A Virus Virtuoso: A Conversation with Molecular Biologist Joe DeRisi

By Jeff Miller on August 01, 2008

UCSF’s Joe DeRisi, PhD, gives science a good name. A relaxed California native, MacArthur Foundation Fellow and imaginative thinker, DeRisi is well-known for being approachable, collaborative, smart and easy to like.

So is his science, which concentrates on finding clues to and cures for infectious diseases.

DeRisi burst onto the public scene in 2003 when, together with postdoctoral fellow David Wang, PhD, and UCSF virologist Don Ganem, MD, he used microarray technology to detect the SARS virus within 24 hours of receiving it from the Centers for Disease Control and Prevention. The team also classified and genetically defined the virus in quick order.

What became known as the ViroChip, a microarray that contains DNA from every known virus – a number that now approaches 22,000 – was used two years later to identify an unknown virus in human prostate tumors.

That same DeRisi-and-Ganem team has now found a virus associated with an infectious disease that has been killing parrots and other exotic birds for more than 30 years. Better yet, they have developed a diagnostic test so that healthy birds – including some endangered species – can be protected from sick ones, checking the spread of what is known as PDD, proventricular dilatation disease.

Such results might be enough for any other scientist, but DeRisi’s ViroChip work represents only half of his lab’s activity. The rest of his interdisciplinary team is dedicated to discovering weak links in the life cycle of the malaria parasite, Plasmodium falciparum. The goal: to identify drug or vaccine targets that could help reduce the annual malaria death toll, which ranges from 800,000 to nearly 3 million. Many of the victims are children under the age of 4.

When DeRisi speaks of this human toll – and the comparative dearth of scientists studying ways to combat malaria – he shakes his head in dismay. But he does not belabor the gesture. There is too much work left to do, too many viruses yet to discover, too much curiosity to sate. And, as he knows and accepts, the public is waiting. He does not plan to keep them waiting long.

Photo of DeRisi by Paul Sakuma

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Podcast transcript

Jeff Miller:
Hello, I'm Jeff Miller, and welcome to Science Café. Today
I'm with Joe DeRisi, a Professor of Biochemistry and Biophysics, and a Howard
Hughes Medical Institute Investigator, welcome Joe.

Joe DeRisi:
Hi, Jeff, great to be here.

Miller: I think it's safe to call you a virus hunter and developer of
what is known as the virus chip or the ViroChip. I know also that you have some
exciting news about your latest infectious disease discovery, which I'd like
you to describe and in doing so, could you also explain what a virus chip is
and how it works?

DeRisi: Sure. So my lab, together with Dr. Don Ganem's lab here at UCSF,
over the last six years or so, have been working on a technology called the
virus chip. Virus Chip is simply a diagnostic assay in which we're able to test
for the presence of literally every virus that's ever been discovered.

Miller: How many would that be, just out of curiosity?

DeRisi: Well, it's hard to put a number on the total number of viruses,
because of all the different mutants and strains and forms. But it's safe to
say we have somewhere on the order of 22,000 viral sequences on this chip.

Miller: Okay, so you can test all at once?

DeRisi: That's right, so we're testing for literally thousands of viruses
simultaneously instead of the one-by-one approach of the past.

Miller: So there's a speed issue, and then the comprehensiveness issue.
So, tell me about the latest discovery that you found –

DeRisi: Right.

Miller: - which I believe is related to a bird virus.

DeRisi: That's right. And I have to add one more detail to Virus Chip.
Not only is it capable of detecting the viruses we already know about, but to
understand this story you have to know that the virus chip is really designed
to detect that which we've never seen before. And so, "how can it do that,"
you say? Well, the chip is basically designed – this diagnostic is designed
to pick up on the evolutionary, the evolutionary conserved bits of the viruses
that are preserved throughout time. And so, certain viruses share little bits
of their pieces in common with other viruses. And so we've maximized that on
our chip. So that if there is a new virus, and it is related to a known virus,
we have the chance of picking it up. And that's what happened with our most
recent discovery.

Miller: So, please tell me about that.

DeRisi: Right. So, for over 30 years, there's been a disease that has been
killing exotic birds. And when I say exotic birds, I'm really referring to Psittacines,
these are parrots and cockatoos and parakeets, macaws, things like this. Sometime
in the last 1970s, macaws were imported from Bolivia into the United States.
And soon afterwards, it was noticed that in many of these birds, there was a
disease. It was then called Macaw Wasting Syndrome, in which the birds just
stopped eating, or couldn't eat. That is, their whole digestive tract became
paralyzed, and of course, they died.
The most frightening thing about this was, is that this disease then began
to spread, not from just the macaws that were imported but to all the other
birds that they'd been housed with. So it was clearly of an infectious nature.

Miller: To all the birds, or were there some who seemed impervious to
the virus?

DeRisi: Well, over 50 different varieties of Psittacines has been documented,
and when they keep looking they keep finding more.

Miller: Right, okay.

DeRisi: No one knows the limit where this virus stops, in the order of
Psittacine birds. But it's also been documented in birds outside Psittacines,
too. So, it's not – I'd say right now we're looking at the tip of the
iceberg, we don't know actually how many kinds of birds can be infected.

Miller: So what prompted you then to study this particular virus?

DeRisi: Right. So, no one really actually had evidence that it was a virus.

Miller: Oh, okay.

DeRisi: All they had evidence was that it was transmissible, and it was
likely a virus. And all the different characteristics of this disease convinced
us that it probably was viral, and so that's where the utility of our Virus
Chip comes in. And so collaborating with two veterinarians, one in the U.S.,
and one in Israel, we obtained samples of birds with this disease. This disease
is called Proventricular Dilation Disease, or PDD, as it's known. And so we
obtained samples from healthy birds and birds with PDD from two different places
in the world. This was nice, because you want sort of geographically different
sources of material, so it can't all be biased in one place or another.
We applied those to our Virus Chip, and we saw a striking signature, a signature
that said that there's likely to be a virus here and it's likely to be a Borna
virus. You've probably never heard of a Borna virus. Borna viruses are viruses
that have only previously been known in horses and other kind of livestock.
And they cause a variety of neurologic symptoms: encephalitis, and so on, in
these animals. It's ultimately fatal. But it also can cause GI dysfunction and
paralysis very similar to what we observed in parrots and other exotic birds.
And so, what we had here was evidence of possibly a new avian Borna virus, the
equivalent of what is in livestock but in birds. And it'd never been found in
birds before.
And so, we then went about cloning the virus from these birds, and we were
able to recover the complete genome of one of these Borna viruses, and pieces
of it from many others.

Miller: So is this virus restricted to birds only, or can it spread to
humans? Is there a human counterpart?

DeRisi: There is no evidence at this time that avian Borna virus can be
spread to humans. That's an important point, because we don't want domestic
bird owners to suddenly start throwing their birds onto the street in fear that
they're going to catch a virus. It's important to note that there's no evidence
right now of transmission to humans. And so, people should not be afraid of
their birds.

Miller: So I want to – so bird owners, was this virus occurring
so frequently and so rapidly that whole populations, if you happened to own
a bird that you were being made aware of the fact that your bird was at risk,
and –

DeRisi: So the most frequent problem for domestic bird owner is, many bird
owners own more than one. They might have two or three parrots, and they buy
or acquire another bird that has PDD, they might not know it. Because it is
quite likely that these birds are shedding virus, and are transmitting virus
before they're obviously symptomatic. And so, when the bird that you've just
brought in finally becomes symptomatic, it's already too late for the other
birds in your house. Because they've already acquired it.

Miller: And how long does it normally take for it to show up, or –

DeRisi: Highly variable, you know, it's depending on the different kind
of bird and there's a lot about the disease we don't know. It can be anywhere
from months to a couple years. And so that, that's actually an exciting new
area that we can now look into. Because previously without any handle on the
disease, without knowing what causes it, those kind of studies were impossible.

Miller: So what does this teach you about viral disease in general, perhaps,
and viruses that do affect humans?

DeRisi: Well, it's an important lead in what I would call GI tract disorders.
So there are diseases in humans that are fairly rare, that bear some similarity
to this, and so it does beg the question that could there be viral etiologies
of these human disorders. And so obviously you want to look at that. And humans
aren't the only ones. There's a wide variety of other animals that also suffer
from similar digestive tract abnormalities. And those could be also virally
caused for all we know. This is an important new lead in a whole new area. And
that's what it really opens up, in addition to providing a diagnostic ultimately
that allow domestic bird owners, aviaries, zoos, conservatories and bird recovery
operations to separate sick from healthy birds.

Miller: Right. So it'd prevent the spread. Now knowing that it's a virus,
does this open the door to some sort of treatment down the road?

DeRisi: Possibly. Curing a virus or making a chemotherapeutic or a drug
or something to cure a bird of a virus or even a human of a virus is much, much
harder than simply separating the sick from the healthy. So simply by quarantine
efforts, you may be able to just eliminate the virus. For example, you know,
in SARS there is no therapeutic for SARS, but by simple quarantine you can stop
the spread of the virus. Now I think this is an important point to say that
we actually don't have concrete proof this virus we found is the causal agent
of PDD. What we have now is a very strong association between the two, and a
lot of supporting evidence. What will remain to be done is a serious transmission
study where we take pure virus and put it into a healthy bird and show whether
it gets PDD or not, and those experiments are ongoing. But it's an exciting
enough lead that it would be foolish not to act on it now.

Miller: And this is not the first time you've had this sort of undiscovered
virus moment, was there not a couple of years ago something related to prostate
cancer?

DeRisi: That's right.

Miller: Similar finding, right?

DeRisi: Yeah, we discovered a novel retrovirus, in the prostate tumors
of a certain subset of men with a genetic abnormality. That's very interesting
and there's a lot of ongoing work on that retrovirus right now as well. Again,
that's another case in which you can find a new virus but you're not actually
showing in that discovery that the virus causes cancer. Far from it, all you
know is that it's associated. So whether it's causal or not takes many, many
years of experiments to figure out.

Miller: So what is your best guess, that there are a lot of unknown really
viral agents that are responsible for conditions and diseases that we just have
not yet connected?

DeRisi: Oh yes, by far. Just taking cancer, for example. We know that 15%
of all cancers, approximately, have an infectious etiology, whether that be
papilloma virus with cervical cancer, or human herpes virus 8 with Kaposi's
Sarcoma, or what not, we know that a substantial fraction of those are caused
by infectious agents. Who's to say there isn't a larger slice of that pie that
has at its source some infectious cause? And that's just cancers. There are
many, many, many other diseases for which likely there is an infectious agent,
but we have not been able to figure it out yet. That's where the Virus Chip
technology can have a large part.

Miller: And is that the technology that you developed?

DeRisi: That's right, it's Dr. Don Ganem and I, together over the last
six or seven years, have been developing the Virus Chip technology.

Miller: And do others, the labs around the world, now use the same technology?

DeRisi: You know, it takes quite a lot of expertise. There are several
labs out there that are using Virus Chip technologies, either to similar or
I would say copies of the technology. But we published all of our chip technology
and what goes into it and how to make it, essentially on the web. So anybody
that reads our papers or comes to our websites can have the entire know-how
to reproduce that technology in their own labs. We don't have a company that
sells virus chips or anything like that, we show people how to do it and expect
them to do it on their own.

Miller: Well, when they do come to your website, they see a lot of information
about malaria. So tell me about your malaria research, and how is that going?

DeRisi: Right. So the other half of my lab, aside from studying viral etiologies
and diseases, the other side of my lab studies plasmodium falsiparum. That's
the causative agent in the most deadly form of human malaria, and so for those
who don't know much about malaria, it causes somewhere between 700,000 and 2,000,000
deaths per year, and half a billion people are sick from it every year. It's
a massive disease, it's a giant burden on much of humanity. Yet, because we
don't have malaria in the United States any more, it's been eradicated from
this country and Europe, or most of Europe, we don't really think about it that
much. The problem is there was a time when we had really good drugs for malaria,
and so it was pretty easy to cure. But many of those drugs including the cheap
ones that of course would be use to many people in the poor world, are no longer
effective. There's drug resistance that's spread worldwide. And, to date, there's
no vaccine with an operational impact against malaria. Plenty of vaccines in
development, but nothing that actually saved anyone.

Miller: So, are there enough people studying malaria since it's such a
huge disease with a huge impact, and if there are not, would it behoove the
scientific community to organize itself in some mammoth effort to fight this
disease.

DeRisi: I believe so. I don't believe there's enough researchers studying
malaria right now. That's a fact. Let's just take, for example, a model organism
like baker's yeast. Baker's yeast is a classic model organism used biochemistry
labs around the country. There's 6,000 genes in the genome of baker's yeast.
There's probably twice that number of labs in the world studying it. So if we
really wanted to solve baker's yeast, we'd have two labs per gene, everybody
gets assigned a gene, we'd be done with it. That's not how science works. Now
malaria, there's also 6,000 genes, approximately. And there's probably only
a few hundred labs total in the world working on this. And that's pretty sad,
considering the burden to humanity that malaria really is.

Miller: So are you collaborating with some of the other labs?

DeRisi: Oh yeah, we collaborate with many different labs.

Miller: And how important is collaboration to the success of science these
days?

DeRisi: Collaboration's essential. There's almost no science that's done
today solely sort of on a one person one lab basis. Almost everybody's collaborating
with somebody all the time, and this is because science has gotten very complex.
A lot of information, science, biochemistry, bioinformatics, genetics, cross-discipline,
inter-disciplinary research, is the way the things are being done now. And so,
my malaria work is done in collaboration with many different labs, my virus
work is done with different collaboration with different labs. We almost never
work solely on our own any more.

Miller: Well, so is there an entrepreneurial spirit in your lab? I mean,
clearly, if you're – one person can't be in charge – with so many
collaborations and so many specialists from different fields, you really have
to rely on individuals to sort of take the ball and run with it, or is there
some strict management technique that's in play?

DeRisi: I'd like to think there's a strict management technique in play,
but there's really not. Basically, what I do is I try and recruit excellent
individuals in wide varieties of different fields so in my lab, we have clinical
M.D.'s in the lab, we have structural biologists, we have bioinformatists, we
have strict computer programmers, we have single molecule biophysical type people,
we have immunology people, genetics people, biochemistry people, molecular biology,
and all these fields sort of brought together, bioengineering as well.

Miller: So when you first confront a problem, are all these people in
the same room and everyone offers an opinion about how best to structure the
experiments to get at the answers, how does that work?

DeRisi: Not usually. Basically, ideas for interesting experiments and things
to tackle come from a variety of different angles. It's not usually a group
project that generates the ideas. The ideas can come form anywhere. But once
the idea is there, I will try and recruit what I think is within the lab, or
within the labs I'm collaborating with, the best team to work on that problem.
So if it involves making the new, let's say, microfluidic device, to launch
a new sort of diagnostic system out in the field or whatever, I will recruit
the people who would be best qualified to do the engineering, to then get the
surface chemistry right, and so on, from within the labs that I work with and
my own lab.

Miller: Did you always want to be a scientist? Even when you were a kid?

DeRisi: Most definitely, I can remember doing experiments in genetics under
safla in junior high. You know, breeding flies with wings and without wings,
and so on. And at that moment, doing those kinds of genetic experiments when
you can obviously see the result right in front of you, I knew then that I really
wanted to be sort of a genetic engineer of sorts, and at least that's what we
called them back then. And so, I've always had my heart set on molecular biology,
infectious disease, genetics, and so on.

Miller: Were there scientists in your family?

DeRisi: My dad is a clinical psychologist, it's a different kind of scientist.
And my mother was a nurse. And so, we had a strong science background but molecular
biology, this was the beginning of molecular biology when I was growing up.
So there really wasn't the same sort of model.

Miller: Joe, thank you so much for joining me on Science Café,
I wish you great luck in your future research.

DeRisi: Thank you for having me.