10,000 Cells on a Chip Signal Start of New Era of Diagnosis

Diseases will soon be defined by biochemical pathways and genetic interactions. Biochips may identify patients likely to respond to therapeutic agents.


Fans of the original Star Trek series will remember some marvelous technology displayed in and out of the Enterprise sick bay. The ship’s doctor, “Bones,” would hold a device over a patient and it diagnosed the condition of the patient. Amazing, but even that technology does not compare with what will soon be available to just about every doctor in America. Star Trek technology provided current diagnostic evidence, but did not tell the future!

Just look at the recent headlines: “Heart Defect Gene Discovered,” “Genetic Variants Can Turn Stress Into Depression,” “Genetics Will Direct Prescribing for Hypertension,” and “Science Getting to Roots of Autism.”

All of these headlines predict a much-awaited approach to medicine, an approach where a disease is not defined by its clinical presentation or the level of sugar in the blood, but by its biochemical pathways and ultimately the genetic interactions that allow multifactorial disorders to develop.

These developments are exciting, but indicate that managed care must start to prepare for this revolution in testing. Most medical and pharmacy directors know of the sweat chloride test for cystic fibrosis and the test for trisomy 21, but few are prepared for the advances being made daily as a result of the rapid accumulation of knowledge that is resulting from the Human Genome Project.

There are an estimated 1,000 genetic tests on the market for specific diseases. The newest technology focuses on multifactorial (read multigene) testing that can review the interaction or associations of thousands of genes or portions of a gene at one time.

Microarray technology

The testing uses microarray technology. These tests, called DNA microarrays or “biochips,” contain an “array” of tests on one chip. These chips currently can contain up to 40,000 unique gene sequences on a single slide, with each array containing 40,000 microscopic “cells” on an array smaller than a credit card. These types of arrays are termed “whole genome” testing arrays. Each of the microscopic cells on the slide can provide the ability to test for a single gene, a specific variant, or other DNA element designed specifically for the laboratory performing the test.

First introduced commercially in 1996, this technology produced gross revenue of $600 million in 2003 and is rapidly expanding. Three California companies, Affymetrix of Santa Clara, Agilent Technologies of Palo Alto, and Applied Biosystems of Foster City, have released this latest “whole genome” technology in the past year, and several others are others close behind.

The term “whole genome” is a bit misleading, however. The 40,000 protein coding genes mentioned above represent only the tip of the iceberg when it comes to the human genome. These 40,000 cells account for only about 2 percent of total DNA transcription. There is still much to be done to truly analyze the entire human genome using millions of DNA probes representative of a complete human genome. This will be a formidable job, as the single nucleotide polymorphisms (SNP) are the most common source of genetic variation among humans with an estimated 10,000,000 contained within the human genome.


To understand this technology, imagine a gigantic bingo card with a grid 100*100 (10,000 cells), each with a different gene or DNA or SNP test. After the material to be tested is washed over these cells, they are fluoresced with a laser. A scanner reads the different colors that fluoresce on the chip at each cell. The exact pattern can be used to relate the unknown sample to a known sample. Think of finding the word BINGO on this gigantic bingo card! Likewise, complex patterns of these different colored fluorescent responses may represent the key to individual diseases or disorders.

Chips can be designed to detect specific genes that control different key cellular functions of malignancies such as growth factors. This form of testing may someday be able to differentiate those people who will respond to a drug such as Avastin or Erbitux or Iressa. All three of these drugs offer profound resolution of a malignant tumor, but only to a percentage of the study groups. Thus, many people are treated to find the few who respond. This is not only very expensive, but it delays other therapy and gives false hope.

It would be very cost-efficient to first determine which drug might best suit an individual patient. Somewhere in the genome lies the key, probably a very complex set of SNP interactions that determine the response. Only by developing a complex gene chip will we discover the targeting mechanism that will allow these expensive drugs to be used in a focused fashion.

This technology can also be used to determine a genetic propensity or tendency to develop a disease of condition. A chip containing those SNPs that are linked to a specific disease such as hypertension or diabetes could be designed and produced in order to determine whether an individual has a high likelihood of developing hypertension or diabetes. Preventive behavioral and medical treatment may prevent or delay the onset of these disorders.

Finally, for decades clinicians have struggled to manage patients needing complex regimes of medications with narrow therapeutic indices. This is also a rich area for these chips. An array of tests for the various cytochrome p450 genes as well as other drug metabolism genes may allow clinicians to do a better job of tailoring therapy to an individual.

Managed care implications

All of this is a big deal for health plans. First, the nearly 1,000 tests that are currently available are already hitting claim-payment computer systems, but there is no easy way to determine exactly what test is being performed, due to the limitations of the current CPT coding system. We will need massive physician education on the appropriate use and interpretation of these tests.

Next, start to prepare for the avalanche of new testing that most certainly will hit your claim systems. Do you understand what you are currently and will be soon be paying for? Do you have the necessary committee structure, processes, criteria, and benefit designs?

And once a predicted future disorder is discovered through a gene array, will you pay to “prevent” it? How will you react when the first request hits your desk? Alternatively, will you take the other approach and actually require a microarray test for initiation of a specific drug?

Establish relations with the major testing companies such as Quest, Labcorp, and Genzyme Genetics. They have programs to assist you in understanding these tests and can assist in managing these tests.

One thing is certain, these and other questions will continue to provide plenty of subjects for Tomorrow’s Medicine.

MD, is president of the National Association of Managed Care Physicians and vice president and medical director of Matria Health Care. He has 20 years of managed care experience at the payer or health plan level.