By DAVID ROY
“Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease.”
—William Osler
Medicine is frequently described as both art and science, a delicate balance of intrinsic and learned creativity accompanied by mechanistic understanding of pathology. The “art” encompasses the more subjective elements of doctoring, mainly the ability to understand the patient and their illness via the medical history. In contrast, the “science” is grounded in objective investigation, usually through research studies that make statistically valid conclusions about groups of individuals as a whole. Due to the plethora of traits unique to each patient — both physical and psychosocial — the clinician is required to interpret the evidence-based guidelines and tailor their recommendation appropriately.
Recently, the new Omics era has forced an irreversible shift in favor of science, allowing the complete capture of individual biologic variation. Omics is a neologism that refers to the study of proteomics, metabolomics and genomics, the latter of which is now primed to transform medical practice.
The power of genomics as a medical modality is derived more from its comprehensiveness than true biological novelty. In fact, it was almost 200 years ago when Charles Darwin first proposed that heritable traits could be passed on to offspring — the underlying structure of this heritable DNA “code” was later characterized by Watson and Crick in 1953. Through advances in DNA sequencing and genetic engineering, many molecular determinants of disease were identified beginning in the 1970s, giving rise to personalized medicine via genetic testing.
The ability to identify disease-causing mutations forced drastic changes in medical decision-making. For example, genetic testing allows the identification of patients with degenerative disease (e.g. Huntington’s Disease), increased risk for cancer (e.g. BRCA1 mutation in breast cancer) and those with high-risk pregnancies (e.g. cystic fibrosis), all before any signs of illness manifest. This actionable information can lead to earlier screening, improved therapy and better outcomes.
The limitations of genetic testing were already apparent decades ago, however. In fact, many hallmark genetic mutations represented only the tip of the iceberg. For example, BRCA1-associated breast cancer comprises only 10 percent of all new cases and even these patients were noted to have considerable variation in outcomes. Therefore, undiscovered genetic factors likely explained this clinical diversity. Unfortunately, the vast majority of all 22,000 genes in the human genome were still uncharacterized by 1990. Without a catalogue of human genes and their role in disease, progress was predicted to slow or even plateau.
In order to jumpstart new discoveries into genetic underpinnings of disease, the Human Genome Project was formed. This massive undertaking successfully sequenced and mapped every gene in the human genome by the year 2003. These data quickly allowed researchers to identify new gene mutations and even design therapies to target specific mutant proteins.
As the puzzle pieces linking genetics to disease were being assembled, two significant challenges remained. First, with traditional genetic testing, only a single gene or small gene “panels” can be tested, due to cost and time limitations. Therefore, clinical suspicion is usually a prerequisite to genetic testing. Unfortunately, chasing genetic mutations in a patient — whether ill or healthy — is highly subjective, inefficient, and prone to missing key “driver(s)” of disease. Second, since most diseases likely result from multiple genetic alterations acting in concert, traditional approaches have been limited in deconstructing the combinatorial nature of genetic-driven illness. In the past 10 years, genomics has helped tackle these obstacles.
Genomics is a new field that aims to understand associations between disease and the genome (i.e. all of our genes), facilitated through innovation in both high-throughput biological platforms and computers. New technologies such as next-generation whole exome/genome sequencing, DNA methylation chips and gene expression profiling allow the exhaustive characterization of all molecular features in individuals. Improved processing power and novel computational algorithms further facilitate the objective understanding of biological processes linked to disease.
For the first time ever, researchers and doctors can be presented with a comprehensive snapshot of the unique molecular features within a patient and make medical recommendations that are personalized and unique. For example, early stage breast cancer patients can now be tested via Oncotype DXTM, a tool which informs whether a patient is high-risk and requires chemotherapy. Across cancer, a new test called MSK-IMPACTTM is being used to screen for specific gene mutations that are responsive to FDA-approved targeted therapies, such as small molecule inhibitors.
Genomics has even allowed us to exploit genetic alterations that are not even causative or linked to the disease itself. For example, immunotherapy has been recently used to stimulate the body’s immune system to eradicate cancer cells, which are generally perceived as non-self or “foreign.” Unfortunately, many patients do not respond and eventually relapse. Exciting research in the past year has used next-generation DNA sequencing to identify mutations in otherwise benign genes that act as neoantigens, which are essential for immunotherapy’s effectiveness. Now, response to this therapy can be predicted upfront, and only those patients who benefit will be placed on this costly and occasionally toxic medication.
The unbiased, exhaustive power behind genomics cannot be overstated. The ability to find all molecular alterations in a patient can better characterize the illness both within and outside of the disease in question. In 2012, the New York Times profiled a cancer researcher that discovered a rare FLT3 alteration in his leukemia cells through next-generation sequencing, allowing the use of an anti-FLT3 drug already in use for kidney cancer.
Remarkably, genomics is not limited to the clinic or research lab. Perhaps most notable is 23andMe, a company that offers independent genomics-based testing for only $99. Their report can be used in conjunction with online tools to determine future risk of many diseases, a controversial subject since there is no medical counseling provided to interpret the findings. As an added bonus, the test also reports one’s relative ethnic heritage and distant relatives who have also paid for the service.
As with the advent of genetic testing, genomics represents only the beginning of a new era in medical innovation and patient-centric medicine. Advanced technologies continue to enter the market, including an exciting portable USB-based sequencing device dubbed the MinIONTM . Of course, clinicians will always be required to extract critical details of the patient’s medical history as well as other relevant non-physical details (e.g. social support networks, ability to pay, safety at home). Regardless, the value of genomics in enabling bona fide personalized medicine is indisputable. Treating the individual, not just the disease, is now more objective and better than ever.
David Roy BS ’08, PhD ’15 is in his final year at the Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program in New York City. He may be reached at [email protected]. What’s Up, Doc? appears alternate Fridays this semester.