I’m kinda bummed that a previous engagement will keep me from attending The Genetic Basis of Adult Medicine: What the Primary Care Provider Needs to Know, a Harvard Medical School CME activity. The course is being given in Boston October 6-8. The Saturday afternoon plenary is devoted to pharmacogenetics.

After the PCR reaction was complete, I watched as the sample was passed through a vacuum filter to remove any “trash,” remaining from the PCR reaction. Following the filtration, with a clean sample in hand, Jason explained that the analysis could proceed along two different paths, depending on the kind of question being asked.

If the analysis were looking for a small set of SNPs in a large number of people—for example, if one were screening for the poor metabolizer genotype of cytochrome p450 2D6—the next step would be to incorporate fluorescently labeled nucleotides in each sample. The labeled samples would next be applied to a DNA hybridization plate where they would form complexes with known sequences of complementary DNA. The plates would next be passed under a laser that would be refracted by the fluorescent dyes. A camera would record the variations in fluorescence and refraction and an algorithm would help determine what sequences were present. That, in short, is how a DNA lab handles high throughput analyses.

But the forensic sample we were analyzing was not a high throughput task. The attorney who ordered the test wanted a complete sequence of his client’s hypervariable region. To do that, my host used a technique called Sanger Sequencing, also known as the chain termination method or dideoxy sequencing. The other Doctor Eshleman–my son–explained that this technique is the most cost-effective and versatile technique for investigating small samples and exploring unknown variation in a particular short stretch of DNA. Read the rest of this entry »

Twenty six years ago when I finished medical school I knew a little bit about DNA—about its structure and how it interacts with messenger RNA to build proteins and, ultimately, everything else. In the following years, I started using a few laboratory tests that involved DNA. In the workup of autoimmune diseases, I could order anti-double-stranded DNA assays. When polymerase chain reaction (PCR) tests became available for Hepatitis C and HIV, I used them. But my level of understanding was pretty basic: I knew when to order the test and how to interpret the results, but I really had no idea what actually went on in a DNA lab.

On those rare occasions that I visit a clinical laboratory, it’s almost always to see why a stat lab is taking so much time. A result may mean the difference between admitting someone to the hospital or following him at home. It’s always rewarding to make these visits because I get to know the lab technicians face to-face and I gain a little more appreciation for the challenges of their jobs. Read the rest of this entry »

16 x 24 DNA Hybridization Plate
Above is a picture of the computer representation of a 384 hybridization plate for SNP [single nucleotide polymorphism] genotyping on the Beckman SNPstream platform. Each 16 dot “well” can genotype 12 SNPs in a sample. Fluorescently labeled DNA from a sample hybridizes to DNA-analogs arranged in a grid at the bottom of each well. Read the rest of this entry »

Many medications require a metabolic transformation before they can actually have a therapeutic effect. This transformation often involves what pharmacologists call a phase 1 reaction. There are three classes of phase 1 reactions: oxidation, reduction, and hydrolysis. All three reactions tend to make drugs more water soluble and thus more able to exert their effects within target cells.

A medication that requires such a metabolic transformation before it can work is called a prodrug. A wide variety of medications are prodrugs. Codeine, Tamoxifen, Enalapril, and L-DOPA are among the many medications that are administered as prodrugs and then metabolized to active, therapeutic compounds. Read the rest of this entry »

The July 18 New York Times “Science Times” features Nicholas Wade’s story “The Quest for the $1,000 Human Genome”. By some estimates, it now costs about $10-15 million to sequence an entire human genome (down from the $500 million it cost to do the first such sequence as part of the Human Genome Project). The production of a new generation of sequencing machines raise the possibility that the costs of a complete sequence will continue to fall. All of this begs the question of what we will do with all this information if it is available for approximately the same cost as a CT scan.

I talked with a molecular geneticist about this article, and he agreed that the $1,000 genome sequencing is not pie-in-the-sky. It may really happen.

This morning’s “Morning Edition” on National Public Radio did a story on pharmacogenetics that managed without being technical to touch on most of the important points. The story mentioned that the Mayo Clinic would be doing more of this testing in the future. Not mentioned was the fact that there are other institutions offering this service, including DNA Direct of San Francisco.

“Genes and Drugs” is a place for physicians and others learn more about how a person’s genetic makeup can affect his or her response to a particular medication–the field of pharmacogenetics or pharmacogenomics. For several dozen medications, there already exist tests that can help predict how a particular patient will respond to a specific drug. These tests have yet to have widespread adoption, but is inevitable that they will find their way into our clinical practice.

Your moderator here, is Alan Eshleman, MD, otherwise known as doctore. I’m neither a geneticist nor pharmacologist. Instead, I’m a board certified general internist with an abiding interest in how new science can affect the social, ethical, and economic aspects of medical practice. I welcome you all.