April 07, 2003
Search For SARS Cause Shows Power Of Gene Array Chips

The search for the cause of Severe Acute Respiratory Syndrome (SARS) has been greatly sped up by the use of DNA microarray gene chip technology. UCSF Assistant Professor Joseph DeRisi built a gene microarray containing all known completely sequenced viruses and used it to classify a pathogen isolated from SARS patients as a coronavirus.

DeRisi placed his computer's cursor over one lit dot and it read "bovine coronavirus." Another dot outputted "avian coronavirus." By the time he got to the turkey and human coronavirus dots, he knew he was dealing with something the world's scientists had never seen before.

If it had been a known virus say the human coronavirus, a cause of the common cold then only human coronavirus dots would have lit up.

DeRisi discovered that SARS is genetically most similar to a virus that infects birds.

Its genetic sequences so far seem to have the most in common with Avian Infectious Bronchitis Virus, according to preliminary molecular data obtained by Joseph DeRisi at the University of California at San Francisco and circulated among virologists.

Working with MIT post-doc David Wang and one other colleague (whose name I haven't been able to locate) DeRisi built a DNA gene microarray chip with the DNA of 12,000 different viruses. This allowed DeRisi to classify the suspected pathogen within 24 hours of the time he received a sample from scientists at the CDC. Let's put that in perspective. It took months to identify the pathogen that caused Legionnaire's Disease back in the 1970s. While DeRisi's assay was only one step of the process of isolation (it had already been tentatively identified as a coronavirus by viewing it with an electron microscope) it was a step that enormously accelerated the overall process.

DeRisi's development of a robot to place DNA samples onto the DNA gene microarray chip was helped along by advances made to do silicon semiconductor chip manufacture.

In fact, the robots that "pick and place" each sample from a small reservoir onto its spot on the slide are descendants of the machines used to build electronic chips.

This demonstrates a recurring FuturePundit theme: advances in electronic technologies are accelerating the rate of advance of biotechnologies.

The role that DeRisi and his colleagues played in identifying a coronavirus as a suspected cause of SARS came to the attention of the national media when CDC Director Dr. Julie Gerberding mentioned the work in a March 24, 2003 press conference.

But in addition, we're collaborating with academic partners. Earlier this week, we sent DNA out to a laboratory at the University of California, San Francisco, so that they could do the absolute state-of-the-art probe for virus genes and help us identify the cause.

Dr. DeRisi has made a more general contribution to the acceleration of the use of gene array technology. He built and released to the world the design of a robot that automates the process of putting DNA samples into gene arrays.

The technology behind the hope works by hybridization, the affinity for complimentary strands of DNA (cDNA) to form double helix structures. More than 40,000 unique DNA samples can be printed on glass slides in pre-determined locations.

DeRisi designed a robot that, at top speed, prints 14,400 elements per minute. These slides are then used to assay fluorescently labeled cDNA from tumors or organisms, like malaria, which are then stored on computers. Comparing these profiles can reveal the unique molecular signature carried by each type of cancer and give clues as to the original defect.

Despite the central role he played in revolutionizing genomics, it was DeRisi's populist approach to science that made him the buzz among academic and industry scientists. DeRisi never pursued a patent for the robot, instead he posted instructions on how to make it on the Internet.

"Joe could be a very rich man if he kept things to himself," says David Wang, a postdoctoral fellow in DeRisi's lab.

The lab maintains a website that disseminates protocols for the use of microarray technology while his UCSF site includes the instructions on building the robot.

What we still need are advances that will accelerate the rate at which vaccines can be developed. Vaccine development time for a disease like SARS is still measured in years. West Nile virus, for which vaccine development was begun in 1999, killed 277 Americans last year while leaving many others with central nervous system damage. Yet a vaccine for West Nile virus will begin undergoing preliminary testing on humans in June 2003, it is still three to five years away from general availability.

There's still a way that an infectious pathogen which is passed human-to-human like SARS can be defended against using biotechnology: be able to quickly and cheaply identify who is infected so that the infected people can be isolated. This can break the chain of infection and prevent a disease from developing into a pandemic. Without a test to identify exactly who is infected all people who have contact with an infected person must be put into quarantine regardless of whether they really are infected. Singapore has used this aggressive standard technique for epidemic control with considerable success. However, because an infected person can come into contact with a great many people who do not themselves become infected public health authorities are reluctant to quarantine them all. A test to identify people who are infected could make quarantine regimes far more acceptable and effective.

What is needed is a test that can identify infected people at a fairly early stage of the infection. Most of the SARS tests currently under development can not detect the infection at an early enough stage.

The development of a diagnostic test, which is being pursued around the clock by the WHO collaborating network of 11 laboratories, has proved more problematic than hoped. Three diagnostic tests are now available and all have limitations as tools for bringing the SARS outbreak quickly under control.

The ELISA detects antibodies reliably but only from about day 20 after the onset of clinical symptoms. It therefore cannot be used to detect cases at an early stage before they have a chance to spread the infection to others. The second test, an immunofluorescence assay (IFA), detects antibodies reliably as of day 10 of infection, but is a demanding and comparatively slow test that requires the growth of virus in cell culture. The presently available PCR molecular test for detection of SARS virus genetic material is useful in the early stages of infection but produces many false-negatives, meaning that many persons who actually carry the virus may not be detected creating a dangerous sense of false security for a virus that is known to spread easily in close person-to-person contact.

What is needed is an advance in biotechnology that will provide a test for SARS with high sensitivity at a very early stage of infection.

(thanks to Hylton Jolliffe for the first link)

Share |      Randall Parker, 2003 April 07 10:04 PM  Dangers Natural Bio

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