Redefining Disease, Genes and All

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Redefining Disease, Genes and All

By Pollack May 6, 2008

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

pagewanted=2 & _r=1 & partner=rssnyt & emc=rss

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 Queen's 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.

The advent of the stethoscope showed that what was thought of as 17

conditions could all be tuberculosis symptoms. Above, Linnaeus, who

categorized creatures in genus and species, also developed a taxonomy

of diseases into 11 classes.

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. "

[Guest guest]

, I LOVE you! You are a prince, thanks SO much! Hope all's well with you

and the dream job and that you'll have an enjoyable summer

Gretchen

[Guest guest]

Love you too Gretchen - if you didn't start this group and post all

you do - I would have continued thinking I was the only one with CMT

and stuck with my depressing useless neurologist!

Anytime you or any group member need computer or web help just post me.

My job is excellent - stable until I retire in 25 years. I continue

working from home via web and I even started doing my meetings over

phone or online - I have not travelled to my office since December.

And to top it off a group of web staff, including me, are negotiating

with the government for a nice pay increase and 2.5 years back pay.

This is still in the works and will take few more months.

After I pay off my huge debt from my wheelchair van - I hope to buy a

house or condo, if not, at least some empty land for future building,

maybe when I walk again.

Hope all is well with you - keep the good news flowing!

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