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UCSF's DeRisi on Using Arrays to Understand and Tackle Infectious Disease

Name: Joseph DeRisi
Title: Associate Professor of Biochemistry and Biophysics, the University of California, San Francisco
Education: PhD, biochemistry, Stanford University, 1999; BA, biochemistry and molecular biology, University of California, Santa Cruz.

Joe DeRisi has achieved prominence in the microarray community for a variety of reasons, beginning with his model-organism work as a graduate student in Pat Brown’s lab at Stanford and continuing through his contribution to the identification of the severe acute respiratory syndrome virus in 2003 (see BAN 4/4/2003).
In more recent years, DeRisi, along with fellow UCSF investigator Don Ganem, has been engrossed in the development of the Virochip, a broad-scale detection tool for identifying unknown pathogens.
DeRisi and Ganem published a case study on using the Virochip to identify an unknown pathogen in a patient in Clinical Infectious Diseases last October. A similar case study was published in May in the Journal of Clinical Microbiology. 2007 May 9; [Epub ahead of print]].
To learn about his latest efforts in virology, BioArray News caught up with DeRisi for an interview during a visit to his lab at the University of California, San Francisco’s Mission Bay campus last week. During the visit DeRisi also gave BioArray News a tour of the Center for Advanced Technology, an open access core facility housed at UCSF that is funded through the university and the California Initiative for Quantitative Biomedical Research.
You published on Virochip last year. How exactly are you using that array?
One use of the Virochip is for discovery of novel viruses associated with chronic human diseases. We would also like to use the chip for the diagnosis of so-called “vexing” cases of respiratory illnesses; that is, acute illnesses where other diagnostic techniques have totally failed. We now have a long history and a large database of samples that we have previously analyzed on this chip, well over a thousand clinical samples. So we have a really good calibration and [that] helps us discriminate between a real positive and a negative.
Also, through our collaborations with folks at UCSF and Stanford, we are able to process samples from patients suffering from critical illnesses.
We are not a CLIA-approved lab, so this isn’t a test that can go on the chart of a patient, but for our purposes we are really interested in learning the answer. One typical case was a 28-year-old female that presented at Stanford. She had a ten-day history of fevers; she was coughing up blood and had muscle pain. She had been treated with oral antibiotics, but she showed no improvement.
On day three she went into acute respiratory failure. As a result they put her on 100-percent mechanical respiration. They changed antibiotics but her condition did not improve. On day six, they did an open lung biopsy. The results were unrevealing. They were clear in that there was no clear result. They did diagnostics that included cultures for bacteria, culture, and fungus. They also tested for respiratory syncytial virus, influenza, parainfluenzas 1, 2, 3, SARS, and even hanta virus. And all of these tests went out in triplicate. Nothing came back positive.
We obtained endotrachael aspirate from day four. We put it on the chip, and the result came back parainfluenza-4.Why is that interesting? Because para4 is a virus that almost nobody studies. There’s very little work done on it, in fact so little work that the whole genome has never been sequenced, which is rather remarkable. The medical lore is that para4 causes a mild, self-limiting infection. While this may be the case in some, or even the majority of individuals, there is little data to examine the spectrum of disease this virus may cause. In this case it was acute respiratory failure.
So you are publishing on a case-by-case basis? 
These are case reports that we are publishing. That is for the critical care illness part of this project. There are two arms to the Virochip project: there is the research angle, which is about discovering new viruses associated with human disease and then the diagnostic angle.
What is your relationship with people at the hospital?
Well, we have an excellent relationship here at UCSF because clinical sciences and basic sciences are well integrated. And we have an excellent collaboration with our clinical friends at Stanford.
How does it work that you get called in for a case?
When the phone rings, a postdoc will drive down and get the sample. It has to pass a number of criteria before it gets to us, however. Obviously, we don’t want to do everything that comes in the door; that would be wasting our time. We need to do cases for which the technology is really going to have an impact.
What does the chip look like now and where is it going in terms of development?
It has approximately 22,000 viral sequences. We are expanding that to about 30,000 viral sequences built with the same general principles as the last version of the chip. We spend a lot of time on the design work and the viral database continues to expand. We have learned a lot about oligo performance by doing over a thousand clinical samples and based on that information, we have a good idea of what kind of sequences give you the most information.
We are going to continue to grow the chip and we are going to press for increased use in the clinic. Now we have an internal UCSF grant to pilot the use of this system in a CLIA-approved setting, which is one step closer to doing this as a routine diagnostic. Beyond diagnostics, we have literally dozens of chronic human diseases we are looking at from the discovery angle.
Why are you interested in infectious diseases?
I have always been interested in infectious disease research. I have also been interested in using technology, originally developed for the study of model organisms, in a way that has direct impact on human health care management. That is why we are really interested in these clinical care cases. These studies provide instant gratification as well.
Even though there are not therapeutics tied to each virus, it doesn’t matter. Knowing what the pathogen is in an acute illness can influence the management of supportive care in such a way that the probability of survival can be maximized. 
For example, if the identity of the pathogen is known, experimental therapies may be possible or in the absence of an experimental therapy, the supportive care can be customized. For example, the physician may decide not to prescribe certain antibiotics or antifungals, since they will not have an effect on a virus, and some of these drugs can be rough on the patient. Amphotericin B is a good example.  
You mention your malaria work. What is going on with that side of your research right now?
There are two angles to our malaria research. We work on the biology of the parasite itself as well as drug design and screening.
Right now there are no new major pharmaceutical efforts in malaria. The people who die of malaria are not the ones carrying credit cards. Keep in mind that the target price of a malaria drug needs to be less than five cents for it to have an impact in places like Sub Saharan Africa, were there is severe poverty. Clearly this is a tough problem.
Historically, many of the drugs used today, such as Lariam, came out of the US Army Walter Reed Research Center. Our malaria research is currently funded by the National Institute of Allergy and Infectious Disease and Howard Hughes Medical Institute. We are certainly looking to collaborate with WRAIR and others on malaria research.
I also noticed you just launched a rhinovirus database?
That just went [up] this month. A postdoc in my lab, Amy Kistler, sequenced several new full-length rhinovirus genomes and computed where in the genome diversifying pressure and purifying selection is occurring. Check out the cool movies and graphics. We have another manuscript that has also been accepted recently. This one has the discovery of brand new clade rhinoviruses and their full-length genomes will also be added to the RhinoBase.
[The database can be accessed here — Ed.]
In your opinion, is the field working well together, or is every lab on its own island?
Well virology is a huge field. Every virus you put out is really exciting because there is a ton of work to be done subsequently. Think about XMRV, this retrovirus we just found in human prostate samples. There is a lot of epidemiology that needs to be done to understand the human health implications. For example, we don’t know the sero-prevalence of this virus. We don’t know the route of transmission. We don’t even know the extent of association with human disease or if this plays any role in oncogenesis. There is so much work to be done with so many different labs.
That is the beauty of the virus chip. In one sense it is a discovery engine and just produces new projects like crazy. Clearly our labs can’t possibly handle all those projects and that’s OK. Many of these projects are spun off with the postdocs that leave to start their own labs.
I saw that you recently had a Febit Geniom installed.
It showed up last week. It is placed in our Center for Advanced Technology, which functions as a technology showcase. It is an open-access facility where students, postdocs, and faculty can use a variety of high-capital equipment. Unlike a traditional fee-for-service core facility, the CAT is also a learning and collaboration center.
How does that benefit the companies?
With regards to industry, we allow companies to place instruments in the CAT. This gives the community here access to the latest technology. Since we have users from all around the Bay Area, this arrangement gives companies broad market exposure, potential for collaborations, direct feedback, and more. Also, when postdocs go off and start their own labs, they tend to buy what they know. From a company perspective, they can seed the market by giving access to their latest and greatest.
The Febit is a good example. The majority of labs in the area could not shoulder the cost of purchasing such a machine for themselves. But by having the company place a machine in the CAT, users can get in the game for just the price of the consumables and some training. We are very excited that we just got a Solexa sequencer, which should attract a lot of users.

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