Implications of a BioChip Age

After spending ten years and five billion dollars, the Human Genome Project should provide scientists with a fascinating map of the three billion DNA bases that comprise the human genome. Undoubtedly the Human Genome Project is an awesome accomplishment in deciphering human genetics. Yet, the true Rosetta stone of functional genetics, the study of gene function, will be the DNA chip. Also known as the biochip or genechip, the DNA chip utilizes silicon valley microchip production technology to dramatically accelerate genetic studies. These DNA chips can gather genetic information at twenty-five times the rate of traditional methods involving PCR and gel electrophoresis (11), at a fraction of their cost. Moore’s law, generally accepted in the computer industry, states that computer processors roughly double in power and halve in cost every year. With the arrival of the biochip, Monsanto Biotechnology has come up with a corollary to Moore’s law: the genetic information used in practical application will roughly double every year (10). According to DNA chip producer Affymetrix, chips that instantly detect the activity of all 100,000 human genes could shortly be available for as little as $5. (6) As with any technology, the potential exists for dangerous misuse of the DNA chip. As Yap points out, social innovation and moral development do not obey Moore’s Law (10). It is extremely important to consider the ethical, legal, and social implications of genetic technology such as the DNA chip. Moral issues potentially affected by DNA chips will be discussed, including drug approval, gene ownership rights, insurance discrimination, and environmental toxicity studies. This list is by no means exhaustive, and will expand as more people contemplate this powerful technology.

The first major breakthrough in DNA chip technology came from Stephen Fodor and his colleagues at Affymax. (8) Looking for ways to rapidly generate many different peptide or oligonucleotide compounds, the team succeeded by adopting the same photolithographic technologies used by silicon valley computer chip manufacturers (13). First, they started with a glass chip covered with a checkerboard array of "linker-agents" that will bind to DNA nucleotides (through deoxyribose-phosphate binding, not base pairing). They then cover the grid of linker-agents with photo-sensitive "protecting-agents." These protecting agents prevent the linker-agents from binding to the nucleotides. Now, a special mask with holes in it and a precise light beam allow the selective removal of the photosensitive protecting-agents. After this stage, some linker-agents are exposed, while others remain protected. The entire glass chip is now immersed with DNA bases of one particular type. The exposed linker-agents bind to the DNA bases which are also specially treated with protective-agents so that they are only exposed on one end. Now, a new mask is applied to the chip, and select linker-agents and DNA bases are exposed. The process repeats itself, and ultimately a matrix of specific DNA sequences is created (12). Affymetrix, where Fodor now works alongside prominent geneticists including Paul Berg, states that they can produce matrices with 400,000 oligonucleotides on a stamp-sized chip. Generally the oligonucleotides contains twenty to forty DNA bases. (3, See Figures 1 & 2.)

Once the chip is made, the final stage is to screen a sample of DNA against the chip. The DNA sample must first be broken into small fragments and treated with a fluorescent dye. The chip is then immersed in the sample DNA. The small fragments bind to complementary "snippets" on the DNA chip. Finally, a special machine is able to read the chip within hours and interpret which snippets on the DNA chip hybridized to fragments of the sample DNA. The DNA chip may only be used once, and they currently cost about $30-$400 a piece. (3)

Affymetrix is not the only producer of DNA chips. In fact, Affymetrix, Incyte Pharmaceuticals, and Hyseq are all involved in patent fights over the rights to DNA chip technology. To complicate matters, in many cases the individual sequences on the biochips may be patented by yet another party. But so far, development of the chips has not been hampered because, according to a Wall Street analyst, "no one company has enough of a patent position to completely block its competitors." (5)

The DNA chip technologies differ considerably between the companies. Hyseq has a process in which the sample DNA does not need to be tagged with a fluorescent dye before screening, simplifying the work of the research labs. (3) Incyte has developed a DNA chip in which two samples are simultaneously screened - cDNA from normal tissue, and cDNA from tissue affected by a drug or disease. Incyte’s DNA chip reader can instantly decipher differences in gene expression between the two types of tissues. Nanogen has a technology that decreases the screening time from several hours to several minutes. They achieve this by using electric fields to move the sample DNA around the DNA chip, instead of waiting for passive diffusion to occur. (3) Argonne Labs, Motorola, and Packard Instruments have launched an initiative to mass produce biochips, indicating that their technological leadership may allow them to create these chips for less than a dollar a piece in the near future. (1)

As of late 1998, Affymetrix alone had over twenty DNA chips developed for different research purposes. One chip can quickly scan a DNA sample for the presence of any of the 140 known mutant versions of the HIV genome. A similar chip can screen for all known variants of the p53 gene, which has been associated with up to half of all known human cancers. A chip called the Cytochrome P450 can rapidly detect variation in gene activity affected by several therapeutics, including many beta-blockers and anti-depressants. (4) When Affymetrix teamed up with a company which specializes in bacterial genomics, they developed an inexpensive chip to test drinking water for the presence of many different strains of pathogenic microbes. (14)

Already near monitoring the activity of all 100,000 human genes, DNA chips may soon be able to map the entire human genome. In fact, geneticists at Stanford and Duke universities were able to use Affymetrix’ DNA chips to quickly map the entire genome of a yeast species. They used a DNA chip containing overlapping "snippet" probes of the entire genome of a similar yeast species. They then screened the DNA of the sample yeast species, and instantly found 3000 markers - sites on the DNA chip that didn’t bind to the sample DNA. Knowing these markers, the work of mapping the genome was considerably expedited. (9)

The potential benefits DNA chips might offer society are considerable. Companies that produce the chips have listed hundreds of potential medical applications (2). One common example is that of rapid-diagnosis of infection. By instantly identifying the cause of an infection, chip makers claim that DNA chips could help reduce the spread of antibiotic resistant bacteria. Today, doctors often prescribe multiple antibiotics when a patient is suffering from some bacterial infection. If a DNA chip could, within minutes, alert the doctor to the exact strain of bacteria causing the patient’s illness, it may be possible to pinpoint the antibiotic that will eradicate the infection with the best efficacy. Society would benefit from fewer antibiotic prescriptions, quicker overall treatment time, and hopefully, significantly reduced levels of antibiotic-resistant bacteria.

In addition to determining the right drugs for a specific infection, DNA chips could guide doctors to the right drugs for a specific patient. Currently the FDA allows the distribution of beneficial pharmaceuticals that have disastrous side effects for some individuals. One example is Prozac, which is toxic to a small percentage of patients. It appears the FDA assumes that the overall benefit to society from the drug outweighs the infrequent complications. However, this philosophy is by no means ideal. We would be much better off if we could use DNA chips to quickly screen an individuals’ genes before treatment, preventing lethal drug - gene interaction. In this case, the DNA chip might resolve an important moral concern by eliminating a difficult issue associated with drug approval.

In addition to the pharmaceutical industry, DNA chips will alter the genetic testing field as we know it. With the advent of genetic tests like those for Cystic Fibrosis, Huntington’s, and BRCA-related breast cancer, doctors have had difficulty explaining the implications of these tests to their patients. Often patients do not fully comprehend the meaning of their test results. BRCA-positive women who underwent risky breast-removal surgery may not have elected this option had they fully understood that they were not destined to get breast cancer. In an era where doctors have even greater time demands, the information yielded by a DNA chip could prove to be overwhelming. A patient, in a matter of minutes, might find out that he/she has fourteen genes that may lead to diabetes, prostate cancer, heart disease, etc. However, this probably is not as catastrophic as it first seems. When we progress from a few tests like BRCA to a complete battery of tests, people will realize that everyone has some "killer genes." With this understanding, hopefully these tests will only be used for rational preventative care. Similarly, fears of insurance company genetic discrimination may be exaggerated. As DNA chip tests become common, insurance companies would likely find it impossible to select customers with "clean genomes." Insurance companies that refuse to insure anyone with "killer genes" may find themselves without customers.

DNA chips could shed light on the ability of plants to produce biodegradable plastics. According to Shauna Somerville, a plant biologist at Stanford University, "we don't know the impact on the plant of ... diverting so much carbon to a novel product[plastics] that the plant has never seen before. Microarrays will help us understand how a plant's metabolism copes with that - and whether that kind of engineering will ever be viable."(8) By understanding all the factors involved in plant engineering before widespread use, the DNA chip might prevent unwelcome ecological surprises that many fear could arise from genetic crop engineering.

Novel drug production would certainly benefit from DNA chip technology. Consider individuals who are unaffected by certain toxins or viruses, for example, people who contract HIV but never seem to develop AIDS. DNA chips would allow scientists to get a quick picture of the differences in gene expression between these individuals and those who develop AIDS. Although efforts like this are possible with older DNA technology, DNA chips would accelerate the process and most likely require less funding. With viruses that could potentially mutate into epidemic proportions, and threats of bioterrorism, the value to society of a technology that can quickly generate new cures is priceless. Legal and ethical complications appear when we consider drugs developed in this fashion. If a novel drug is developed from one person’s genomic data, does he/she have the right to control its use and/or charge a royalty? It seems ridiculous that one person could have the authority to dictate who can receive treatment and how much it costs. It is unclear how we can support the individual’s right to privacy, including their genes, while allowing the free exchange of scientific information. Little legal precedent exists for such a situation.

The creation of DNA Population Libraries would become feasible once DNA chips become available that can sequence human genomes rapidly. Consider a database containing the entire genome of every individual in the United States. According to Moore’s Law, this may be a distinct possibility within the next decade or so. If we wanted to study, for example, the mutagenic effects of living in proximity to nuclear power plants (or any environmental factor), we could make these comparisons using such a database. DNA Population Libraries could also be used to advance Biodiversity studies. Instead of sequencing the genome of 250 million United States citizens, we could sequence the genome of hundreds of thousands of different species. The possible applications of such a database are only bounded by one’s imagination. Studying evolutionary history, protecting endangered species, and pharmaceutical development are just a few.

Along with the benefits of DNA Population Libraries emerge important moral concerns. Consider the following scenario: FutureFuel, Inc. develops a new engine that runs on a proprietary eco-fuel. This new fuel/engine combination will dramatically reduce the cost of transportation, and will also reduce emissions of carbon dioxide, hopefully reducing global warming. However, a simple by-product of their fuel, which doesn’t occur naturally, is toxic to a small group of people who possess a rare gene that would convert the by-product into a lethal toxin. After searching the DNA Population Library, FutureFuel finds that exactly 100 people in the United States could die from exposure to the by-product, which would be widespread. FutureFuel goes ahead with its production, figuring that they are doing society a greater good by making hydrocarbon fuel obsolete. Does this group of 100 people have the right to stop the production? Should the government intervene?

The point of this scenario, however far-fetched it may seem, is to demonstrate that a functional genetic revolution could, in the not-so-distant future, affect people on an individual basis to a greater degree than most ever anticipated. DNA Population Libraries, cheap genetic screening, and ‘personalized’ pharmaceuticals are all exciting, but dangerously empowering, applications of the DNA chip. Stephen Fodor, the inventor of the DNA Chip, has undoubtedly contemplated some of the implications of his work: "Ninety-nine percent of people have no inkling about how fast this revolution is coming." (11)

References

1. Argonne National Labs Website, "Biochip Commercialization Project", <http://www.anl.gov/OPA/news98/biobackgrounder.htm>

2. Argonne National Labs Website, "Motorola, Packard Instrument Co. and Argonne to develop advanced biochip technology", <http://www.anl.gov/OPA/news98/news980629.htm>

3. Service, Robert F., "Microchip Arrays Put DNA on the Spot.", Science 5388 (Oct. 16 '98) : 396-9.

4. Service, Robert F., "Coming soon: the pocket DNA sequencer.", Science 5388 (Oct. 16 '98) : 399-401.

5. Service, Robert F., "Will patent fights hold DNA chips hostage?", Science 5388 (Oct. 16 '98): 397.

6. Wade, Nicholas., "Meeting of Computers and Biology: The DNA Chip.", The New York Times (Apr. 8 '97) : Front page, 6.

7. Papanikolaw, Jim., "A Chip off the Genomics Block.", Chemical Market Reporter (Nov. 9 '98): Front page, 6.

8. Daviss, Bennett., "Speed freaks.", New Scientist 2160 (Nov. 14 '98) : 46-50.

9. Service, Robert F., "DNA chips survey an entire genome.", Science 5380 (Aug. 21 '97) : 1122.

10. Yap, Wendy. "Environmental policy in the age of genetics." Issues in Science and Technology v.15 no. 1 (Fall '98): 33-6.

11. Stipp, David. "Gene Chip Breakthrough." Fortune v.151 (Mar. 31 '97): 56-73.

12. Carr, Geoffrey. "The chip-top laboratory." The Economist v.346 (Feb. 21 '98):p. s6.

13. Fodor, Stephen, et al., "Light-directed, spatially addressable parallel chemical synthesis.", Science 4995 (Feb. 15 '91) : 767.

14. "DNA project aims at water testing." The Financial Times (Feb. 25 ‘00) : p. 22.

15. Affymetrix Website, "Quicktime movie of GeneChip Production," http://www.affymetrix.com/movies/affy_tech.mov