In my previous entry, I discussed how the Human Genome Project has served as the foundation for additional research that has produced new insights into the genomic basis of disease and resulted in new tools and reagents that continue to generate new discoveries. Every endeavor—even those that may not result in a significant leap in technology or a new targeted drug therapy for patients—has contributed to our knowledge and understanding of the vastness and diversity of our genome, and is propelling us toward the reality of personalized medicine. Indeed, there are examples across disease areas of how personalized medicine is improving our ability to detect, prevent, and treat disease. 

Personalized medicine informs our understanding of disease origin

In the past and perhaps in much of today’s practice of medicine, diagnosis and treatment decisions are based upon observations within a clinical setting.  However, it is becoming increasingly clear that clinical features alone are not sufficient for diagnostic or treatment decision purposes.  Some good examples include:

• Hypertrophic cardiomyopathy (HCM) is a relatively common disorder characterized by an adult onset hypertrophy of the heart muscle sometimes more genes. 
• Noonan syndrome, a childhood disorder that has many manifestations was considered to be one clinically defined entity, but is now understood to be a disease resulting from the mutations in any one of ten or more different genes.
• Adult macular degeneration is an important cause of blindness in older individuals and genetic variants in a particular gene have been identified to be responsible.

Today, many clinicians would not make a diagnosis of these and many other disorders until the patient’s DNA is tested.  Having a more comprehensive picture of the underlying cause of the disease can lead to earlier, more accurate diagnosis, more informed treatment decisions, and better outcomes for patients.

Personalized medicine informs our understanding of disease risk

As we understand the role of specific genetic and genomic variants in the human population, it will become possible to assess the relative risk and absolute risk of individuals for particular diseases. Having such a risk assessment can allow for the development of prevention or postponement strategies for a specific disorder. As an example, our ability to detect individuals at high risk for cardiovascular disease through testing for lipid levels has had and continues to have a major impact on heart disease incidence in the United States and elsewhere in the world.  With seventy-five cents of every healthcare dollar going to the treatment of preventable chronic disease, prevention and early interventions for our most common and treatable chronic illnesses could save a significant amount of money and result in better health outcomes across the country.

Personalized medicine informs our understanding of disease treatment

Another area where genomics has had a great impact is in the area of pharmacogenomics.  Although for many years clinicians and researchers alike have known that not all drugs are equally effective in all individuals, the molecular basis for these differences has not been well understood.  This is changing very dramatically.  Pharmacogenomics is the study of how genetic variation affects a patient’s response to a treatment.  In cancer, for example, we now know that the molecular changes that cause the progression of particular types of cancer are very complex.  In turn, organ-based treatment approaches are not completely adequate.  In non small-cell lung cancer (NSCLC) some tumors have mutations that result in the activation of epidermal growth factor receptor (EGFR) and these tumors are exquisitely sensitive to treatment with some oral inhibitors of EGFR function.  Other NSCLC tumors have mutations in a gene called K-RAS a protein that acts downstream from the action of EGFR and tumors with this mutation do not respond to EGFR inhibitors.  Yet other NSCLC tumors are now known to have to overexpress Her2/Neu and treatment of these tumors with an inhibitor of Her2/Neu may be warranted.  In other lung tumors a gene called Met is amplified and treatment with Met inhibitors (under development) may be warranted.  Yet others have a novel translocation called EML-ALK4 and a drug that inhibits the fusion product appears very promising.  This is but one example of a tumor type where patient stratification is becoming critical for making appropriate clinical decisions.  Having a better understanding of how patients will respond to a drug based on their genetic makeup can lead to more optimal treatment choices, reduced side effects, and overall better patient outcomes.

The use of personalized medicine is beginning to impact many disease areas, and there is evidence that it is already improving the outcomes for patients at a reduced cost to society.  In our current status of healthcare where the costs are increasing at a pace that cannot be sustained by our economy, personalized medicine, illuminated by our ever-increasing understanding of the complexity of the human genome, shines as a beacon for solving some of the most important problems in our fight against disease.

Ten years ago, Bill Clinton and Tony Blair made a joint announcement that an international consortium had completed the draft sequence of the human genome.  The following year, papers describing the mapping and sequencing of the human genome were published by the public effort and a biotech company, appearing in Nature and Science respectively.  These were indeed, historic events as scientific innovation led us to decipher our genetic blueprint.  This year, we can mark this occasion by taking stock of what advances have occurred since the genome sequence and how its discovery continues to inform our understanding of medicine and influence medical care.

Diversity of the human genome

The International HapMap project was among the first to build on the initial sequencing of the human genome, and sought to achieve greater understanding of the diversity of the genome. What we discovered is that every human being has approximately the same amount of genetic information.  The similarities in the sequence of DNA, among all populations in the world, illustrate just how similar we are at the genetic level and put a spotlight on our common origins.  But there are differences among us.  If we compare the DNA of any two individuals their sequence would differ in approximately one out of every thousand nucleotides.  Some of these changes occur in coding sequences and others in non-coding regions of the genome. Some of these changes are certainly benign and others are certainly important and result in the diversity of the individuals.  Much research remains to uncover the connection between our genetic makeup and health and disease.  A large catalog of the genetic differences among individuals and populations is now publicly available and continues to grow, feeding researchers’ need for this valuable data to inform their work.

Genomic basis of disease

One of the reasons for launching the human genome effort was to provide the tools and reagents for rapid identification of the human genes and their variants responsible for human health and disease.  For example, a large number of genes important in Mendelian disorders have already been identified.  There is a large body of evidence that many common disorders such as cancer, diabetes, autoimmune disorders, and psychiatric disorders also have a strong genetic contribution.  Building on years of scientific effort, researchers have revealed strong associations between specific genetic variants in the human populations and their susceptibility to human disease.  Despite periodic criticisms of the genomic approaches and their cost, it is clear that genetic approaches are opening new doors to our understanding of human health and disease.  These efforts will continue.

Decreasing cost of whole genome sequencing

An important driver of the genomic revolution is the rapid reduction in the cost of DNA sequencing.  Many estimates indicate that the description of the first human genome sequence cost about three billion dollars.  In 2010 several commercial entities are offering human DNA sequence and sometimes its interpretation for less than $10,000.  This is close to five orders of magnitude in the reduction of the cost of sequencing and it is anticipated that this cost would go down by one or two orders of magnitude to $1,000 and perhaps even $100 in the not too distant future.  By any measure, this cost reduction has to be considered nothing short of phenomenal and a tribute to human ingenuity in its efforts to advance scientific discovery.

Advent of personalized medicine

What has been the impact of all these genomic developments on medicine?  Identification of genes involved in disease and how loss of function, alteration of function, or acquisition of new functions in the gene products are providing clues to our understanding of the molecular etiology and molecular pathology of disease.  Such information is critical for prediction of disease susceptibility, progression, and therapeutic response on an individual level.  The use of genetic and genomic information for diagnosis, prognosis and treatment decisions is called personalized medicine and it is gaining greater traction in medical practice.