Mining the human genome for new health therapies☆

Types of genetic contributions to medical disorders 

There are three groups of genetic disorders (5):

Genetic testing: an early outcome of the “genetic revolution” 

The “genetic revolution” occurred long before the completion of the HGP. Among the first practical and commercial outcomes of deciphering the DNA sequence of the human genome was DNA-based testing. Molecular testing technology was used to detect possible disease predisposition, or the existence of disease in asymptomatic individuals and their progeny. The tests were also used to diagnose disease, confirm diagnosis, provide prognosis, and provide disease follow-up. Most of the current hundreds of clinically used genetic tests are aimed at detecting mutations associated with rare genetic disorders that demonstrate Mendelian inheritance patterns, including Tay-Sachs, cystic fibrosis, sickle-cell anemia, and Huntington's disease.

With the blueprint of the human genome at hand, scientists are setting out to discover and develop tests for every possible mutation and chromosomal aberration. Readily available DNA-based testing is revolutionizing prenatal diagnosis and care. Genetic testing is now routinely applied to chorionic villi and amniocyte samples. Distinct as well as subtle chromosomal abnormalities, and devastating as well as inconsequential single-gene mutations, can be detected early in pregnancy. Rarely, early detection confers an opportunity for heroic intrauterine intervention. In most cases, however, the dilemma of pregnancy termination rises to the fore. The dilemma becomes more poignant when genetic testing reveals the existence of a mutation or a chromosomal abnormality but falls short of predicting the eventual severity of the resulting condition. Similarly, difficult decisions need to be made when genetic testing involves late-onset diseases such as Huntington's disease.

Recent advances in reproductive medicine open the door to genetic testing of gametes and embryos in vitro. While allowing for selection before implantation (and in the near future, possibly even before fertilization), genetic diagnosis is currently inefficient and costly, and poses significant clinical risks to women (7).

For a few of the more complex conditions, such as breast, ovarian, and colon cancers, it is already possible to detect mutations. These tests are fraught with limitations; nevertheless, they are gaining ground and are used to make risk estimates in asymptomatic individuals with a family history of certain disorders.

In the context of women's health, genetic tests could identify individuals who require more intensive detection measures or preemptive procedures, for example, performing more frequent imaging of the breasts or prophylactic oophorectomy, for women with BRCA1 and BRCA2 mutations, and ordering regular colonoscopies for those with mutations associated with colon cancer.

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Genomic-based assessment of the common complex multifactorial conditions is on the horizon. Perfecting genetic tests for multifactorial disorders—e.g., bone diseases, osteoporosis, cardiovascular disease, diabetes, Alzheimer's disease, autoimmune diseases—is the Holy Grail for the management of menopause and aging. Advances in comparative genomic research may also reveal gender differences that in turn will lead to customized gender-specific diagnosis and therapy.

Nhgri's vision for genomic research 

In April 2003, with the effective completion of the original goals of the HGP, the National Human Genome Research Institute (NHGRI), endorsed by the National Advisory Council for Human Genome Research, presented its vision for the future of genomic research (2). The implications to the field of women's health can be gleaned from reviewing the challenges set forth by the NHGRI when contemplating the theme of “genomics to health.”

The NHGRI predicts that the genome-based knowledge will be translated into large-scale strategies that will confer the following achievements (2, quoted verbatim):

In regard to the first NHGRI strategy item: it has been estimated recently that the human genome includes approximately 30,000 to 35,000 genes that give rise through alternative splicing to more than 100,000 proteins (8). Currently marketed drugs are aimed at only 500 molecular targets. Extrapolations from the now complete sequence of the human genome predict as many as 5,000 to 10,000 potential targets, which are involved in 150 clinically important multifactorial diseases (8). Gene expression (protein production), protein structure, and protein interactions are key elements of normal cellular physiology. Disruptions to genes cause disorders because the proteins they encode are defective and incapable of maintaining normal cellular protein circuitry.

Until recently, functional genomic studies were limited to the elucidation of single gene function and aberrations. Emerging strategies now allow the probing of nucleotide arrays (“gene chips”) for automatic and simultaneous screening of a multitude of genes. New microproteinomics tools allow protein pathway analysis of microdissected cells. It is increasingly possible to map changes in key protein networks in response to multiple stimuli, or to compare the differences in proteins' disposition between activated and inactivated, or healthy and diseased, cells. As a result of this microanalysis, new drugs that specifically target crucial protein intersections without affecting normal pathways are in clinical trials. Other potential products of these technologies include disease detection by protein analysis in body fluids, individualized therapies, and real-time efficacy and toxicity assessment 8, 9.

Recently, it has become clear that female menopause is not an isolated gonadal hormone deficiency but a compilation of complex multifactorial conditions. The Women's Health Initiative (WHI) recently reported that estrogen and progesterone combinations did not confer protection from cardiovascular complications and also failed to improve cognitive function (10). These reports reinforce the notion that hormone replacement should be used only for menopausal symptoms rather than for prevention in an unscreened population. It has become increasingly more evident that the risk/benefit balance associated with blanketing large populations of menopausal women with estrogen replacement may tip toward risk in many circumstances. Genomic-based screening may provide an individualized and rational management for menopause. Numerous genome-derived drug candidates have been identified as potential alternatives to gonadal hormone replacement.

Increased understanding of the molecular underpinnings of bone remodeling and the genetics of osteoporosis would allow targeting of molecules like osteocalcin, calcium sensing receptor, vitamin D-binding protein, osteopontin, osteonectin, estrogen receptor α, calcitonin receptor, specific collagens, parathyroid hormone, vitamin D receptor, transforming growth factor-β1, and cathepsin K (11). These classes of drugs are now in different stages of clinical development; parathyroid hormone is already marketed as an anabolic drug to build bone in osteoporotic women and men. Caregivers who manage menopausal women should become accustomed to the rapid pace of developments in genomics and proteinomics. They should pay attention to breakthroughs in the understanding of the genetic attributes of common complex multifactorial disorders in forming strategies for menopausal care.

Caregivers should also be aware of the immense complexity of the interactions between genetics and the environment, and they should be capable of conveying this new knowledge to their patients using clear and nondirective counseling tools.

The second NHGRI strategy item is to develop genome-based diagnostic methods for disease susceptibility, early disease detection, the prediction of drug response, and the accurate molecular classification of disease. Many of the management schemes in the area of women's health employ long-term preventive measures applied to large populations of individuals who have diversified risk levels. Developing gene-based individualized predisposition tests and incorporating them rationally and ethically into prevention and management protocols for cancer (e.g., breast, ovarian, endometrial, colon), osteoporosis, psychoneurological deterioration, and cardiovascular disorders will have a tremendous impact on public health, especially on women's health.

Patients respond differently to the same medication. Pharmacogenomics (known in past texts as pharmacogenetics) studies the role of genetics and inheritance in the individual response to drugs. In addition to gender, age, type of disease or condition, and drug interaction, genetic factors determine 20%–95% of the individual's drug disposition (12). The extent of genetic influence on the rate of adverse events due to drugs is still not fully elucidated (13). In a few situations, the genetic attribute stems from a monogenic factor. In most cases however, several genes and their products interplay to influence the pharmacokinetics and pharmacodynamics of medications. The ultimate goal for the future is to develop individualized effective and safe therapies based on a predetermined individual genomic profile.

Currently, the main challenges are to identify polygenic factors of individual drug disposition by genome-wide searches for polymorphism associated with drug effects, and to utilize current knowledge in pharmacology and physiology to identify candidate genes and their expression using genomic maps and proteinomic pathways (12). Reducing the risk of developing thromboembolic events in women receiving contraception pills or estrogen replacement therapy is one of numerous potential benefits of pharmacogenomics research.

The third NHGRI strategy is to assess how genomic medicine, with its extension into proteinomics, can bring drugs from the bench to the clinic or the bedside. Due to the rapid pace of discoveries in genomics and proteinomics, traditional drug discovery will soon be enhanced by additional information from the level of genomic DNA, mRNA profiles in cells and tissues, and protein pathways (2).

Whatever the source of drug candidates, assessment of novel therapeutics universally follows a strict pattern. Initially, new drug development requires robust preclinical design and execution and well thought-out early hypothesis testing. Human testing follows with demonstration of tolerability, safety in smaller population for shorter exposure, and first signals of efficacy (in phases I and II). Finally, validation (to prove safety and efficacy) of any pharmaceutical target must come from well-designed, pivotal, clinical studies (in phase III). Drug development is an incredibly long and costly enterprise that currently requires decades of research and development and hundreds of millions of dollars. It is traditionally a partnership among researchers, industry, government, third-party payers, caregivers, consumer advocates, and consumers. If genomic medicine will fulfill its promise it will shorten the length of time required for drug development and it will significantly reduce the research and development costs associated with licensing new drugs.

Pharmacogenomic approaches will increase safety in clinical trials by reducing adverse events 12, 13. Genomics and proteinomics shorten the process of identifying new drug candidates. Non-human species genomics identifies more appropriate animal models for preclinical studies. Genome-based tests will identify appropriate subgroups to decrease the sample size required to elicit efficacy signals in pivotal clinical trials. This in turn will decrease the time-line for conducting trials. Genomic medicine today has already increased the size of the overall new drug development pipeline.

A promising future 

Menopause management will surely gain from genomic developments in cardiovascular disease and Alzheimer's therapy. But the benefits will not be limited to the most common conditions. If drug development paths are made faster and cheaper, there will be higher motivation to develop drugs for rare disorders of fertility, for example, or even for common gynecological disorders with small markets and low reimbursement rates.

Genomic medicine holds formidable promise for the future of medicine; it is bound to revolutionize health care. But there are many ethical concerns and limitations to be addressed. Legislation surrounding privacy issues, genetic testing of large populations, storage of genetic data, and access to genetic data is not yet in place. Equal access to emerging therapies is not guaranteed. Moreover, the extraordinary affect of the “new genetics” on the human condition and future generations is not clear. It is incumbent upon medical institutions to prepare for great change. Caregivers must educate themselves so they can confer the benefits of the genomic medicine upon their patients without the associated hazards.