by Holly Korschun

prostate cancer patient newly referred to The Emory Clinic waits expectantly as his urologist weighs treatment options. Although the patient had prostate surgery several years ago, his PSA count indicates his cancer has likely returned and metastasized. The urologist touches his computer screen several times, revealing a detailed medical history and results of routine lab tests. Now he accesses the patient's genetic profile, including the particular genes being expressed in the patient's tumor. Touching several more buttons, the urologist receives data on how this patient's genetic profile compares with that of other prostate cancer patients, then information on current clinical trials for prostate cancer at Emory and nationwide.

Soon he has his answer -- a specific recommendation suggesting the most successful therapies and most pertinent clinical trials for this particular patient, based on a combination of medical history, symptoms, lab reports, genetic profiling, and available therapy.

A young child visits the outpatient clinic at Grady Memorial Hospital for a routine physical. A blood sample sent to the lab for a panel of tests identifies a protein from a gene that could greatly increase the child's risk for developing asthma. The parents are alerted to the danger, educated about preventive measures, and told that a new drug, targeting the recently discovered protein, is available should symptoms appear.

A cocaine addict visits a local drug addiction center. Her blood sample reveals specific genetic markers that might make it harder for her to break her habit. Basic genetic research at Emory, however, has led to the development of drugs that target those genes and should help the patient conquer her addiction.

None of these scenarios exists in 2001, yet all are on the near horizon. We are living in the new era of postgenomic science -- a time of accelerated discovery in medicine based on the recent decoding of the human genome. And just as the scientific community as a whole is experiencing an explosion of genetics information, Emory is entering its own genomics revolution.

JUST IMAGINE . . .

Effective legislative solutions to genetic
discrimination and privacy

In 2020

Gene-based designer drugs for diabetes,
hypertension, and other disorders
coming on the market

Cancer therapy is precisely targeted to
the molecular fingerprint of the tumor

DX/RX pharmacogenomic approach is
standard practice for many drugs

Mental illness diagnosis transformed with
molecular understanding -- new therapies,
shift in societal views

Homologous recombination technology
improves from "gene replacement" to
"gene correction"

In 2030

Comprehensive genomic-based health
care is the norm

Individualized preventive medicine
available

Illnesses are detected early by
molecular surveillance

Gene therapy and gene-based drug
therapy available for many diseases

Full computer model of the human cell
replaces many laboratory experiments

Average life span reaches 90 years


A microarray chip uses colored dots to
highlight gene expression.

In January, Howard Hughes investigator Steve Warren became new chair of what will become a greatly expanded department of genetics. Warren, who has been on the Emory faculty since 1985, plans to expand the genetics faculty to 20 members over the next five years, occupy the entire third floor of the new Joseph B. Whitehead Research Building when it opens in November, and develop a new center for medical genomics. This center will be a leader and a collaborator throughout the Woodruff Health Sciences Center (WHSC) in studying the genetic basis of human disease.

Genetic screening already exists for certain diseases, such as Tay-Sachs among Ashkenazi Jews, sickle cell anemia in African-Americans, and, on a limited basis, some cancers, such as breast cancer. Warren predicts that within 10 years, genetics will become a standard tool of the primary care physician's practice. Presymptomatic tests will screen for a variety of diseases, and genetic tests will determine the best therapies for a particular patient's condition.

"Genetic testing won't affect every disease, but it will affect a substantial portion of patients," he predicts. "Today genetics is only practiced in medical schools and is a very small slice of the medical pie. In the coming decade, genetics will be pervasive not just in medical schools but within the community. Within 20 years, designer drugs will be available to target specific individual genetic variations in diseases.

"All diseases have some genetic component," he points out. "Some, like cystic fibrosis, are largely genetic, while diseases like diabetes are about 50-50. About 10% of people infected with HIV have some genetic resistance to developing AIDS. And complex diseases like cancer usually include a combination of genetic variations along with an environmental trigger. From the newly sequenced human genome, we can see that the genetic sequence of all humans is about 99.9% the same, which means each of us carries only about 50 different mutations that influence our health to some degree."

The new genetics department will focus on how genetic mutations or changes affect the development of common diseases, such as schizophrenia, hypertension, or asthma. Researchers will develop screening tests and targets for drugs and tailor therapies for individual patients. Warren believes genetics will have a huge impact on treatment of mental illness, neurodegenerative diseases, and cardiovascular disease, to name just a few.

"Although we really don't understand the molecular basis of psychiatric disease, we do know that almost all of it has a strong genetic component. If we could understand how genes influence behavior, we could have an entry point to treat mental disorders. And finding the genes that influence neurological conditions such as epilepsy would give us insights into treatment. In cardiovascular medicine, we know that blood clots differently in individuals based on inherited differences. Patients whose blood has a tendency to clot, for example, develop deep-vein thrombosis when bedridden."

Emory's diverse patient population presents an ideal environment for discovery of new screening tests and new drugs that target genetic variations, Warren says. However, the new department's plans for genetic discovery will require equipment and personnel far beyond existing capabilities.

For example, Warren suggests that a study of the genetic causes of asthma might require approximately 1,000 blood samples from patients at Children's Healthcare of Atlanta. Robots would be needed to convert the blood samples to DNA, then scientists would determine genetic variations in asthma patients. If a gene is identified that relates directly to asthma development, a diagnostic test could be developed and commercialized and used to prescreen children before asthma's onset. Using their new understanding of asthma's basic biochemistry, geneticists and biochemists could then identify a potential drug target to inhibit a protein that leads to asthma development.

"As soon as we identify a gene that influences a disease," Warren explains, "even before we find out why, we would work with clinical departments to develop a screening test. Meanwhile, we would go back to our basic science departments to determine the particular biochemistry and cell biology involved, and we would work with drug companies to develop new therapies.

Besides figuring out the scientific and clinical applications, resolving the knotty issues of ethics and privacy will be a necessity if the new science of genomics is truly to benefit patients, says Warren. As a scientist at the forefront of national discussions on the ethical issues surrounding genetic discoveries, he expects Emory's genetics department to assume a leadership role in convincing state and national governments to enact legislation to protect patients' genetic privacy. This could help prevent discrimination in the workplace and in insurance coverage. He foresees partnerships with Emory's law school and theology school and ethics center in dealing with these tough ethical issues.

SAY WHAT?

YOUR GENE-SPEAK GLOSSARY

With the vocabulary of genetics evolving
faster than the unscrambling of the human
genome, this basic primer may prepare you
for your next "gene-speak" encounter.

Bioinformatics: method in which scien-
tists, mathematicians, and computer sci-
entists learn about health and disease by
using computer science and math tools to
help explain complex biological and
genomic data

DNA microarray technology: using
small chips to compare thousands of genes
at the same time.

Gene: chromosome pieces whose parti-
cular combination of four chemical bases
(ACTG) spell out the information required
to produce a particular protein

Gene expression: activity of a gene;
when, where, and how much of a protein
will be produced in a cell or tissue

Genetic sequence: string of millions of
letters (ACTG) representing the four chem-
ical bases arranged in a certain order and
combination within the DNA of each
chromosome

Genetics: study of patterns of inheritance
due to variation in DNA

Genome: total set of genes in an organism

Genomics: study of an organism's genes
and genome

Genotype: genetic constitution of varia-
tion of an individual

Mitochondria: "power plants" in the cyto-
plasm of a cell with their own DNA

Pharmacogenomics: the use of genomics
data to design drugs that target specific
genetic variations

Phenotype: characteristics displayed by
an organism derived by variation in the
genes (genotype) and the interplay with
the environment

Proteins: products of gene expression
that are combinations of amino acids that
serve as life's basic building blocks and
carry out all bodily functions

Proteomics: analysis of proteins within a
cell and how those proteins interact and
influence each other

Transcribing: directing cells to make
proteins by activating genes

Transcriptome: how a cell responds to a
particular environment by modulation of
gene expression

Before microarray technology, scientists were restricted to studying only one or just a few genes at the same time. Now they can compare the activity of up to 40,000 genes simultaneously by arraying genetic sequences on chips the size of standard microscope slides. Having access to the expression patterns of numerous genes at the same time opens countless possibilities for research and discovery, including how genes function relative to one another, how their expression varies in different diseases, how genes change during aging, and how they are influenced by drugs. Biopsied tissue can be compared to normal tissue as a screening test, for prognostic clues, or to test the effectiveness of drugs, for instance.

Conventional tests such as functional MRIs provide a broad measure of how drugs like cocaine affect the brain, but microarray technology gives scientists access to an entire panel of genetic changes. Using the microarray equipment in the Core Facility for Functional Genomics, located in the Yerkes Primate Research Center, neuropharmacologist Scott Hemby and his colleagues have identified more than 400 human genes that are affected by long-term cocaine abuse. Their work represents the first molecular profile for human drug addiction. The core facility was developed through and also serves the Georgia Research Alliance (GRA) -- a partnership of industry, government, and the state's leading research universities.

Hemby is comparing the genetic profiles of postmortem brain tissue from cocaine addicts with those of age-matched controls and is correlating the results with information from interviews with family and friends. He hopes to develop medications to target specific aspects of the biochemical pathways that promote craving for cocaine.

Gastroenterologist Curt Hagedorn uses the genomics facility to study gene expression variations in patients infected with hepatitis C. Some patients have mild forms of the disease, while others develop severe fibrotic disease and require liver transplants. Hagedorn and his colleagues hope their research will help physicians target their treatments more effectively and lead to better drugs that clear chronic HCV infections or reduce liver fibrosis.

Scientists in Emory's Center for Molecular Medicine, led by director Doug Wallace, are using microarray technology to uncover information about diseases of the mitochondria -- the power plants located in the cytoplasm of the cell. Diseases associated with mitochondrial defects include certain movement disorders, some cases of Alzheimer's disease, hypertropic cardiomyopathy, muscular dystrophy, some forms of epilepsy, and adult onset diabetes. With genomics technology, Wallace and his colleagues are discovering the biochemical causes underlying clinical problems and linking conditions involving energy deficiency to genetic mutations. Armed with genetic profiles of problems involving the mitochondria, they hope to compensate for metabolic problems using drug therapy.

In the department of pathology and laboratory medicine, microarray technology helps scientists study gene expression variations in various types of neural tumors and breast tumors to improve diagnosis and tailor therapies to specific patients. Emory pathologists and urologists are profiling genes that are activated in renal cell and prostate cancer. The US Department of Defense recently gave Emory's urology department $2.5 million to establish a comprehensive prostate cancer research center to study relevant genes.

More than 250 investigators throughout the health sciences center use the School of Medicine's DNA sequencing core facility and its gene chip technology at the Atlanta Veterans Affairs Medical Center. Projects include the genetic mechanisms in clogged arteries of atherosclerosis patients, gene expression in kidney disease and kidney transplantation, and gene regulation in bone growth.

Genomics refers to the primary DNA sequence of genes (the arrangement of the letters A, C, G, and T). With microarray technology, scientists reach the next level of analysis -- the transcriptome or how a cell responds to a particular environment. Proteomics, which takes DNA analysis one step further by analyzing the proteins within a cell, is one focus of the joint Emory-Georgia Tech Coulter Department of Biomedical Engineering, which is developing new proteomics equipment for the center for medical genomics. The next level - the "holy grail" of genomics - will not be realized for quite some time. This is the metabalome or the simultaneous definition of all chemical reactions and protein-protein interactions taking place within the cell.

Emory and Tech scientists and their colleagues at the University of Georgia, Georgia State University, Medical College of Georgia, and Clark Atlanta University are collaborating in an aggressive GRA program to put the state on the cutting edge of genomics and proteomics. Included in the program are a network of microarray and proteomics core facilities and the recruitment of a cadre of "eminent scholars" to lead proteomics and genomics research and development.

"If you're buying commercial technology, you're already behind the leaders," says Warren. "If you want to be at the top of departments or universities, you have to be developing the technologies."

"Genomics is pretty much a done deal," agrees Paul Doetsch, associate director for basic research of the Winship Cancer Institute (WCI). "We can look at gene chips and do the transcriptome -- that will be fairly standard for lots of people. What we need are techniques that allow us to address proteomics. With the equipment and techniques for this now being developed, Emory can be a pioneer in this area."

Already, scientists in departments such as biochemistry and pathology and laboratory medicine are beginning to use advanced mass spectrometry equipment to analyze "protein signatures" for diseases such as bladder cancer.

To prepare for the onslaught of laboratory data with the addition of genetics information, pathology has been developing its own bioinformatics capabilities and hiring new informatics faculty. Chair James Madara knows a large share of the responsibility for dealing with new patient data will fall on the shoulders of his department.

"At Grady Hospital alone we already produce more than a million laboratory tests each month and distribute that information to our physicians," Madara says. "Genomics data will add a new level of complexity. Until this point, much of what we at Emory and others have been doing could fairly be called either development or research. But ultimately this kind of testing will be used in real patient management and diagnosis. When that happens, pathologists will be called on to run equipment, distribute information, and set up quality assurance. That's an important reason for us to be involved in the development stage."

The forward-thinking alliance of academic, business, and government interests in genomics engineered through the GRA recently led to a major breakthrough in bioinformatics that promises to benefit the entire state. Last fall, bioinformatics pioneer NuTec Sciences moved its headquarters from Houston to Atlanta and agreed to crunch the data for EmTech Biosciences, its start-up biotechnology companies, and all GRA-affiliated research institutions.

NuTec was formed in Houston by Georgia Tech graduate Michael Keehan to develop computational sciences for identifying new oil deposits. Its bioinformatics technology fit nicely into the needs of the growing genomics revolution, and NuTec was fortunate to form early relationships with the Department of Energy (DOE-Livermore Labs), the National Institutes of Health's National Human Genome Research Institute (NHGRI), and Sandia National Laboratory. NHGRI was responsible for the publicly funded Human Genome Project's recent sequencing of the human genome.

In December, NuTec teamed up with IBM to build in Atlanta the world's largest supercomputer devoted to the life sciences. In a whirlwind of activity that rivals the speed of a computer calculation, NuTec has sewn up exclusive licenses from DOE and NHGRI to develop and commercialize NuTec's current and future software systems for bioinformatics in genomics and proteomics. For example, GeneSeeker will allow researchers and clinicians to mine genomic data for screening, research, and drug development. Data Foundry allows simultaneous access to multiple worldwide genetics databases and can query clinical databases like OMIM (Online Mendelian Inheritance in Man), which has meticulously documented the phenotype (physical and biochemical signs) of every known genetic disease. It can report which genes are expressed in certain disease states or under the influence of particular drugs. It also can access the genotype of various diseases, including chromosomal abnormalities.

"Let's say you, as a physician, have the gene expression (transcriptome) information on the computer screen and want to know what other kinds of phenotypes in terms of types of patients or types of tumors that transcriptome has been associated with," explains Vice President for Academic Health Affairs David Blake. "At the touch of a button, Data Foundry goes out and queries all the databases worldwide, Ômines' the data, and brings back the information. If there are 2,000 possibilities of genes being expressed with that tumor, you can tell Data Foundry to give you the top five."

Tech who?

No "tech" in this name, but the Georgia
Research Alliance (GRA) has been the
powerhouse behind the state's movement
forward in genetic research. GRA is an
alliance of industry, government, and the
state's leading research universities, which
drives programs that help turn laboratory
discoveries into economic gains for the
state. www.gra.org

Finding the ideal combination of resources, expertise, and institutional support to develop such a system of "seamless informatics" was the vision of Jonathan Simons when he was recruited from Johns Hopkins last fall to head the Winship Cancer Institute (WCI). Simons is using genomic therapy as a new approach to treating cancers that are resistant to conventional chemotherapy and radiation therapy and hormonal therapy. He and his colleagues already have used genomics tools to help develop a drug that targets a gene involved in prostate cancer metastasis to the bone.

Simons may well have realized his future vision in the bioinformatics capabilities of NuTec. In March, the WCI, NuTec, and IBM agreed to collaborate on developing cancer genomics software (called the Genesys Seamless Informatics System) that for the first time will allow physicians and basic scientists to integrate clinical and genomics data.

Genesys, which will access the new supercomputer, should translate into accelerated delivery of modern cancer treatment, including more accurate diagnoses, precisely targeted therapies, and better patient matching to appropriate clinical trials. Routine medical information will be combined with the patient's genetic fingerprint and real-time gene expression information from the patient's tumor. For basic scientists, it will mean greater access to clinical data, a direct connection between laboratory markers of gene expression and real-time experience in patients, and new drug development.

Simons will continue to use the new genomics tools to identify targets for anti-cancer drugs based on genomic vulnerability -- the science of oncopharmacogenomics. New cancer institute faculty soon will use genomics chips to treat lung, breast, and prostate cancer patients by individualizing their treatment with new drugs, all done in a visit via NuTec and the supercomputer.

"For example, our mining tool might tell us that in the first 100 patients getting a particular drug, a certain pattern of breast tumor transcriptome was associated with a better outcome than another pattern," explains Blake, who will be program manager of the NuTec-Emory initiative. "At that point we really don't care why, because we can still benefit the patient by being able to make an informed selection about treatment today. Later it will be great to learn why, and people back in the lab will be working on those answers."

To advance knowledge, the bioinformatics tool also needs to work in reverse. "The only way this new approach is going to move ahead is if every patient-clinician interaction is a new piece of data that an astute clinician enters into the system," explains Blake. "Then, when we put that transcriptome pattern into the computer and compare it to outcome and toxicity and blood cell count and suddenly a tremendous association lights up, that's when the clinician has accelerated knowledge."

As long as their new genomics tool is in the development stage, NuTec has agreed to market it only to the WCI and the NIH. After that, Emory has the first option to expand the platform to other clinical disciplines. Cardiology and neurology could be next, and the platform might eventually extend throughout the health sciences center. Emory will pay NuTec for its proprietary software and in return will receive substantial equity in NuTec, which eventually plans to become a publicly held company.

From the Director  /  Letters

On the front lines of health care

Half century of cooperation (photos)

Research: The VA's secret weapon

Designer medicine

Moving Forward  /  Noteworthy

Unfinished business: The prospects for health care reform in the 107th Congress

Looking for greener pastures

The NuTec partnership is just the beginning of exciting bioinformatics collaborations between the state's research universities and industry, according to Mike Cassidy, president of the GRA. "For example, we have just entered a partnership with Amersham Pharmacia, a leading pharmaceutical company, to help develop our proteomics core facilities," he said. "Our aggressive program in genomics, proteomics, and bioinformatics is designed to trigger new companies and to attract industry leaders to the state. This effort has the potential to put Georgia at the forefront of an enterprise with enormous quality-of-life and economic implications."

Holly Korschun is director of science communications for health sciences media relations.