large number of cells to the wall of their selectin-coated device, and that 38% of these captured cells were stem cells.  King envisioned a system by which doctors could remove stem cells from the bloodstream by flowing the cells through a device, and make a more concentrated mixture containing, say, 20-40 percent stem cells.  These stem cells could then be used for tissue engineering or bone marrow transplantation.

This is a non-controversial way of obtaining stem cells that can be differentiated into other, useful cells.

Michael King's Device Supplies a Concentrated Mixure of Stem Cells:

King’s team can capture significant amounts of cells of the lymphatic and circulatory systems, and potentially mesenchymal stem cells, which are unspecialized cells that form tissue, bone, and cartilage.  Current procedures enable the specific capture of hematopoietic stem cells, which grow (or differentiate) over time into all of the different blood cells, and the specific capture of stem cells that differentiate into bone marrow cells.  The device itself uses a combination of microfluidics, or fluid flow properties, and specialized selectin coatings.

Killing Cancer Cells:

Another exciting application of King’s invention is filtering the blood for cancer cells and triggering their death, an innovative, new method to prevent the spread of cancer.  When someone has a primary cancer tumor, a small number of cancer cells circulates through the bloodstream.  In a process called metastasis, these cells are transmitted from the primary tumor to other locations in the body, where they form secondary, cancerous growths.

As a cancer cell flows along the implanted surface, King’s device captures it and delivers an apoptosis signal, a biochemical way of telling the cancer cell to kill itself.  Within two days, that cancer cell is dead.  Normal cells are left totally unharmed because the device selectively targets cancer cells.

The apoptosis signal is delivered by a molecule called TRAIL that coats the cancer-killing device.  Cancer cells have five types of proteins that recognize and bind to TRAIL, but only two trigger cell death.  The other three are called decoy receptors.  Healthy cells contain a lot of decoy receptors, giving them a natural protection against TRAIL, whereas cancer cells mainly express the two receptors that signal cell death.

Michael King's Device Kills Cancer Cells:

During the death of the cancer cells, TRAIL is not depleted or used up in any way, and in fact, it stays active for many weeks or months.  The same TRAIL molecules can kill enormous numbers of cancer cells.

A possible way to use the cancer-killing invention is to implant the device in the body before primary tumor surgery or chemotherapy.  When doctors remove a primary tumor, the procedure itself can release cancer cells into the bloodstream.  King’s device would grab those cancer cells and kill them, greatly reducing the possibility of metastasis.

Associate Professor King envisions that the device would use a shunt similar to the type used in hospitals today.  This shunt would reside on the exterior of the arm or be implanted beneath the skin.  Some of the blood flow would bypass the capillary bed and instead go into the shunt, which could remain implanted for many weeks, continually removing and killing cancer cells.  King’s first targets are colorectal cancer and blood malignancies such as leukemia.