'Gorgeous Genome' (and Gorgeous George, part man, part genome pictured as well)

  Bombs 'n genes

Genetics moves on

Genetic building blocks

Making medicines match

Proteins first, genes second

 

  Tailoring the medicine to the individual?
Medicine bottles and multi-colored pills, a baby in the background. POSTED 19 NOV 1998 Courtesy of ever-faster sequencing techniques, we now expect a complete roadmap of the human genome within five years. But as that milestone looms, scientists are becoming fascinated not in what we share, but in what we don't.

Doctors will treat diseases like cancer and diabetes before the symptoms begin, using medications that boost or counteract the effects of individual proteins. Fortunately, you won't have to pronounce "pharmacogenomics" to benefit! Courtesy Centers for Disease Control.

The Human Genome Project, after all, was designed to document a generic human being. But genes explain differences as well as similarities. Why, for example, do anti-hypertensive medicines correctly lower the blood pressure in some people, while not affecting others, and causing deadly side effects in a third group?

It's not that some people are more obedient. Rather, each individual's biochemical interaction with a drug depends on genetics, says Charles Cantor, an expert in the relation between genes and drugs at Boston University and Sequenom Corp. Just as genes give us different hair colors and textures, they also cause variations in the enzymes and proteins that interact with medicines. Thus, Cantor says, "It's not reasonable to assume that people will have the same response to a drug."

Dif'rent DNA for dif'rent folks
Cantor says studying the genetic basis for these differences -- called, ponderously, "pharmacogenomics" -- has become a hot topic in the drug business. Knowing who should or shouldn't get a particular drug will cause a "revolutionary change" in drug treatment, he contends, and the drug companies see this as "the future of medicine. Over the next 10 to 20 years, people will be tested genetically before getting a drug, to test its efficacy and side reactions."

An advanced genetic analyzer may tell us who should– and who shoudln't –take a particular drug Cantor explains that to understand why people respond differently to drugs, we must know how their DNA differs, yet the exact DNA lettering in any two people will have from 6 million to 30 million variations. Presently, finding those variations represents a huge hurdle to identifying who, for example, lacks the enzymes needed to break down a particular drug at the average rate. (Failure to metabolize drugs can leave too much in the system and cause disastrous side effects).

Still, there's a major incentive to identify who will respond -- and how -- to a drug. Today, a drug that helps "only" 20 percent of people in an experiment would likely fail approval. But a drug that always helped the 20 percent of people with a specific genetic marker might be approved for that limited population -- if those people could be identified. That's a key goal of pharmacogenomics.

Drop-dead science
Actually, it was the reverse situation -- trying to identify those at risk of side effects -- that spurred pharmacogenomics in the first place. About 20 years ago, Richard Smith, a British pharmacologist, almost died while taking part in a small test of a drug to control blood pressure. It later developed that while this medication is safe and effective for most people, 3 percent suffer that deadly reaction. Today, doctors identify those people by watching for side effects while slowly boosting the dose. Far preferable would be fingering the susceptible with quick genetic screening rather than exposing them to deadly medicine.

But before we reach that stage, and abandon today's "one-size-fits-all" approach, we'll have to accelerate the sluggish pace of the conventional technique for "reading" the sequence of DNA. Though time-tested and incredibly valuable, the technique for measuring the length of DNA in an electric field -- or electrophoresis -- is far too expensive and time-consuming for everyday screening. Even though it's theoretically possible to figure out who stands to benefit and who stands to lose from a particular medication, in reality we can't do it.

diagram shows how mass spectrometry works with Sequenom's device
This new device uses mass spectrometry to quickly measure the mass of DNA fragments. The DNA is loaded onto a sample plate, vaporized and moved through an electric field. Courtesy of Sequenom, Inc. Used with permission.

Enter one of the newest and hottest techniques in rapid-fire DNA sequencing, a product of a company Cantor helped start called Sequenom. Rather than using electricity to slowly move fragments of DNA across a plate of jelly, this machine shoots the fragments through a vacuum and quickly measures their mass in a mass spectrometer. From that, it's a quick step to calculate which letters, or chemical bases, make up that piece of DNA.

A word for small sample science
In a new application of mass spectrometry, DNA is dissolved in an organic acid and tiny droplets -- each containing about one-billionth of a liter -- are squirted onto a silicon plate. When zapped with a laser, the droplets vaporize and some of the DNA fragments become electrically charged, or ionized. These ions are accelerated by an electric field, and their flight time to the target is measured. Since the electric field exerts the same force on each ion, the more massive ones accelerate slower, and the time of flight gives an exact readout of the mass, avoiding the inaccuracies of conventional sequencing techniques.

Large rectangular machine with microplates used to carry DNA samples. One automated DNA analyzer replaces thousands of over-caffienated, underpaid graduate students. Courtesy Oak Ridge National Laboratory - Genomics Laboratory.

Once the mass of a string of DNA is known, it's simple to figure out what bases, or subunits of DNA, it contains. Because each of the four bases has a different mass, the masses found by the spectrometer can only result from a specific combination of bases. To get an idea of how this works, say you were weighing four kinds of bricks weighing 7, 12, 13 and 19 pounds. If you knew a group of bricks weighed 21 pounds, it could only contain three 7-pound bricks, since no other combination adds up to 21 pounds.

These calculations are possible because mass spectrometry is at least 100 times as accurate as conventional sequencing, Cantor says. Once the number and nature of the component bases is known, a computer uses conventional methods to figure out the sequence of bases.

Since a single robotic machine can measure 20,000 DNA fragments per day, the new robotic machine could reduce the price and time required for sequencing. And once the measurement's price -- in time and dollars -- drops, the door to delivering drugs tailored to an individual's biochemistry is opened. If the problem of giving out the wrong drug is eliminated -- which will not happen overnight -- Cantor anticipates, "The costs of trials will go down, more drugs will reach the market, and patients will get better therapy, with fewer side effects."

Yet despite the admitted accuracy advantages of mass spectrometry, gel electrophoresis is "not sitting still," says Timothy Mitchison, a cell biologist at Harvard. The older technique can analyze larger pieces of DNA, and a new, robotized sequencer just on the market is encouraging genetic scientists to move up the completion date for the human genome.

Speed kills -- except when you're finding new genes.

 

 

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