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Leaping beyond the genome—what lies ahead? July 2002 (Editor’s note: William B. Neaves, PhD, delivered this talk at the Association for Pathology Informatics’ Clinical Information System/Life Science Roundtable, which is generously sponsored by Cerner Corp. Dr. Neaves is president and CEO of Stowers Institute for Medical Research and professor, University of Missouri at Kansas City School of Medicine.) Within a 12-month period at the end of the old millennium and the beginning of the new, Science and Nature published the first sequences of insect,1 plant,2 and human genomes.3,4 Although these papers do not represent finished work for the genome sequences of any of the three species, they rank among the most influential contributions to human knowledge. They ushered humankind into the beginning of the Postgenome Era, a historic moment when comparative genomics changed forever how people think about themselves in relationship to other species. The Human Genome Project showed that the instructions for assembling the molecular machinery of the human body are encoded in approximately 30,000 to 40,000 distinct genes.3,4 Human beings share 10 percent of these genes with the fruit fly, a model organism at the forefront of genetics research for the last 100 years. Already nearly 200 genes implicated in the etiology of human disease have been found in the fly genome. These include genes associated with numerous forms of cancer as well as Alzheimer’s disease, Parkinson’s disease, cystic fibrosis, muscular dystrophy, and fragile X syndrome.5 Prior to the sequencing of the Drosophila genome, few would have expected an animal without kidneys to hold much interest for nephrologists. Several human genes involved in renal disease have counterparts in the fly genome.5 These genes produce proteins that play crucial roles in transporting fluid and electrolytes across epithelia. Like humans, flies must excrete metabolic byproducts to maintain homeostasis. They rely on malpighian tubules rather than kidneys, but the movement of ions across membranes is common to both systems. At the level of molecular machinery, effective means of accomplishing a task are shared across a broad diversity of animal species. Physicians should be prepared for astounding insights into the cause and prevention of human disease resulting from studies of fly genetics. In addition to many of the fly’s own genes that are homologues of human disease-causing genes, it is possible to insert actual human genes into flies. For example, a humanized fly model of neurodegeneration caused by an introduced human ataxia gene was recently created.6 These flies express the human gene responsible for causing Machado-Joseph disease, also known as spinocerebellar ataxia type 3. This is the most common dominantly inherited progressive ataxia in humans that results from polyglutamine expansion. The abnormal protein produced by the mutant gene has a greatly expanded polyglutamine domain, and it is prone to form harmful aggregates in the cytoplasm of neurons. Neuronal degeneration in these flies follows the formation of cytoplasmic protein aggregates just as it does in the human disease. This humanized fly model is being used to develop new therapies that suppress the onset of the disease. One of the most promising approaches thus far has been the introduction and overexpression of a human heat-shock gene in these flies.7 This gene produces a protein that functions as a molecular chaperone to prevent misfolding and aggregation of the mutant polyglutamine-enriched protein of Machado-Joseph disease. Flies doomed by the introduction of the human disease-causing gene are rescued by the introduction and expression of a second human gene that produces a protective protein. Flies will clearly play an important role in understanding the genetic etiology of human disease and in exploring ways to rectify disease phenotypes. But if the relevance of fly genetics to human disease was surprising, physicians faced an even more unlikely revelation. In December 2000, the first sequenced plant genome was published, and the mustard weed was found to have more than 25,000 genes, nearly twice as many as the fly and almost as many as humans.2 Astoundingly, more than 100 mustard weed genes are homologues of human genes that are involved in diseases such as xeroderma pigmentosum, hyperinsulinism, Wilson’s disease, ataxia-telangiectasia, cystic fibrosis, and breast cancer.2 Obviously, the mustard weed lacks lungs and breasts, but the same genes that control fundamental processes such as ion movement across cell membranes, repair of damaged DNA, and division of cells are present in this plant as well as in us. When these genes are expressed inappropriately or undergo deleterious mutations, diseases characteristic of the host organism appear. Perhaps the most significant similarities between the genomes of mustard weeds and humans reside in the family of DNA repair genes. These are the genes involved in diseases such as xeroderma pigmentosum and ataxia-telangiectasia. Upon reflection, this makes sense. As different as plants and humans are, they both must maintain and repair an information-encoding system based on the integrity and fidelity of sequences of DNA bases over extended periods of time. This is why the mustard weed genome contains homologues of many DNA repair genes that are defective in human diseases such as hereditary breast cancer, nonpolyposis colon cancer, and xeroderma pigmentosum.2 Suddenly, scientists who study plant genetics are publishing papers that cannot be ignored by the medical profession. This too is a portent of things to come in the Postgenome Era. Physicians must prepare for an exponential increase in the mass of medically relevant new information that patients will expect their doctors to master. And patients’ expectations grow every day as they rely on the Internet to educate themselves about the latest medical advances. Physicians in the Postgenome Era confront a challenge similar to that experienced by priests during the Reformation. Prior to the Reformation, priests in medieval Europe enjoyed a monopoly on religious knowledge. Dissemination of the holy word relied on an inefficient, labor-intensive technology. Generating a single copy of the Bible consumed at least a full year of effort by a well-trained and highly skilled scribe wielding a goose quill over vellum sheets. Only the Church possessed enough wealth to sustain the transmission of biblical knowledge from one generation of the priesthood to the next. Ordinary people were ignorant of the written word residing in scarce and inaccessible Bibles. Only ordained priests had direct access to a Bible, and laypeople depended on them to reveal its contents. Priests occupied positions of trust, prestige, and power. In pre-Reformation Europe, it was good to be a priest. In the second half of the 15th century, a technological breakthrough sowed the seeds of a revolution in the way people acquired information. Gutenberg invented the moveable-type printing press and mass-produced Bibles, an act that triggered many unintended and unimagined consequences. One of them was the Reformation, which shook the foundations of the Church and changed forever the relationship between the priesthood and laypeople. By the end of the 16th century, ordinary people could own a Bible and read for themselves what was in it. For example, Proverbs 24:5, "vir sapiens fortis est et vir doctus robustus et validus," articulates the concept that knowledge is power. The knowledge monopoly of the priesthood disintegrated, and survivors had to find new ways to add value to the lives of their parishioners. In post-Reformation Europe, it became much harder for priests to know more than their congregations. Fast-forward 500 years to the second half of the 20th century and consider the parallel between the priesthood during the Reformation and the medical profession as it enters the Postgenome Era. Formerly ignorant patients are being empowered by a new technology that gives ordinary people access to the latest medical information. This time it is the Internet rather than the printing press, but the threat posed to professional hegemony is the same. Physicians must learn to survive in the Postgenome Era by practicing informatic medicine, the next level in the evolution of scientific medicine. Armed with a good medical education and a mental prosthesis (a portable computer connected to an interactive network), physicians in the 21st century will add value to the lives of their patients in ways that previous generations of physicians never dreamed possible. Only the best information management tools will enable physicians to keep up with the avalanche of new information relevant to human medicine. As the Postgenome Era begins, privately endowed medical research institutes, universities, and hospitals are adding their efforts to those funded by the $20 billion-plus annual budget of the National Institutes of Health. Pouring forth from this collective endeavor is a growing avalanche of new information that threatens to bury physicians. Every week sees the publication of breakthroughs in our understanding of the genetic causes of disease. And the rate at which these breakthroughs are coming increases each month. The burgeoning productivity of this research fuels the revolution in biomedicine and illustrates the overwhelming task faced by physicians, who must assimilate and use this new knowledge. The low-hanging fruit of the Postgenome Era are diseases in which single gene mutations play a decisive pathogenic role. Many recent examples represent subsets of a larger disease category. Each traditional disease category—each distinctive constellation of symptoms—may be divided into many different subsets involving one or more genes. Clearly, some subsets and some entire categories of disease will involve more complex causes. Some will involve tens or even hundreds of different genes. In all cases, interactions among genes as well as those between genes and the environment must be considered. Although much low-hanging fruit will be harvested in the next decade, many multigenic diseases will keep the research community busy for several decades. Along the way, how we think about disease will change dramatically. If diagnosing disease is the first step to effective therapy, physicians will increasingly think of diseases more in terms of causes than symptoms. Knowing that someone has hypertension or muscular dystrophy or leukemia means relatively little in the new age of personalized medicine. To treat such diseases effectively, physicians need to know if the problem resides in a mutated serine-threonine kinase gene, as in the case of pseudohypoaldosteronism type II hypertension from work by Wilson and colleagues at Yale8; a mutated ZNF9 gene in myotonic dystrophy type II from work by Liquori and colleagues at Minnesota9; or a mutated tyrosine kinase gene in chronic myelogenous leukemia from work by Druker and colleagues at Oregon.10 For almost a century after Rudolph Virchow described a patient with "white blood" in 1845,11 leukemia was thought to be a single disease. In much of the 20th century, leukemia was classified according to the course of the disease (acute or chronic) and the type of cell giving rise to the malignancy (lymphocytic or myelogenous). Leukemia is now known to result from a multitude of pathogenic mechanisms, many involving chromosomal translocations and gene fusions.12 Leukemia illustrates how diseases in the Postgenome Era will be defined less by signs and symptoms and more by molecular pathogenesis.13 The ability to target specifically each of the many fusion proteins that cause various forms of lymphocytic and myelogenous leukemia holds great promise for personalized treatment of patients with blood cancer. One category of leukemia, recognized in the Pregenome Era as chronic myelogenous leukemia, results predominantly from a chromosomal translocation that disrupts the normal DNA sequence of the gene for a growth-promoting enzyme known as tyrosine kinase. Fusion of the c-abl gene of chromosome 9 with the bcr gene of chromosome 22 creates a novel chimeric oncogene. White blood cells carrying this chromosomal translocation produce a fusion protein, Bcr/Abl tyrosine kinase, that has five- to 10-fold greater enzymatic activity than c-Abl tyrosine kinase. The constitutively expressed and overly active enzyme causes cancerous proliferation of the affected cells.14 The Novartis drug Gleevec binds to the active site of the mutant tyrosine kinase and blocks its ability to promote abnormal cellular growth.10 Although Gleevec can also bind normal tyrosine kinase found in white blood cells lacking the chromosomal translocation, it does no apparent harm to healthy cells and avoids the devastating side effects associated with non-specific chemotherapeutic agents traditionally used in cancer therapy. This new drug exhibits remarkable efficacy in patients with chronic myelogenous leukemia. Gleevec has quickly come to exemplify the Holy Grail of the pharmaceutical industry, knocking out cancer cells while leaving healthy cells alone. But all is not perfect with this magic bullet. Despite taking Gleevec, some patients progress from the chronic phase of myelogenous leukemia to the acute, blast phase of the disease. Gleevec’s failure to suppress leukemia in these patients yields fascinating insight into the molecular pathology of the disease.15 In some of the resistant patients, amplification of the mutant tyrosine kinase gene outpaced the ability of the inhibitory drug to bind enough of the target enzymes and allowed uncontrolled growth to occur. In most of the resistant patients, an additional single amino acid substitution in the mutant tyrosine kinase had occurred. Substituting an isoleucine for a threonine at the 315th amino acid in the enzyme caused steric hinderance that blocked the binding site of Gleevec. The doubly mutated tyrosine kinase retained its cancer-producing activity, but Gleevec could no longer inhibit it. Hence, it remains a rational drug target, and high-throughput screening of candidate drugs may yield a new molecule capable of specifically inhibiting the altered enzyme that Gleevec no longer affects. Gleevec offers insight into the kind of personalized therapies promised by gene-based molecular medicine. It is a dramatic departure from the one-size-fits-all pharmacology of the 20th century and opens the way for pharmacogenomics, one of many manifestations of the Postgenome Era. Pharmacogenomics owes its existence to genetic variation among members of the human species. Among the individuals whose DNA was studied, the Celera and the public sequencing projects revealed fewer than three million single nucleotide differences out of nearly three billion base pairs in the human genome.3,4 However, this one-base pair difference out of every thousand in the human genome is enough to provide the theoretical basis for identifying prospectively patients who will benefit from a therapeutic drug and those who will develop harmful side effects. Many patients will soon be genotyped, with their personal array of single nucleotide differences sorted into two categories: those that are also found in at least one percent of the population (single nucleotide polymorphisms, or SNPs) and those that occur less frequently (mutations). One can hardly imagine what this will mean in terms of storing and retrieving relevant information. It will present enormous challenges to developers and managers of clinical databases and patient records. The underlying concept of pharmacogenomics is not new. Karl Landsteiner introduced personalized medicine nearly a century ago with his classification of humans into four phenotypes based on blood antigens of the A, B, AB, and O groups.16 We now know that these phenotypes result from a diploid combination in each of us of three different alleles at the ABO gene locus.17 If an individual with only A alleles at the ABO locus receives a transfusion of blood from an individual with only B alleles at the ABO locus, that recipient experiences devastating side effects. Knowing the genotype of a blood transfusion recipient permits informed selection of the therapeutic agent (i.e. blood from a compatible donor). Similarly, knowing the SNP profile of a patient will allow a physician to avoid certain drugs in favor of those that are known to produce only desirable outcomes in people with that genotype. But as Gleevec illustrates, pharmacogenomics offers additional opportunities beyond the ability to deploy existing drugs more intelligently. In this age of personalized medicine, pharmaceutical companies will develop entirely new drugs that target the abnormal proteins produced by SNPs, mutations, and other individual genetic variants (including chromosomal rearrangements) that alter gene sequences. Pharmaceutical companies will also focus on protein targets that turn genes on or off. There will soon emerge a new pharmacology based on drugs that target protein transcription factors to suppress expression of a disease-causing gene or to promote expression of a disease-suppressing gene. We now know that the human body has many more proteins than genes. Although we have a few tens of thousands of genes in our genome, those genes are capable of producing many hundreds of thousands of distinct proteins. Add to this the potential of our personal SNPs and mutations to yield thousands more variant proteins, and one begins to appreciate the potential magnitude of the new proteomic pharmacopoeia and the database required to deploy it intelligently. Doctors must prepare for a Physician’s Desk Reference that will rival the Oxford English Dictionary in its bulk. Like the OED, the expanded PDR will be user-friendly only in an electronically searchable format. Gleevec also points to the financial dilemma society faces as the new pharmacology of personalized medicine gains momentum. Highly specific drugs tailored to a small subset of patients who will benefit from custom-designed therapy will cost much more than traditional drugs. A year’s supply of Gleevec for a patient known to have chronic myelogenous leukemia costs $40,000.18 It is already known that a small number of patients relapse while taking Gleevec and become nonresponders due to a new mutation in the abnormal tyrosine kinase that originally caused their disease.15 Suppose a pharmaceutical company rises to the challenge of finding, developing, and marketing a drug that will specifically target and inactivate the doubly aberrant tyrosine kinase in these Gleevec-resistant patients. How much must the company charge to recover its investment in such a personalized drug? Raising this question is not intended to discourage pursuit of personalized therapies. But it does acknowledge an economic consequence of pharmacogenomics. Society must decide how much of the economy can be devoted to implementing the technologies resulting from the revolution in biomedicine. And the health care industry must decide how many resources can be devoted to managing the massive amounts of patient data that pharmacogenomics portends. Gleevec also shows how the Internet is changing the environment in which medicine is practiced. Novartis has a Web site that tells physicians how to prescribe Gleevec and how to help their patients pay for it.19 This official Gleevec site is intended for physicians, but patients can also visit it. There is an unofficial Gleevec site, conscientiously maintained by a grateful patient with chronic myelogenous leukemia whose disease has been suppressed by the new drug.20 This site provides information to other CML patients and was created specifically for them. In the equal-opportunity Internet age, physicians may also visit this site. This unofficial site is maintained by a man who spent 21 years as a trooper with the Louisiana State Police, was diagnosed with CML three years ago, and started Gleevec therapy a year later. He operates the site as a labor of love for other CML victims and directs all donations to the Leukemia and Lymphoma Society. He exemplifies the contrast between the new age of smart clients versus the old days of "helpless" patients. Gleevec illustrates how the Internet will make the knowledge that empowers physicians equally accessible to patients in the same way the printing press and moveable type made the knowledge contained in the Bible accessible to parishioners in 16th-century Europe. Consider this statement from a CML patient whose spouse learned about Gleevec on the Internet.21 "My doctors were very supportive, but sadly doctors are the last to know about some developments. Get on the Internet, look at medical progress made. I would not have (been in the Gleevec trials) if it weren’t for my husband’s research (on the Internet)." So how should physicians cope with continuous subclassification and redefinition of diseases afflicting patients who aggressively seek news of the latest breakthroughs in their areas of interest? The situation will only get much worse, since research-intensive biomedical institutions will generate new knowledge faster than individual physicians can assimilate it. First and foremost, physicians in training and physicians in practice must learn to understand, appreciate, and use the best tools information technology can offer. The platform of this tool kit is a mental prosthesis. Many of us need visual prostheses (eyeglasses, contact lenses) to improve our ability to see. Eventually, many of us will need auditory prostheses (hearing aids) to improve our ability to hear. Already, all of us need mental prostheses to improve our ability to acquire, organize, and interpret information. Physicians cannot survive without a mental prosthesis. The massive amount of information that must be retrieved and used each day is far beyond the capacity of human memory. It can only be accomplished with the help of a portable computer connected to an interactive network and equipped with data-mining software that exercises logic to locate and assemble information specific to the individual physician’s professional requirements. For those who deliver health care in the 21st century, the challenge is to bring all the relevant information together at the same time and place so physicians can make informed decisions about what is best for the patient. Just as medical education had to be transformed in the early 20th century to enable physicians to practice scientific medicine, the training of physicians in the 21st century will have to change to allow them to practice informatic medicine. Physicians must prepare for lifelong, everyday, just-in-time acquisition of knowledge from afar, and they will need new and better information management tools. The world of free enterprise will address this need. It represents a substantial business opportunity. Being among the first to know, or at least knowing as soon as smart clients, is crucial to maintaining the physician’s role in health care. Innovative software developers will create the new tools, and physicians will pay for them, since effectiveness and status in a knowledge-based profession utterly depend on it.
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