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By Daniel A. Casciano, Ph.D.
New technologies and tools have been developed as a direct result of the nation's decade-long effort to understand the entire sequence of the molecule that holds the genetic information that makes us who we are.
The effort to decode the sequence of the molecule called deoxyribonucleic acid--DNA for short--is called the Human Genome Project. It is the basis for understanding the blueprint that directs our external appearance, such as hair and eye color, skin color, sex, height, and behavior, as well as the quality of our internal organs.
This special issue of FDA Consumer presents the Food and Drug Administration's response to several of these emerging technologies as they relate to the discovery of and the safety assessment of the food, drugs, biologics, and medical devices it regulates.
The gene is a unit or segment of the DNA that contains the information for a protein, which is a building block or a catalyst in each of our cells. The complete DNA content of our cells, called the human genome, contains many such segments or genes. A gene or set of genes are expressed, that is, function, when there is a need for the building blocks to sustain the life of the organism. In this way, the genome contains the architectural blueprint that dictates each individual's makeup.
Humans develop from a single fertilized egg to become a multicellular organism made up of a variety of organs and tissues. The DNA of the human genome contains all the information that prescribes whether a particular cell becomes part of the liver, or part of the brain, kidney, or bone. This comes about mainly through the extremely well-coordinated and differential expression of genes within the particular cell. When this ordered expression of genes goes awry, called perturbed by scientists, diseases such as cancer can result.
Functional Genomics is the study of gene function on a whole or partial genome scale that includes the study of gene expression using DNA microarray technology. It measures the expression of genes under normal and perturbed conditions and attempts to predict the gene expression profiles for these conditions.
Structural Genomics involves identification of genes that predispose people to various diseases, including cancer. Those working in structural genomics also study genes that may alter a person's response to a drug or other substance, resulting in an adverse event. An example of the latter is the recent episode of some patients' reaction to Vioxx (rofecoxib) and other Cox-2 inhibitors. Functional and structural genomics are considered emerging technologies that will help the development of personalized medicine to eventually replace the "one size fits all" approach to medicine.
Proteomics, the protein complement expressed by the genome of an organism, is the global analysis of cellular proteins. Proteins play a role in maintaining the structure of the cell or organism and also can act as enzymes or catalysts converting one molecule into another.
The molecules that are altered by enzymes are termed metabolites. Metabolomics, also called metabonomics, is the study of metabolite profiles in biological samples, in particular urine, saliva, and blood plasma. In some instances, cerebrospinal fluid may be the source for analysis. The Holy Grail of these new technologies is to prove that the study of metabolites can accurately predict gene expression and protein production using only a sample obtained from a patient in a non-invasive way.
Until several years ago, scientists were limited to studying a single gene at a time and to attempting to understand how that gene contributed to the normal physiological status of an organism. Sometimes, the gene studied was chosen because of its importance in specific disease pathways or because the product of that gene, a protein, was a target of a drug that was under development. The data generated were generally small in quantity and could easily be assessed by the person developing the hypothesis to try to understand how the gene works.
Today, however, scientists have the capacity to simultaneously study all the expressed genes in an organism. In humans, there are about 30,000 genes that can be expressed during the course of a human's normal life cycle. Sometimes, these genes are inappropriately expressed at an inopportune time because of a genetic defect of an individual or because an individual may have been exposed to a chemical or physical agent, either accidentally or purposefully, that induces toxicity or some pathology in that individual. The inappropriate expression of a gene or set of genes may result in cancer, heart or blood vessel disease, a behavioral change, or some other adverse event.
The study of thousands of genes at a time requires the use of another discipline called bioinformatics. This scientific discipline encompasses computer science and engineering, statistics, and mathematics. The necessary bioinformatic tools include a repository for the large amounts of data developed, a database; tools to analyze and visualize the data in a format that is familiar to the scientist developing the hypothesis; and tools to help the scientist interpret that information stored in the database. Ideally, the database is available to any interested party and is public; however, in some instances, the data are proprietary, such as the data assessed by the FDA, and, therefore, not available to the public.
The new technologies discussed in this issue of FDA Consumer are being used in a variety of different scientific disciplines including the discipline of toxicology, which attempts to understand how adverse events are induced in organisms as a function of exposure to potential toxic substances or poisons. The term toxicogenomics is used to describe a new subdiscipline of toxicology that combines the emerging technologies of functional and structural genomics, proteomics, and bioinformatics to address biological or toxicological problems and to identify and characterize the action of known or suspected toxic substances.
Why is the FDA interested in encouraging the applications for approval of these new technologies? There are many reasons. The most important one, in my opinion, is bridging the data gaps that exist in preclinical and clinical studies used to assess the efficacy and safety of products regulated by the FDA.
Pharmaceutical companies develop drugs to alleviate or prevent human diseases. The process of drug discovery and approval includes identifying a chemical that targets a specific cellular molecule associated with a particular disease and assessing the safety and efficacy of the proposed drug.
The safety of these proposed compounds usually is evaluated initially in preclinical studies done in rats, mice, dogs, and sometimes monkeys. If these studies don't reveal unacceptable toxicity, safety and efficacy are evaluated in humans in clinical studies.
In many instances, the human studies are not large enough to identify a rare toxic or adverse event that a drug may induce in a small subset of susceptible individuals. To identify these events generally requires prescriptions of millions of doses of a drug. Scientists in the pharmaceutical industry and the FDA are interested in predicting these adverse events prior to the approval and marketing of a drug, thus the intense interest in determining the value of these new technologies in preclinical and clinical studies. The great value of these new tools is their application in the assessment of the safety of a product in non-human model systems and in the human. Such assessments result in the development of more relevant data used to identify the potential toxicity of a drug prior to prescribing it to many individuals.
Another reason the FDA is interested in these technologies is that they will be used not only in the discovery phase of potential products, but also in the safety evaluation phase of development and submission to the FDA. So, it is important for agency employees to become experts in understanding the value of these tools to avoid becoming a barrier to medical product development.
It benefits the FDA and the public to be actively involved in the development, standardization, and validation of these new technologies. One example of the FDA's role as a facilitator is the recent publication of a Pharmacogenomic Guideline for submission of data generated using these technologies to the FDA.
These technologies have great merit because they can be used to assess potential adverse events in patients and in animal model systems that are used to mimic the human. If a chemical or drug induces an adverse biological response, such as cancer, there are usually early indicators of this response or markers we call biomarkers that predict an adverse response. A biomarker that most people are familiar with is the metabolite called cholesterol. Scientists have shown that a certain quantity of cholesterol in the blood indicates an increased probability that the person with this level of cholesterol will have an increased risk of developing heart disease. To reduce the possibility of an adverse heart disease, drugs have been developed to reduce the amount of cholesterol and consequently reduce the risk of heart disease.
The scientific community, especially toxicologists, search for biomarkers of toxicity, cancer, reproductive problems, behavioral deficits, and other problems in an effort to prevent their occurrence.
Although I have concentrated on the use of these technologies in evaluating the safety of human drugs, they are applicable to understanding the safety of other FDA-regulated products such as medical devices, animal drugs, and biologics. Additionally, they are tailor-made for understanding the nutritional components in food and the safety of food additives, food contaminants, and dietary supplements.
The articles in this special issue of FDA Consumer expand upon some of the concepts described in this overview and explain the value of these new technologies and tools in helping the FDA to protect and promote the public health.
Daniel A. Casciano, Ph.D., is director of the FDA's National Center for Toxicological Research located in Jefferson, Ark.
Each person has a unique set of chemical blueprints that determine how his or her body looks and functions. These blueprints are contained in their own deoxyribonucleic acid, or DNA, which is made up of two twisting sequences or single strands that are able to be paired with another.
Each single-stranded DNA fragment is made up of four different coding molecules, or base pairs, called nucleotides: adenine (A), thymine (T), guanine (G), and cytosine (C) that are linked end to end. Each base on the opposite strand specifically pairs with, or is the complement of, the other: an A always pairs with a T, and a C always pairs with a G. A DNA molecule with the sequence A-T-T-G-C, for example, will stick to or complement another with the sequence T-A-A-C-G to form a double-stranded DNA. This sequence, or the order of these pairs, spells out the exact instructions for creating an organism, such as the human genome, with its own unique traits, or genetic code.
Specific segments of DNA that contain the instructions for making specific body proteins, such as those that determine the physical features of blue eyes or curly hair, are called genes. Other DNA segments provide the instructions for the body to produce important chemicals called enzymes that help to direct and control the chemical reactions that occur within the body. Depending on the codes of a specific gene, even a small error within the DNA structure sometimes can mean serious problems for the entire body. An error in just one gene can even result in a shortened life.
Genes are found in specific segments along the length of human DNA, neatly packaged within structures called chromosomes. Each chromosome consists of one piece of DNA about 4 centimeters long. Every human cell contains 46 chromosomes, arranged in 23 pairs, with one member of each pair inherited from each parent. These 46 chromosomes replicate again and again to pass on the same genetic information to each new cell as it develops.
According to the National Human Genome Research Institute (NHGRI), the DNA sequence of any two people is 99.9 percent identical. Slight variations in people's DNA sequences can have a major impact on whether or not they develop a disease and on their responses to such environmental factors as infectious microbes, toxins, and drugs. One of the most common types of sequence variations occurs in single nucleotide polymorphisms (SNPs), which are sites in the human genome where individuals differ in their DNA sequence.
Scientists now believe that all diseases have a genetic component, whether inherited or resulting from the body's response to environmental stresses like viruses or toxins. A genetic disorder is a disease caused by an unusual form, or "variation," of a gene. Other terms for problem genes include "mutation" and "alteration."
Genetic disorders can be passed on to family members who inherit abnormal genes. A small number of rare disorders are caused by a mistake in a single gene. But most disorders involving genetic factors--such as heart disease and many types of cancers--arise from multiple genetic changes and influences in the environment.
--Carol Rados