Redefining Disease, Genes and All: Mapping the Human 'Diseaseome'

[Guest guest]

foto: , 6, of Aldie, Va., was given a diagnosis of Type 1

diabetes shortly after birth. Doctors now know he has a rare form of

diabetes that can be treated with pills instead of insulin.

Councill for The New York Times

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Interactive Graphic: Mapping the Human 'Diseaseome'*

http://www.nytimes.com/interactive/2008/05/05/science/20080506_DISEASE.html

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May 6, 2008

*Redefining Disease, Genes and All*

By ANDREW POLLACK

http://www.nytimes.com/2008/05/06/health/research/06dise.html

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. , 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. 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.

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 s

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

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. 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. , 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. 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. "

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