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The Path to Precision Medicine

October 17, 2018

On June 26, 2000, President Bill Clinton stepped to a podium in the East Room of the White House to deliver remarks celebrating the completion of the first draft of the human genome. At that press conference, he said:

"Nearly two centuries ago, in this room, on this floor, Thomas Jefferson and a trusted aide spread out a magnificent map - a map Jefferson had long prayed he would get to see in his lifetime. The aide was Meriwether Lewis and the map was the product of his courageous expedition across the American frontier, all the way to the Pacific. It was a map that defined the contours and forever expanded the frontiers of our continent and our imagination.

Today, the world is joining us here in the East Room to behold a map of even greater significance. We are here to celebrate the completion of the first survey of the entire human genome. Without a doubt, this is the most important, most wondrous map ever produced by humankind." 

Those were heady days for the human genome project and all the talk back then was how this would open the door to "personalized" medicine. We would soon be able sequence an individual's genome and tailor medical treatments to their genetic makeup.

Two decades later, for a variety of reasons, the promise of personalized medicine has largely been unfulfilled. Indeed, you hardly hear the term anymore. This point was driven home for me when I attended a recent conference on campus entitled "The Road from Nanomedicine to Precision Medicine."

The conference was organized by Professor Shaker Mousa of ACPHS's Pharmaceutical Research Institute. Dr. Mousa's idea was to juxtapose nanomedicine, which creates nanoparticles that have great specificity for tissue-specific targets, with "precision" medicine.

Precision medicine is the term that has largely replaced personalized medicine. Of course, many things beyond the terminology have changed since 2000. The technology for DNA sequencing has exploded and by some measures advanced faster than computer technology. Through a number of commercial enterprises, genome-wide scans are accessible to everyone at a modest cost. Additionally, we have seen incredible advances in technologies for monitoring physiological functions, many of which provide real-time data.

So we are increasingly able to determine both the genetic traits and current physiological state of an individual. This, in principle, allows us to dial up a therapy to match that state - hence, precision medicine.

There are many paths to precision medicine and one of them most certainly runs through pharmacogenomics. Pharmacogenomics is the study of how genetic variations cause different people to react to drugs in different ways. A large part of pharmacogenomics is how drugs get cleared by the system. In humans, there are more than 200 commonly occurring genetic variants of the enzyme cytochrome P450 (CYP), responsible for the detoxification of drugs.

At the Nanomedicine conference, two faculty members from ACPHS were among the list of distinguished speakers. They effectively illustrated the span of pharmacogenomics from basic science to clinical practice and also the central role of the CYP gene.

Assistant Professor Manish Shah from our Department of Pharmaceutical Sciences talked about his work on the structural biology of the CYP gene. It is easy to think in terms of single nucleotide polymorphisms (SNPs) where a member of the genetic alphabet is replaced by another, say a G for a C. Dr. Shah's work shows how these genetic changes affect the molecular machinery of detoxification. He showed fascinating images of the CYP protein at the molecular level and how genetic changes lead to protein structural changes which ultimately lead to changes in the ability to metabolize Losartan, an anti-hypertensive drug.

Most importantly, Dr. Shah's protein structures at this high level of resolution aid computer-assisted drug design and allow for the development of the next generation of drugs. His research demonstrates the complexity of moving from genotype to phenotype. Different genetic variants can result in the same protein structure, so there are deeper and more subtle things going on here. Changing a G to a C or an A to a T in the genetic sequence is just the beginning of the story and additional protein chemistry is needed to follow up on the genetics.

Assistant Professor Jacqueline Cleary of the Department of Pharmacy Practice talked about her work at the Hometown Health Clinic in Schenectady were she is using a commercially available genetic panel designed for pharmacogenomic indicators in pain management. This panel detects patients with different genetic variants, usually SNPs in the CYP gene that cause some pain medications to be ineffective or to have undesirable side effects. These variants can be classified as poor, intermediate, extensive, or ultra-rapid metabolizers.

A poor metabolizer can be dangerous to the patient because the drug does not get cleared fast enough and may accumulate to toxic levels. An ultra-rapid metabolizer, on the other hand, can also be harmful because it is cleared so rapidly that the drug never reaches an effective level.

Dr. Cleary presented a case study of a female patient with four genetic variants detected by the panel, three being in the CYP gene. This insight allowed Dr. Cleary to adjust the patient's medication to make it more effective and relieve unwanted side effects, a clear demonstration of the effectiveness of this basic application of pharmacogenomics.

The true value of any map is that it allows safe navigation to a desired destination. Since the first map of the human genome was revealed to the public nearly 20 years ago, scientists and clinicians have encountered a few detours as they look to translate this knowledge into practice. Through the work of individuals like Drs. Shah and Cleary, however, the road ahead is becoming clearer. And the promise once foretold by this "most wondrous map" may soon be a reality.

Greg Dewey, Ph.D., is President of Albany College of Pharmacy and Health Sciences.

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