In many areas of our lives, we seek individualized attention. We want our children educated in a "one-on-one" environment, not led through instruction like a herd of cattle. We ask state-level officials to remember that solutions for the problems of one town will not work for those of another. We may wear uniforms or bear titles that place us in categories—dental hygienist, laboratory researcher, oral surgeon, prosthodontist, orthodontist, dentist—but we resist mass categorization and stereotyping.
Science, however, has a problem with individuality: it messes up statistical analysis. For example, the statistical mean—commonly known as the average—is calculated by adding individual measurements together and then dividing the sum by the number of measurements. A research study on the ability of a potential drug to kill cancer cells, for example, might discover that application of the drug destroyed an average of 50 percent of the existing cells.
Let us assume the experiment used thousands of petri dishes, each filled with millions of cells. The calculated 50 percent value represents an amalgam of all those thousands of dishes—an "average" dish. Some petri dishes would have lost many more cells—maybe close to 100 percent—and some would have lost very few.
This concept necessarily extends to the treatment of many human diseases. Some treatments work only in a subset of patients—but better in those patients than in none at all. For example, in phase 2 cancer clinical trials—a crucial part of developing new therapies—a therapy is considered "successful" if it shrinks tumors in at least 20 percent of patients.1 (The therapy then goes on to phase 3 trials, which compare it with current treatments.)
Although a treatment may work in only a small percentage of patients, it has been difficult, if not impossible, to identify which patients will benefit from selected therapies. As a result, health care providers must rely on the tenet of "one disease, one treatment," although we all realize that people are different (sex, age, ethnicity, socioeconomic status) and that a disease process does not act the same in everyone.
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MULTIPLE DIFFERENCES
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Generally, the histories of many epidemics have provided superb analyses of the variance in the prevalence of infectious diseases. For example, a strain of influenza that is a nuisance to an otherwise healthy young adult can kill an infant, an elderly person or a young adult with a compromised immune system. A chemotherapeutic agent that works well in one person may produce nothing but side effects in another.
In the first example, there is a simple explanation for the alternate courses of the flu: robust immune systems combat the disease, while weak or compromised immune systems all too often succumb to the disease. In the second example, the question of why chemotherapy works well for one person but not another is thornier. Perhaps one person has a genetic polymorphism that makes his or her cancer cells resistant to chemotherapy, the other has a mutation that makes his or her cells susceptible to chemotherapy, both cases are true, or neither case is true.
The concept of genetic differences producing differing responses to disease is not new, but discovering what those differences are and how to tackle the obstacles they present have been possible only with the advent of molecular medicine. We now have opened the doors to the concept of individually tailored diagnoses and therapies, but what lies behind those doors is a maze of complexity.
In his "Essay on Man," Alexander Pope declared, "‘Tis but a part we see, and not a whole."2 The "parts" easiest to see in human disease are epidemiologic ones—the distribution and patterns of disease among subpopulations. There are dramatic differences in the distribution of many diseases by sex, age, socioeconomic status and ethnicity. We can use these parts to provide clues that will set us on the path to finding genetic polymorphisms that might explain some of the variation in disease distributions.
For example, autoimmune disorders such as lupus, rheumatoid arthritis, sclero-derma, Sjögren’s syndrome and fibromyalgia disproportionately affect women. Women are 10 to 15 times more likely to be diagnosed with lupus then are men.3 Thus far, no definitive gene has been identified in conjunction with the disease. Although lupus is known to occur within families, only 10 percent of patients with lupus will have a close relative (parent or sibling) with lupus, and only about 5 percent of children born to a parent with lupus will develop the disorder.3
As we delve deeper into the human genome, we find that in many cases there is no "average" patient.
Research on pain also has revealed stark sex-based differences. Women have more pain receptors and, therefore, a lower pain threshold than men. A recent study, however, found that only men had a statistically significant response to ibuprofen.4 Thus, we are confronted with a paradox of medicine: women are more likely to be diagnosed with painful conditions—such as rheumatoid arthritis—yet they do not respond to commonly prescribed medications for these conditions.
Ethnic and socioeconomic differences also are apparent in many diseases. The difficulty here is in teasing apart the possible genetic susceptibilities, lifestyle factors and social factors. One social factor recently highlighted is that African-Americans with non–small-cell lung cancer are less likely than whites to be treated with surgery.5 Using data on nearly 11,000 patients, analyses showed that the surgery rate for blacks was 12.4 percent lower than that for whites, and the survival rate for blacks was 7.5 percent lower than that for whites.5 Among all patients undergoing surgery, survival rates were equivalent. This also held true among those patients who did not undergo surgery. In this case, the reason for the health disparity is nebulous: are there subtle differences in doctor-patient communication, in patient decision-making processes or in access to comparable health care?
In the previous example, the "one disease, one treatment" dogma is upheld, in that surgery increases the average survival rate. Other behavioral or socioeconomic factors, however, are keeping some patients from receiving necessary or optimal health care.
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DEEPER INTO THE HUMAN GENOME
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The average survival rate for lung cancer or any other disease does not reflect the individual differences that science is beginning to discover. As we delve deeper into the human genome, we find that in many cases there is no "average" patient, and that individualized dentistry and medicine are the future paths to revolutionizing detection, surveillance, diagnosis, therapeutics and treatments of human diseases and disorders.
In the nucleus of each human somatic cell there are an estimated 100,000 genes encoded in approximately 1 meter of double-stranded DNA. This DNA is packaged within 46 chromosomes—22 pairs of auto-somal chromosomes and one pair of sex (XX or XY) chromosomes. Each chromosome consists of 50 to 250 million nucleotide bases—adenosine, or A; thymine, or T; cytosine, or C; and guanine, or G—rearranged and repeated into a code that provides the language of life. Three nucleotides in sequence represent a codon; codons strung together represent genes.
During DNA replication and on exposure to environmental insults (chemical carcinogens, ultraviolet light, radiation), changes or mutations can occur. These changes include the substitution of one base for another, the loss of one base from a codon or the movement of a DNA segment to a new location.
When a gene contains a mutation, the protein encoded by that gene can be a normal variant or it can be abnormal. Some protein changes are clinically insignificant, but others alter the protein’s structure or eliminate it entirely, such as mutations in the globin gene associated with sickle-cell anemia. Even then, there may be no obvious difference between a person with the normal variant of the gene and one with a changed gene. Most genes have many forms—called genetic polymorphisms. Discovering the ultimate results of these genetic changes is at the forefront of attacking human disease from the individualized perspective.
A recent finding in prostate cancer research illustrates the striking differences effected by genetic polymorphisms on diagnosing and treating human disease.6 Although its causes are largely unknown, prostate cancer is a hormone-dependent cancer, and androgens—male hormones including testosterone—have been proposed as having a substantial role in disease predisposition.
When a gene contains a mutation, the protein encoded by that gene can be a normal variant or it can be abnormal.
In a case-controlled study of black and Hispanic men, researchers found that a specific genetic polymorphism increased prostate cancer risk sevenfold in blacks and nearly fourfold in Hispanics.6 The polymorphism results in a change in one amino acid in the human prostatic (or type II) steroid 5-alpha-reductase gene—SRD5A2. The enzyme encoded by this gene controls the metabolism of testosterone to dihydrotestosterone, or DHT. DHT is a potent hormone that has been implicated in both prostate cancer and benign prostatic hyperplasia, or enlargement of the prostate. The mutant enzyme seemed to work overtime, producing higher levels of DHT.
In this study, researchers also discovered that men with this genetic polymorphism did not respond to treatment with finasteride, which blocks the enzyme that converts testosterone to DHT. It is possible that finasteride does not block the mutant enzyme, or it only partially blocks its effects.
What is vexing is that 30 percent of men diagnosed with limited-stage prostate cancer go on to have clinically significant disease.7 We are challenged with a fascinating question: how to evaluate new therapies for a neoplastic disease when more than two-thirds of these men will die with prostate cancer, not from it?
The National Institutes of Health’s National Human Genome Research Institute and the National Cancer Institute are conducting a study of genetic determinants of prostate cancer in black families with histories of prostate cancer. The study is focused on determining whether genetic polymorphisms may be associated with the increased prostate cancer risk noted in black men.8 While only 1 percent of the total population seems to carry this mutated SRD5A2 gene, approximately 10 percent of black and Hispanic men carry the gene.6
Genetic polymorphisms or allele variations—such as breast cancer 1 and breast cancer 2, or BRCA1 and BRCA2, respectively—may be associated with susceptibility to a disease or with response to therapy after a disease has been diagnosed. A British group studying a group of genes called glutathione s-transferases, or GSTs, have found that women with ovarian cancer who are missing two specific GST genes have significantly lower survival rates than do women who have one or both of these genes. The women lacking both genes also do not respond to platinum-based chemotherapy (Richard C. Strange, B.Sc., Ph.D., Keele University, Staffordshire, England; personal communication; Sept. 30, 1999). The enzymes encoded by GST genes are involved in detoxifying cells.
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ENVIRONMENTAL INFLUENCES
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Looking at genetic polymorphisms as isolated events, however, is shortsighted. Certainly the genes interact with one another and also have complex relationships with a person’s environment and lifestyle factors such as diet and tobacco and alcohol use. Sometimes, lifestyle factors overwhelm all other variables. In a recent study of head and neck cancer in Puerto Rico, exposure to alcohol and smoking were identified as predisposing risk factors in 95 percent of cases.9
These data dovetail with research in the Americas that shows Puerto Rico has very high rates of tobacco-related cancers—lung, oral, laryngeal, pharyngeal and esophageal.10 Other countries with high rates of tobacco-related cancers include Uruguay, Cuba and Argentina; Peru, Ecuador, Dominican Republic, Mexico and Colombia have the lowest rates.10 Evidence also reveals a trend of increasing lung cancer mortality rates over time in most of these countries.10 It seems that in the Americas, the tobacco-related lung cancer epidemic still is in its early phase—a dose of jarring reality that indicates that lifestyle factors can often drown out, or at least minimize, the effects of genetic polymorphisms.
Even in the case of tobacco use, individual variation comes into play. Smoking may be responsible for as many as one in five deaths in the United States, and tobacco use costs the United States more than $100 billion each year in health care expenses and lost productivity.11 Many people, however, smoke for years and remain cancer-free, while others who have never used tobacco are diagnosed with lung cancer. Although nearly 90 percent of lung cancer cases can be attributed to smoking,11 only a small percentage of smokers will ever develop lung cancer. According to the American Cancer Society, an estimated 47 million adults were current smokers in the United States in 1995,11 and there were approximately 172,000 lung cancer cases diagnosed in 1998.12
Technological advances such as gene chips and microarray technology may allow health care providers to screen and identify subpopulations at risk of developing a particular disease or disorder.
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CONCLUSION
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How disease strikes and who it strikes is a conundrum hidden and encoded within the DNA. We can help answer these questions through a genetic understanding of human diseases and disorders, a major part of which is the mapping of the entire human genome that is scheduled to be completed by 2003. The completion of the human genome project and its complementary library of single nucleotide polymorphisms will allow research to move forward and to accelerate and revolutionize the detection and diagnosis of diseases and disorders.
In tandem, we have an extraordinary opportunity to revise the curriculum for dental education. The emerging knowledge base in molecular genetics will catalyze the development of gene-based diagnostic and therapeutic strategies that acknowledge people’s individual and subtle differences. Dentists and physicians have begun to mention "tailored therapy" or "individualized therapy" for diseases and disorders such as periodontal disease, osteoporosis, cardiovascular disease, temporomandibular joint disorder, fibromyalgia and neoplastic diseases.
In the near future, technological advances such as gene chips and microarray technology may allow health care providers to screen and identify sub-populations at risk of developing a particular disease or disorder, as well as to provide people with disease-specific targeted therapies.
The best is yet to come. We are entering "the biotechnology century."
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MULTIPLE DIFFERENCES
DEEPER INTO THE HUMAN...
