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Researchers Seek to Demystify the Metabolic Magic of Sled Dogs
By DOUGLAS ROBSON, The New York Times, May 6, 2008
When humans engage in highly strenuous exercise day after day, they start to metabolize the body’s reserves, depleting glycogen and fat stores. When cells run out of energy, a result is fatigue, and exercise grinds to a halt until those sources are replenished.
Dogs are different, in particular the sled dogs that run the annual Iditarod Trail Sled Dog Race in Alaska. This is a grueling 1,100-mile race, and studies show that the dogs somehow change their metabolism during the race.
Dr. Michael S. Davis, an associate professor of veterinary physiology at Oklahoma State University and an animal exercise researcher, said: “Before the race, the dogs’ metabolic makeup is similar to humans. Then suddenly they throw a switch — we don’t know what it is yet — that reverses all of that. In a 24-hour period, they go back to the same type of metabolic baseline you see in resting subjects. But it’s while they are running 100 miles a day.”
Dr. Davis, who studied the sled dogs, found they did not chew up their reserves and avoided the worst aspects of fatigue. He is pursuing the research for the Defense Advanced Research Projects Agency, which gave him a $1.4 million grant in 2003 to study the physiology of fatigue resistance of sled dogs.
Dr. Davis, who is teaming with researchers at Texas A&M in a $300,000 Darpa grant, awarded last fall, has been traveling to Alaska for years to learn why the sled dogs are “fatigue-proof.”
“They have a hidden strategy that they can turn on,” he said. “We are confident that humans have the capacity for that strategy. We have to figure out how dogs are turning it on to turn it on in humans.”
Researchers have not demonstrated that ability in other species, but Dr. Davis said migratory mammals or birds could have it. Nor is it similar to the mammalian diving reflex that lets aquatic mammals like seals, otters and dolphins stay under water for long periods of time by slowing metabolic rates.
“The level of metabolism is staying the same,” Dr. Davis said. “It’s not slowing down their calorie burn rate.”
In fact, sled dogs in long-distance racing typically burn 240 calories a pound per day for one to two weeks nonstop. The average Tour de France cyclist burns 100 calories a pound of weight daily, researchers say.
How the dogs maintain such a high level of caloric burn for an extended period without tapping into their reserves of fat and glycogen (and thus grinding to a halt like the rest of us) is what makes them “magical,” Davis says.
If Dr. Davis and the Texas A&M researchers identify the biomarker, or “switch,” that could help the military understand and develop ways to control and prevent the physiological effects of fatigue in strenuous cases like combat.
“Soldiers’ duties often require extreme exertion, which causes them to become fatigued,” Jan Walker of Darpa wrote in an e-mail message. “Severe fatigue can result in a compromised immune system, making soldiers more susceptible to illness or injury.”
Family Science Project Yields Surprising Data About a Siberian Lake
By CORNELIA DEAN, The New York Times, May 6, 2008
In 1945, when Stalin ruled the Soviet Union, Mikhail M. Kozhov began keeping track of what was happening under the surface of Lake Baikal, the ancient Siberian lake that is the deepest and largest body of fresh water on earth.
Every week to 10 days, by boat in summer and over the ice in winter, he crossed the lake to a spot about a mile and a half from Bolshie Koty, a small village in the piney woods on Baikal’s northwest shore. There, Dr. Kozhov, a professor at Irkutsk State University, would record water temperature and clarity and track the plant and animal plankton species as deep as 2,400 feet.
Soon his daughter Olga M. Kozhova began assisting him and, eventually her daughter, Lyubov Izmesteva, joined the project. They kept at it over the years, producing an extraordinary record of the lake and its health.
Now Dr. Izmesteva and scientists in the United States have analyzed the data and concluded, to their surprise, that the water in Lake Baikal is rapidly warming. As a result, its highly unusual food web is reorganizing, as warmer water species of plankton become more prevalent. These shifts at the bottom of the food web could have important implications for all of the creatures that live in the lake, they say.
Although Dr. Kozhov is famous among scientists who study lakes — his 1961 book “Lake Baikal and Its Life” is considered a classic — the new report is “the international debut of the Kozhov family’s legacy of research,” Stephanie E. Hampton of the National Center for Ecological Analysis and Synthesis at the University of California, Santa Barbara, said in an e-mail message.
She led the work along with Dr. Izmesteva who, like her mother and grandfather before her, is a professor at the university and a researcher at the biological field station it established in Bolshie Koty in 1918. Their findings are being reported this month in the journal Global Change Biology.
Like others who have seen the data, Dr. Hampton said in an interview that she was in awe of the people who had collected it. “Even in the spring, summer and fall, this is tough,” she said. “In the winter to go out a mile and a half on the ice and break through it to take water samples, in a year-round effort for 60 years, is pretty amazing to me. Every time I think about it I am humbled.”
Marianne V. Moore, an ecologist at Wellesley College and another researcher on the project, said she learned about the data in 2001 when she took students in her class, “Baikal and the Soul of Siberia,” to the lake. Dr. Izmesteva spoke to the group and showed a few slides, which the translator said had been drawn from a 60-year record. “I thought he had made a mistake,” Dr. Moore recalled. “So I basically ignored it.”
When she returned with another class two years later and another scientist mentioned the data, “my jaw dropped to the floor,” she said. “I realized this is just extraordinary.”
She got in touch with Dr. Hamilton, who is an expert in the analysis of complex ecological field data, particularly the use of statistical techniques to discern real trends in the messy ups and downs of nature. The center in Santa Barbara financed the collaboration.
Baikal is a place of unusual biodiversity, with many species found nowhere else. Among them are giant shrimp, bright green sponges that grow in shallow water forests and the Baikal seal, the world’s only exclusively freshwater seal. In 1996, the United Nations Educational, Scientific and Cultural Organization, or Unesco, designated the lake a World Heritage Site.
Although it is known that warming is more intense at high latitudes, as in the Baikal area, and that water is warming in other major lakes, including Lake Tahoe in Nevada and Lake Tanganyika in central Africa, many scientists had thought that Lake Baikal’s enormous volume and unusual water circulation patterns would buffer the effects of global warming.
Instead, the researchers report, surface waters in Lake Baikal are warming quickly, on average by about 0.4 degrees Fahrenheit every decade. At a depth of about 75 feet, the increase is about 0.2 degrees per decade, they say, enough to jeopardize species “unable to adapt evolutionarily or behaviorally.”
Over the last 137 years, the researchers say, the ice-free season has lengthened by more than two weeks, primarily because ice forms later in the year. The database, including data on chlorophyll that the family started collecting in 1979, suggest that the “growing season” for plankton and algae has lengthened in the lake. Chlorophyll levels have tripled since measurement began, the researchers said.
Ordinarily, the researchers said in their report, this increased plant growth would be accompanied by decreases in water clarity, but that is not what the data show at Lake Baikal. This finding, they said, “highlights the importance of establishing monitoring for ‘early warming’ before a need for monitoring may be perceived visually.”
Now, Dr. Hampton said, she and other researchers are examining how the Kozhov family’s data fit with records of ecological phenomena elsewhere. So far, she said, “the data correlate well.”
“You could not make up something like this.” she added.
Dr. Moore said Dr. Kozhov died in 1968 and his daughter Olga died in 2000. The family persisted in their work through years of political, economic and social turmoil, especially the collapse of the Soviet Union after the fall of the Berlin Wall in 1989 when, Dr. Moore said, “funds for the program just dried up.”
Today, she said, Dr. Izmesteva and her colleagues pay for their work in part with fees they earn by consulting or doing environmental impact assessments.
“They sustain the program any way they can,” Dr. Moore said.
Redefining Disease, Genes and All
By ANDREW POLLACK, The New York Times, May 6, 2008
Duchenne muscular dystrophy may not seem to have much in common with heart attacks. One is a rare inherited disease that primarily strikes boys. The other is a common cause of death in both men and women. To Atul J. Butte, they are surprisingly similar.
Dr. Butte, an assistant professor of medicine at Stanford, is among a growing band of researchers trying to redefine how diseases are classified — by looking not at their symptoms or physiological measurements, but at their genetic underpinnings. It turns out that a similar set of genes is active in boys with Duchenne and adults who have heart attacks.
The research is already starting to change nosology, as the field of disease classification is known. Seemingly dissimilar diseases are being lumped together. What were thought to be single diseases are being split into separate ailments. Just as they once mapped the human genome, scientists are trying to map the “diseasome,” the collection of all diseases and the genes associated with them.
“We are now in a unique position in the history of medicine to define human disease precisely, uniquely and unequivocally,” three scientists wrote of the new approach last year in the journal Molecular Systems Biology. Such research aims to do more than just satisfy some basic intellectual urge to organize and categorize. It also promises to improve treatments and public health.
Scientists are finding that two tumors that arise in the same part of the body and look the same on a pathologist’s slide might be quite different in terms of what is occurring at the gene and protein level. Certain breast cancers are already being treated differently from others because of genetic markers like estrogen receptor and Her2, and also more complicated patterns of genetic activity.
“In the not too distant future, we will think about these diseases based on the molecular pathways that are aberrant, rather than the anatomical origin of the tumor,” said Dr. Todd Golub, director of the cancer program at the Broad Institute in Cambridge, Mass.
The reclassification may also help find drugs. “There are 40 drugs to treat heart attacks, but none to treat muscular dystrophy,” Dr. Butte said. If the diseases are similar in some molecular pathways, perhaps the heart attack drugs should be tested against muscular dystrophy.
Dr. Golub and colleagues at the Broad Institute have developed a “Connectivity Map,” which profiles drugs by the genes they activate as a way to find new uses for existing drugs.
The research will also improve understanding of the causes of disease and of the functions of particular genes. For instance, two genes have recently been found to influence the risk of both diabetes and prostate cancer.
“I’m shaking my head with disbelief that two genes would pop up in these two diseases that have absolutely nothing in common,” said Dr. Francis S. Collins, the director of the National Human Genome Research Institute. He said another gene, cyclin-dependent kinase inhibitor 2A, seemed to be involved in cancer, diabetes and heart disease.
A consistent way to classify diseases is also essential for tracking public health and detecting epidemics. The World Health Organization takes pains to periodically revise its International Classification of Diseases, which is used, among other ways, to tally the causes of death throughout the world. The classification is also the basis of the ICD-9 codes used for medical billing in the United States.
The first international classification, in the 1850s, had about 140 categories of disease, according to Dr. Christopher G. Chute, chairman of biomedical informatics at the Mayo Clinic. The 10th edition, in 1993, had 12,000 categories, said Dr. Chute, chairman of the committee developing the 11th version, due in 2015.
The increase stems mainly from better knowledge and diagnostic techniques that allow diseases to be distinguished from one another. For most of human history, diseases were named and classified by symptoms, which was all people could observe.
Linnaeus, the 18th-century Swedish scientist known for categorizing creatures into genus and species, also developed a taxonomy of disease. He had 11 classes — painful disease, motor diseases, blemishes and so on — that were further broken down into orders and species. But not knowing about viruses, for instance, he classified rabies as a mental disease, Dr. Chute said.
In the 19th century, a big shift occurred. Doctors began learning how to peer inside the body. And diseases began to be classified by their anatomic or physiological features.
The stethoscope let doctors realize that what had been thought of as 17 conditions — like coughing up blood and shortness of breath — could all be different symptoms of the same disease, tuberculosis.
“The advent of the stethoscope made it possible to unify tuberculosis,” said Dr. Jacalyn Duffin, a professor of the history of medicine at Queens University in Ontario.
The shift from symptoms to anatomical measurements had big implications for patients, said Dr. Duffin, who is also a hematologist.
“Up until the 18th century, you had to feel sick to be sick,” she said. But now people can be considered sick based on measurements like high blood pressure without feeling ill at all.
Indeed, Dr. Duffin said, people who feel sick nowadays “don’t get to have a disease unless the doctor can find something” and instead might be told that it’s all in their head. Doctors argue, for instance, about whether fibromyalgia or chronic fatigue syndrome, which have no obvious anatomical causes, are really diseases.
Genes might allow the study of diseases at a finer level than even physiological tests. Genes are the instructions for the production of proteins, which interact in complex ways to carry out functions in the body. Disruptions in these molecular pathways can cause disease.
“It gives you a direct connection to what the root causes are,” said Dr. David Altshuler, a professor of medicine and genetics at Harvard and Massachusetts General Hospital, and a researcher at the Broad Institute. “That is different from listening to a stethoscope.”
Some of the earliest work has until now been with inherited diseases caused by mutations in a single gene. Diseases have been subdivided by the type of mutation. Hemophilia was divided into hemophilia A and B, caused by mutations in different genes for different clotting factors. And what was once considered a mild form of hemophilia was later identified as a variant of a different clotting disorder, von Willebrand disease, caused by mutations in a different gene and requiring a different clotting factor as treatment.
Diseases are being lumped, as well as split. Researchers at Johns Hopkins reported in the April issue of Nature Genetics that two rare syndromes with different symptoms might represent a continuum of one disease. One syndrome, Meckel-Gruber, is tied to neural defects and death in babies. The other, Bardet-Biedl, is marked by vision loss, obesity, diabetes and extra fingers and toes.
The techniques are being applied to diseases for which the genetic cause is not as clearly known and which might be a result of multiple genes.
Dr. Butte uses data from gene chips that measure which genes are active, or expressed, in a cell. Amid thousands of studies using such chips, many compared the gene activity patterns in diseased tissue with that of healthy tissue.
Much of the raw data from such studies are deposited in a database. So Dr. Butte can gather data on gene activity for scores of diseases without leaving his desk. He then performs statistical analyses to map diseases based on similarities in their patterns of gene activity.
Other scientists use data on which genes appear to cause disease or contribute to the risk of contracting it.
Using such data, Marc Vidal, a biologist at Harvard, and Albert-Laszlo Barabasi, now a physicist at Northeastern University, created a map of what they called the “diseasome” that was published last year in The Proceedings of the National Academy of Sciences.
Diseases were represented by circles, or nodes, and linked to other diseases by lines that represent genes they have in common — something like the charts linking actors to one another (and ultimately to Kevin Bacon) based on the movies they appeared in together.
The number of genes associated with diseases is expanding rapidly because of so-called whole genome association studies. In these studies, gene chips are used to look for differences between the genomes of people with a disease and those without.
Multiple techniques can be combined. In a paper published online in Nature in March, scientists at Merck reconstructed the network of genes involved in obesity.
One area that might benefit from genetic disease classification is psychiatry. Because of the difficulty of measuring the brain, psychiatric diagnoses are still mainly based on symptoms. The Diagnostic and Statistical Manual of Mental Disorders contains descriptions of conditions as diverse as acute stress disorder and voyeurism.
Scientists have found that certain genes appear to be associated with both schizophrenia and bipolar disorder. Those links, and the fact that some drugs work for both diseases, have prompted a debate over whether they are truly distinct disorders. “The way we categorize these into two separate entities is almost certainly not correct,” said Dr. Wade H. Berrettini, a professor of psychiatry at the University of Pennsylvania.
But Dr. Kenneth S. Kendler, a professor of psychiatry and human genetics at Virginia Commonwealth University, said that even if the two diseases shared genes, the diseases remained distinct. Schizophrenia is marked by hallucinations and impaired social functioning, and bipolar disorder by mood swings.
“It’s extremely naïve to think that psychiatric illnesses will collapse into categories defined by a gene,” he said. “Each gene at most has a quite modest effect on the illness.”
Some experts say that such limitations may hold true for other diseases, as well, and that genetics will not be able to unequivocally define and distinguish diseases. “We shouldn’t expect, nor will we get, this decisive clarity,” said Fiona A. Miller, associate professor of health policy, management and evaluation at the University of Toronto.
She and others said genetic classification could bring its own ambiguities. Newborns are now often screened for cystic fibrosis with the idea that they can be treated early to help avoid complications. But some infants with a mutation in the gene responsible for the disease are unlikely ever to have symptoms. Do they have the disease?
“We don’t know what to call these infants,” said Dr. Frank J. Accurso, a professor of pediatrics at the University of Colorado. “We don’t even have a good language for it yet.”
Still, Dr. Butte said nosology based on genes would one day make today’s classifications look as quaint as ones from 100 years ago look now. One category in the 1909 listing of the causes of death, for instance, was “visitation of God.”
“Imagine how they are going to be laughing at us,” he said. “Not 100 years from now, but even 50 or 20 years from now.”
Really? The Claim: Running Outdoors Burns More Calories
By ANAHAD O’CONNOR, The New York Times, May 6, 2008
THE FACTS
Pavement or treadmill? Most avid runners have a strong preference for one or the other, but how do the two differ in producing results?
According to several studies, the answer is not so simple. Researchers have found in general that while outdoor running tends to promote a more intense exercise, running on a treadmill helps reduce the likelihood of injury, and thus may allow some people to run longer and farther.
A number of studies have shown that in general, outdoor running burns about 5 percent more calories than treadmills do, in part because there is greater wind resistance and no assistance from the treadmill belt. Some studies show, for example, that when adults are allowed to set their own paces on treadmills and on tracks, they move more slowly and with shorter strides when they train on treadmills.
But other studies show that treadmill exercisers suffer fewer stress injuries in the leg. One study published in 2003 in the British journal of sports medicine, for example, analyzed a group of runners and found significantly higher rates of bone strain and tension during pavement running than during treadmill running, particularly in the tibia, or shinbone. This increased strain can heighten the risk of stress fractures by more than 50 percent, the study found.
THE BOTTOM LINE
Studies suggest that running on pavement generally burns slightly more calories, but also raises the risk of stress fractures.
By DOUGLAS ROBSON, The New York Times, May 6, 2008
When humans engage in highly strenuous exercise day after day, they start to metabolize the body’s reserves, depleting glycogen and fat stores. When cells run out of energy, a result is fatigue, and exercise grinds to a halt until those sources are replenished.
Dogs are different, in particular the sled dogs that run the annual Iditarod Trail Sled Dog Race in Alaska. This is a grueling 1,100-mile race, and studies show that the dogs somehow change their metabolism during the race.
Dr. Michael S. Davis, an associate professor of veterinary physiology at Oklahoma State University and an animal exercise researcher, said: “Before the race, the dogs’ metabolic makeup is similar to humans. Then suddenly they throw a switch — we don’t know what it is yet — that reverses all of that. In a 24-hour period, they go back to the same type of metabolic baseline you see in resting subjects. But it’s while they are running 100 miles a day.”
Dr. Davis, who studied the sled dogs, found they did not chew up their reserves and avoided the worst aspects of fatigue. He is pursuing the research for the Defense Advanced Research Projects Agency, which gave him a $1.4 million grant in 2003 to study the physiology of fatigue resistance of sled dogs.
Dr. Davis, who is teaming with researchers at Texas A&M in a $300,000 Darpa grant, awarded last fall, has been traveling to Alaska for years to learn why the sled dogs are “fatigue-proof.”
“They have a hidden strategy that they can turn on,” he said. “We are confident that humans have the capacity for that strategy. We have to figure out how dogs are turning it on to turn it on in humans.”
Researchers have not demonstrated that ability in other species, but Dr. Davis said migratory mammals or birds could have it. Nor is it similar to the mammalian diving reflex that lets aquatic mammals like seals, otters and dolphins stay under water for long periods of time by slowing metabolic rates.
“The level of metabolism is staying the same,” Dr. Davis said. “It’s not slowing down their calorie burn rate.”
In fact, sled dogs in long-distance racing typically burn 240 calories a pound per day for one to two weeks nonstop. The average Tour de France cyclist burns 100 calories a pound of weight daily, researchers say.
How the dogs maintain such a high level of caloric burn for an extended period without tapping into their reserves of fat and glycogen (and thus grinding to a halt like the rest of us) is what makes them “magical,” Davis says.
If Dr. Davis and the Texas A&M researchers identify the biomarker, or “switch,” that could help the military understand and develop ways to control and prevent the physiological effects of fatigue in strenuous cases like combat.
“Soldiers’ duties often require extreme exertion, which causes them to become fatigued,” Jan Walker of Darpa wrote in an e-mail message. “Severe fatigue can result in a compromised immune system, making soldiers more susceptible to illness or injury.”
Family Science Project Yields Surprising Data About a Siberian Lake
By CORNELIA DEAN, The New York Times, May 6, 2008
In 1945, when Stalin ruled the Soviet Union, Mikhail M. Kozhov began keeping track of what was happening under the surface of Lake Baikal, the ancient Siberian lake that is the deepest and largest body of fresh water on earth.
Every week to 10 days, by boat in summer and over the ice in winter, he crossed the lake to a spot about a mile and a half from Bolshie Koty, a small village in the piney woods on Baikal’s northwest shore. There, Dr. Kozhov, a professor at Irkutsk State University, would record water temperature and clarity and track the plant and animal plankton species as deep as 2,400 feet.
Soon his daughter Olga M. Kozhova began assisting him and, eventually her daughter, Lyubov Izmesteva, joined the project. They kept at it over the years, producing an extraordinary record of the lake and its health.
Now Dr. Izmesteva and scientists in the United States have analyzed the data and concluded, to their surprise, that the water in Lake Baikal is rapidly warming. As a result, its highly unusual food web is reorganizing, as warmer water species of plankton become more prevalent. These shifts at the bottom of the food web could have important implications for all of the creatures that live in the lake, they say.
Although Dr. Kozhov is famous among scientists who study lakes — his 1961 book “Lake Baikal and Its Life” is considered a classic — the new report is “the international debut of the Kozhov family’s legacy of research,” Stephanie E. Hampton of the National Center for Ecological Analysis and Synthesis at the University of California, Santa Barbara, said in an e-mail message.
She led the work along with Dr. Izmesteva who, like her mother and grandfather before her, is a professor at the university and a researcher at the biological field station it established in Bolshie Koty in 1918. Their findings are being reported this month in the journal Global Change Biology.
Like others who have seen the data, Dr. Hampton said in an interview that she was in awe of the people who had collected it. “Even in the spring, summer and fall, this is tough,” she said. “In the winter to go out a mile and a half on the ice and break through it to take water samples, in a year-round effort for 60 years, is pretty amazing to me. Every time I think about it I am humbled.”
Marianne V. Moore, an ecologist at Wellesley College and another researcher on the project, said she learned about the data in 2001 when she took students in her class, “Baikal and the Soul of Siberia,” to the lake. Dr. Izmesteva spoke to the group and showed a few slides, which the translator said had been drawn from a 60-year record. “I thought he had made a mistake,” Dr. Moore recalled. “So I basically ignored it.”
When she returned with another class two years later and another scientist mentioned the data, “my jaw dropped to the floor,” she said. “I realized this is just extraordinary.”
She got in touch with Dr. Hamilton, who is an expert in the analysis of complex ecological field data, particularly the use of statistical techniques to discern real trends in the messy ups and downs of nature. The center in Santa Barbara financed the collaboration.
Baikal is a place of unusual biodiversity, with many species found nowhere else. Among them are giant shrimp, bright green sponges that grow in shallow water forests and the Baikal seal, the world’s only exclusively freshwater seal. In 1996, the United Nations Educational, Scientific and Cultural Organization, or Unesco, designated the lake a World Heritage Site.
Although it is known that warming is more intense at high latitudes, as in the Baikal area, and that water is warming in other major lakes, including Lake Tahoe in Nevada and Lake Tanganyika in central Africa, many scientists had thought that Lake Baikal’s enormous volume and unusual water circulation patterns would buffer the effects of global warming.
Instead, the researchers report, surface waters in Lake Baikal are warming quickly, on average by about 0.4 degrees Fahrenheit every decade. At a depth of about 75 feet, the increase is about 0.2 degrees per decade, they say, enough to jeopardize species “unable to adapt evolutionarily or behaviorally.”
Over the last 137 years, the researchers say, the ice-free season has lengthened by more than two weeks, primarily because ice forms later in the year. The database, including data on chlorophyll that the family started collecting in 1979, suggest that the “growing season” for plankton and algae has lengthened in the lake. Chlorophyll levels have tripled since measurement began, the researchers said.
Ordinarily, the researchers said in their report, this increased plant growth would be accompanied by decreases in water clarity, but that is not what the data show at Lake Baikal. This finding, they said, “highlights the importance of establishing monitoring for ‘early warming’ before a need for monitoring may be perceived visually.”
Now, Dr. Hampton said, she and other researchers are examining how the Kozhov family’s data fit with records of ecological phenomena elsewhere. So far, she said, “the data correlate well.”
“You could not make up something like this.” she added.
Dr. Moore said Dr. Kozhov died in 1968 and his daughter Olga died in 2000. The family persisted in their work through years of political, economic and social turmoil, especially the collapse of the Soviet Union after the fall of the Berlin Wall in 1989 when, Dr. Moore said, “funds for the program just dried up.”
Today, she said, Dr. Izmesteva and her colleagues pay for their work in part with fees they earn by consulting or doing environmental impact assessments.
“They sustain the program any way they can,” Dr. Moore said.
Redefining Disease, Genes and All
By ANDREW POLLACK, The New York Times, May 6, 2008
Duchenne muscular dystrophy may not seem to have much in common with heart attacks. One is a rare inherited disease that primarily strikes boys. The other is a common cause of death in both men and women. To Atul J. Butte, they are surprisingly similar.
Dr. Butte, an assistant professor of medicine at Stanford, is among a growing band of researchers trying to redefine how diseases are classified — by looking not at their symptoms or physiological measurements, but at their genetic underpinnings. It turns out that a similar set of genes is active in boys with Duchenne and adults who have heart attacks.
The research is already starting to change nosology, as the field of disease classification is known. Seemingly dissimilar diseases are being lumped together. What were thought to be single diseases are being split into separate ailments. Just as they once mapped the human genome, scientists are trying to map the “diseasome,” the collection of all diseases and the genes associated with them.
“We are now in a unique position in the history of medicine to define human disease precisely, uniquely and unequivocally,” three scientists wrote of the new approach last year in the journal Molecular Systems Biology. Such research aims to do more than just satisfy some basic intellectual urge to organize and categorize. It also promises to improve treatments and public health.
Scientists are finding that two tumors that arise in the same part of the body and look the same on a pathologist’s slide might be quite different in terms of what is occurring at the gene and protein level. Certain breast cancers are already being treated differently from others because of genetic markers like estrogen receptor and Her2, and also more complicated patterns of genetic activity.
“In the not too distant future, we will think about these diseases based on the molecular pathways that are aberrant, rather than the anatomical origin of the tumor,” said Dr. Todd Golub, director of the cancer program at the Broad Institute in Cambridge, Mass.
The reclassification may also help find drugs. “There are 40 drugs to treat heart attacks, but none to treat muscular dystrophy,” Dr. Butte said. If the diseases are similar in some molecular pathways, perhaps the heart attack drugs should be tested against muscular dystrophy.
Dr. Golub and colleagues at the Broad Institute have developed a “Connectivity Map,” which profiles drugs by the genes they activate as a way to find new uses for existing drugs.
The research will also improve understanding of the causes of disease and of the functions of particular genes. For instance, two genes have recently been found to influence the risk of both diabetes and prostate cancer.
“I’m shaking my head with disbelief that two genes would pop up in these two diseases that have absolutely nothing in common,” said Dr. Francis S. Collins, the director of the National Human Genome Research Institute. He said another gene, cyclin-dependent kinase inhibitor 2A, seemed to be involved in cancer, diabetes and heart disease.
A consistent way to classify diseases is also essential for tracking public health and detecting epidemics. The World Health Organization takes pains to periodically revise its International Classification of Diseases, which is used, among other ways, to tally the causes of death throughout the world. The classification is also the basis of the ICD-9 codes used for medical billing in the United States.
The first international classification, in the 1850s, had about 140 categories of disease, according to Dr. Christopher G. Chute, chairman of biomedical informatics at the Mayo Clinic. The 10th edition, in 1993, had 12,000 categories, said Dr. Chute, chairman of the committee developing the 11th version, due in 2015.
The increase stems mainly from better knowledge and diagnostic techniques that allow diseases to be distinguished from one another. For most of human history, diseases were named and classified by symptoms, which was all people could observe.
Linnaeus, the 18th-century Swedish scientist known for categorizing creatures into genus and species, also developed a taxonomy of disease. He had 11 classes — painful disease, motor diseases, blemishes and so on — that were further broken down into orders and species. But not knowing about viruses, for instance, he classified rabies as a mental disease, Dr. Chute said.
In the 19th century, a big shift occurred. Doctors began learning how to peer inside the body. And diseases began to be classified by their anatomic or physiological features.
The stethoscope let doctors realize that what had been thought of as 17 conditions — like coughing up blood and shortness of breath — could all be different symptoms of the same disease, tuberculosis.
“The advent of the stethoscope made it possible to unify tuberculosis,” said Dr. Jacalyn Duffin, a professor of the history of medicine at Queens University in Ontario.
The shift from symptoms to anatomical measurements had big implications for patients, said Dr. Duffin, who is also a hematologist.
“Up until the 18th century, you had to feel sick to be sick,” she said. But now people can be considered sick based on measurements like high blood pressure without feeling ill at all.
Indeed, Dr. Duffin said, people who feel sick nowadays “don’t get to have a disease unless the doctor can find something” and instead might be told that it’s all in their head. Doctors argue, for instance, about whether fibromyalgia or chronic fatigue syndrome, which have no obvious anatomical causes, are really diseases.
Genes might allow the study of diseases at a finer level than even physiological tests. Genes are the instructions for the production of proteins, which interact in complex ways to carry out functions in the body. Disruptions in these molecular pathways can cause disease.
“It gives you a direct connection to what the root causes are,” said Dr. David Altshuler, a professor of medicine and genetics at Harvard and Massachusetts General Hospital, and a researcher at the Broad Institute. “That is different from listening to a stethoscope.”
Some of the earliest work has until now been with inherited diseases caused by mutations in a single gene. Diseases have been subdivided by the type of mutation. Hemophilia was divided into hemophilia A and B, caused by mutations in different genes for different clotting factors. And what was once considered a mild form of hemophilia was later identified as a variant of a different clotting disorder, von Willebrand disease, caused by mutations in a different gene and requiring a different clotting factor as treatment.
Diseases are being lumped, as well as split. Researchers at Johns Hopkins reported in the April issue of Nature Genetics that two rare syndromes with different symptoms might represent a continuum of one disease. One syndrome, Meckel-Gruber, is tied to neural defects and death in babies. The other, Bardet-Biedl, is marked by vision loss, obesity, diabetes and extra fingers and toes.
The techniques are being applied to diseases for which the genetic cause is not as clearly known and which might be a result of multiple genes.
Dr. Butte uses data from gene chips that measure which genes are active, or expressed, in a cell. Amid thousands of studies using such chips, many compared the gene activity patterns in diseased tissue with that of healthy tissue.
Much of the raw data from such studies are deposited in a database. So Dr. Butte can gather data on gene activity for scores of diseases without leaving his desk. He then performs statistical analyses to map diseases based on similarities in their patterns of gene activity.
Other scientists use data on which genes appear to cause disease or contribute to the risk of contracting it.
Using such data, Marc Vidal, a biologist at Harvard, and Albert-Laszlo Barabasi, now a physicist at Northeastern University, created a map of what they called the “diseasome” that was published last year in The Proceedings of the National Academy of Sciences.
Diseases were represented by circles, or nodes, and linked to other diseases by lines that represent genes they have in common — something like the charts linking actors to one another (and ultimately to Kevin Bacon) based on the movies they appeared in together.
The number of genes associated with diseases is expanding rapidly because of so-called whole genome association studies. In these studies, gene chips are used to look for differences between the genomes of people with a disease and those without.
Multiple techniques can be combined. In a paper published online in Nature in March, scientists at Merck reconstructed the network of genes involved in obesity.
One area that might benefit from genetic disease classification is psychiatry. Because of the difficulty of measuring the brain, psychiatric diagnoses are still mainly based on symptoms. The Diagnostic and Statistical Manual of Mental Disorders contains descriptions of conditions as diverse as acute stress disorder and voyeurism.
Scientists have found that certain genes appear to be associated with both schizophrenia and bipolar disorder. Those links, and the fact that some drugs work for both diseases, have prompted a debate over whether they are truly distinct disorders. “The way we categorize these into two separate entities is almost certainly not correct,” said Dr. Wade H. Berrettini, a professor of psychiatry at the University of Pennsylvania.
But Dr. Kenneth S. Kendler, a professor of psychiatry and human genetics at Virginia Commonwealth University, said that even if the two diseases shared genes, the diseases remained distinct. Schizophrenia is marked by hallucinations and impaired social functioning, and bipolar disorder by mood swings.
“It’s extremely naïve to think that psychiatric illnesses will collapse into categories defined by a gene,” he said. “Each gene at most has a quite modest effect on the illness.”
Some experts say that such limitations may hold true for other diseases, as well, and that genetics will not be able to unequivocally define and distinguish diseases. “We shouldn’t expect, nor will we get, this decisive clarity,” said Fiona A. Miller, associate professor of health policy, management and evaluation at the University of Toronto.
She and others said genetic classification could bring its own ambiguities. Newborns are now often screened for cystic fibrosis with the idea that they can be treated early to help avoid complications. But some infants with a mutation in the gene responsible for the disease are unlikely ever to have symptoms. Do they have the disease?
“We don’t know what to call these infants,” said Dr. Frank J. Accurso, a professor of pediatrics at the University of Colorado. “We don’t even have a good language for it yet.”
Still, Dr. Butte said nosology based on genes would one day make today’s classifications look as quaint as ones from 100 years ago look now. One category in the 1909 listing of the causes of death, for instance, was “visitation of God.”
“Imagine how they are going to be laughing at us,” he said. “Not 100 years from now, but even 50 or 20 years from now.”
Really? The Claim: Running Outdoors Burns More Calories
By ANAHAD O’CONNOR, The New York Times, May 6, 2008
THE FACTS
Pavement or treadmill? Most avid runners have a strong preference for one or the other, but how do the two differ in producing results?
According to several studies, the answer is not so simple. Researchers have found in general that while outdoor running tends to promote a more intense exercise, running on a treadmill helps reduce the likelihood of injury, and thus may allow some people to run longer and farther.
A number of studies have shown that in general, outdoor running burns about 5 percent more calories than treadmills do, in part because there is greater wind resistance and no assistance from the treadmill belt. Some studies show, for example, that when adults are allowed to set their own paces on treadmills and on tracks, they move more slowly and with shorter strides when they train on treadmills.
But other studies show that treadmill exercisers suffer fewer stress injuries in the leg. One study published in 2003 in the British journal of sports medicine, for example, analyzed a group of runners and found significantly higher rates of bone strain and tension during pavement running than during treadmill running, particularly in the tibia, or shinbone. This increased strain can heighten the risk of stress fractures by more than 50 percent, the study found.
THE BOTTOM LINE
Studies suggest that running on pavement generally burns slightly more calories, but also raises the risk of stress fractures.
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Date: 2008-05-06 05:45 pm (UTC)