When SARS cases broke out among human beings for the first time,
early this year, it didn't take long for scientists around the
world to begin collaborating on ways to stop the disease. Reporting
from the epicenter of the SARS outbreak in Hong Kong, FRONTLINE/World's
Renata Simone caught up with an international team of researchers
during their experimental trials on a possible
treatment for SARS. In this overview of the science being brought
to bear on the new virus, three of the researchers -- Malik Peiris,
David Ho and Richard Kao -- explain what was happening under the
microscope in a series of experiments they conducted at the University
of Hong Kong in May 2003.
Identifying a Virus
Dr. Malik Peiris explains how the team discovered that SARS
was a type of virus known as a coronavirus. They also determined
that SARS was unique, never having been detected in animals
or human beings before.
Making the AIDS Connection
Dr. David Ho, known worldwide for innovative AIDS research,
outlines the connection between AIDS research and SARS research. Ho and
his colleague, Dr. LinQi Zhang, try treating SARS-infected cells
with methods similar to those that have worked with AIDS.
Dr. Richard Kao talks about the breakthrough for the team, when
they find that one of the substances they've used to treat cells
seems to prevent the cells from becoming infected by SARS.
Assistant Dean, Department of Microbiology, University of Hong
May 3, 2003
Tell us about that moment when you figured out you had
a unique virus.
What we were seeing was something from these patients' clinical
specimens that was killing the cells. Of course there are other
things that can cause this type of effect, but viruses are among
them. We went on to show that we could actually transfer this
[result] to new cells and the new cells also would die in the
same fashion -- so we were quite confident that it was a virus.
We wanted to be more certain that the virus we had [identified]
had something to do with the disease of SARS. [In the meantime,
the World Health Organization had coined the term SARS to cover
this emerging disease.]
we did was take blood samples from a number of other patients
who had typical SARS and test their blood to see if they had
to this virus that they got. And to our great excitement we
found that patient after patient who had clinical SARS had antibodies
that reacted with this virus.
When they looked at blood from other patients they had no antibodies
to the virus. So that really was the time I think we were confident
that we really had the virus causing SARS captured.
Talk about the speed of the discovery.
At that point, we knew we had the virus that causes SARS.
But we did not know what this virus was. We then took a train
track approach. On the one hand, we tried to look at the virus
under the electron
microscope to see what it looks like. It looked like
Corona viruses are viruses that have spikes on their surface,
and the term corona comes from "crown," the spikes on a crown,
so to speak.
While we were taking that [track], my colleague
Leo Poon, who is a molecular virologist, was going on a blind
fishing expedition trying to fish out genes of something unknown
from these infected cells. I think he tried
38 times or so and fished out total rubbish. But on the 39th
try he fished out something. Then he sequenced that and matched
that sequence with what sequences are available in the public
databases of genetic sequences. It seemed to be very similar
to the family of coronaviruses. At that point of course the
conclusion was obvious: You're dealing with a coronavirus.
The next question was where did this virus come from? This
was not one of the known human coronaviruses. There are two
coronaviruses that are very common in humans. They cause the
common cold, they're very trivial, and do not cause [behavior]
anything like this. From the way it was behaving in the laboratory,
it was not like one of the normal human coronaviruses.
How was this virus different from other coronaviruses?
It was growing in types of cell cultures that normally they
wouldn't grow in. We compared the genetic fragment that we had
with other coronaviruses that are known, human and animal, and
you could see that this one was sticking out like a sore thumb.
Our tentative conclusion at that point was that we were dealing
with a new virus that was probably not present in humans before.
When we looked at blood from mammal and human subjects in Hong
Kong, no one had any antibody to this virus except patients
who had the disease. So it [seemed clear that the virus] was
not something that was kicking around in humans before. So we
were confident it was not a human coronavirus. But it was also
not one of the recognized animal coronaviruses. The conclusion
had to be that it was coming from some type of animal, but it
was a virus that was new to science.
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Director, Aaron Diamond AIDS Research Center
May 3, 2003
Explain how your experience in AIDS research led to this
Well you know HIV binds to a CD4 T-cell, right?
Like any virus?
Right, any virus [does this]. HIV does so by binding to the
and CCR5 co-receptor. After engaging these receptors, a fusion
protein called GP41 [forms on the surface of the virus].
Viruses, then, attach to the CD4 cells in two places?
just attach in one, but HIV attaches to two. We don't know about
SARS yet. After attachment, the GP41 is the one that mediates
a fusion. It's like a harpoon, so it uncoils and just tosses
the sharp part into the membrane.
Then what happens is that what we call HR1 and HR2 [heptad repeats]
form an alpha-helical coil. The HR1 and HR2 yank the membrane
close to the virus membrane and the two fuse. [That's how] the
virus gets inside the cell. T20 [a peptide synthesized to disable
HIV's entry into cells] is a mimic of HR2, so that it gums this
process up. It's a competitive
inhibitor. It gums it up so that the virus cannot yank
the membrane toward itself.
Is this something like sticking something into a hinge
or door jam?
Right. When the SARS virus sequence
came out, we looked at the envelope protein, the spiked protein
on the surface and figured out just by analogy that there's
a portion that's probably binding a receptor. If you look, there's
a portion that looks like HR1 or HR2. So we simply made peptides
that look like HR1 or HR2. We made twelve of them and now several
of them are blocking this process, we think.
The peptides are gumming up the works?
Right, gumming up the works. Obviously, some [peptides] are
more potent than others. And I don't think it's extremely original.
We just [focused on] what we can do right now to develop specific
When did the idea come to you?
The day we heard the sequences were available and then we
said, well maybe let's analyze the sequences and see if we could
do anything. Now for HIV, if you make HR1, it doesn't work very
well. For this virus the HR1 peptides do work.
Was it a team effort?
I told LinQi, let's go ahead and do this. And then he -- he's
very good with the computer -- did the analytical work. There's
a tendency to do just what people have done in HIV, and that's
to make HR2 peptides. I think it was lucky that I said, "Let's
not be too smart, let's go ahead and make HR1 and HR2." Now
we're finding the HR1s are working better. So it's a little
different from the HIV story.
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Research Assistant Professor, Department of Microbiology, University
of Hong Kong
May 10, 2003
What happened today?
What happened today is that after several days of incubation,
this morning we got a chance to look at the cells, and we found
out that some of the peptides actually can inhibit the virus.
That means that with the peptides the virus cannot get into
the cell, so that's extremely exciting for us.
You seem surprised.
Yeah, actually we were. We were very nervous over the past
few days because of all those new drugs or peptides synthesized
by David Ho and LinQi Zhang. We don't know whether they would
have an effect or not, so basically you are waiting. So you're
just building up, building up, building up. So today -- this
morning -- is the moment of truth, and I'm very glad that actually
some of the peptides worked out beautifully at this stage.
What does this result mean?
Today's result basically
tells us that there will be a way -- a simple, very effective
way -- that the virus can be blocked [from] getting into the
cell in the first place. Hopefully in the near future, those
peptides will be actually put into clinical trials and maybe
the market, so that people suffering from SARS will not be killed
by this virus.
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Emily Coven is an Interactive producer
at KQED in San Francisco.