Baltimore’s Lecture on Viruses

[Guest guest]

Viruses, Viruses, Viruses by Baltimore

Almost every day some virus or other makes news—HIV, SARS, smallpox

as a bioweapon, last fall's new flu, and, most recently, the avian

flu in Southeast Asia. But it's my impression that most people don't

know what a virus is. So, since viruses have played a critical role

in my professional career, I felt that I was in a good position to be

useful and explain a bit about them.

Viruses exist in uncountable variety, since every animal, plant, and

bacterial species has its own set of them. It's not sufficiently

interesting for anyone to bother to find out how many different

viruses exist on every obscure species, so I think we'll never really

know the extent of these tiny devils. But scientists have already

isolated tens of thousands of them. You can observe them in an

electron microscope, get an idea what their shape is, do a little

molecular biology, put them in their place relative to other viruses,

and thus classify them. We now recognize more than 1,500 species of

viruses, each one of which can be broken down into subspecies and

further.

The notion of a virus goes back only to 1892, when Ivanovski in

Russia showed that a filter that would hold back bacteria would pass

the agent that caused mosaic disease in tobacco. That agent, he

realized, is much smaller than a bacterium. Bacteria were at the

limit of a light microscope's resolution, so no one could see these

objects then; all they knew was that they were very small.

In 1911 Peyton Rous discovered that one agent that passed through

bacterial filters could cause cancer. This was one of the seminal

experiments in cancer research, but because such tiny agents were

difficult to conceive of, the work wasn't immediately appreciated.

Rous finally won the Nobel Prize in 1966, 55 years later; it took

that long to realize how critical his discovery was to unraveling the

problem of cancer.

When the electron microscope was invented around World War II, the

first pictures could be taken of viruses. Then scientists could see

that the particles were indeed very small, in the range of 25 to 100

nanometers (10-9 meters; by comparison, the wavelengths of visible

light are 380–780 nanometers). From chemical analysis, we learned

pretty quickly that viruses consisted mostly of protein and that they

contained either RNA or DNA. Of course, by the 1950s, it was clear

that DNA was the hereditary material of higher organisms, bacteria,

and many viruses, so it was a bit of an anomaly that some viruses

didn't have DNA. But it was demonstrated in 1957 that the RNA

isolated from a plant virus was infectious, showing that RNA could be

hereditary material just like DNA.

Hermann Muller, a great drosophila geneticist, wrote a paper in 1927

saying that because viruses are so small, there's just no space in

there for anything other than the hereditary material of life. That

insight, which took many years, and the advent of molecular biology,

to prove, was actually the key to understanding viruses. Viruses are,

in fact, protein shells packed full of genetic information. They have

no cellular machinery (or at most, very little) of their own.

Viruses can grow only inside of cells. They can't multiply in the

environment and are to some extent dead objects there. There's a

running debate about whether viruses are alive or dead because, when

you crystallize them and they behave like crystalline proteins,

they're like dead chemical objects. (Bacteria, on the other hand, are

definitely living organisms.) And yet, when allowed into a cell, they

can hijack the total metabolism of the cell (in minutes in a

bacterium, hours in a mammalian cell) and completely reprogram that

cell so that the only thing it can do effectively anymore is make

more viruses.

To that extent I think they're about as alive as anything. In a cell

they can multiply extremely rapidly, a thousandfold in six hours. But

to stay alive, since they have to grow inside cells (and cells exist

only as parts of living beings), they have to spread from host to

host. That's a tough way to earn a living, especially when the host

has an immune system, as we do, and can fight off the virus. Usually,

when we get a virus infection, our immune system is activated and

within days is making antibodies and Tlymphocytes that can attack

viruses and virus-infected cells and clear the virus from the body

within a week. That, for instance, is the course of the common cold.

So, the virus has to pass to another host before the immune system

revs up and inactivates it. If it doesn't pass to at least one other

individual before the immune system clears it, it dies out. If at

each instance of infection it is able to infect one more person, it

effectively lives forever. Measles virus, for instance, passed

continually from person to person, used to spread very widely before

we had a vaccine. Young children usually got it, and when they got

over it, they were immune thereafter; the immune system has a

wonderful memory of what it has seen before. But when some isolated

populations who had never seen measles were exposed, it was

devastating to them because they had to fight it off as adults. For

one reason or another, young people usually fight off viruses much

better than older people do.

When viruses pass from one organism to another, they adapt to that

host; viruses of humans adapt to the specific ways that humans

interact. We shake hands; that's one of the best ways to pass

viruses. I think the Japanese learned to bow because they realized

they stayed healthier if they bowed to one another rather than

shaking hands. When I feel as if I have a virus disease, I just don't

shake hands with people. (I have to explain so they don't get

insulted.) Sneezing and coughing, obviously, are good ways, but

mostly just in the immediate local area, because a sneeze dries up

very rapidly in dry air. And then there are other wonderful things we

do, such as kissing and sex, which provide the opportunity to pass

viruses as well as sentiments.

Over many, many years, viruses have adapted to our way of life. If

you put one of our viruses in a mouse, it won't survive because mice

don't kiss or shake hands, and they don't raise their kids in

communal kindergartens. The fact that viruses have become attuned to

our lifestyle is wonderful in one way: it means that if you eradicate

a particular human virus, it will never come back, because it can

exist only in humans. That is, in fact, what happened when a

worldwide vaccination campaign got rid of smallpox. Lots of other

species have related pox viruses, but they're not adapted to us.

Stopping the spread of smallpox faced the world with a difficult

decision: whether or not to get rid of all the smallpox stocks that

exist in the world's laboratories. An edict came down from the World

Health Organization: yes, we should make smallpox extinct, but an

exception was made for two laboratories, one in the United States and

one in the Soviet Union.

Why do we keep it at all? I am one of those who believe that we

should totally get rid of it. It only continues to exist because some

people got sentimental over smallpox. Environmentalists, in

particular, feel that we should never eradicate a living species. Of

course it happens all the time, but this would have been conscious,

and some people felt bad about it. To be fair, the environmentalists

were joined by a large number of virologists who did not want to see

an object of their potential inquiry taken from them.

The question also arose as to whether some countries lied. We're

still worried that there are caches of smallpox held by rogue

governments or terrorists that could be developed as bioweapons.

Since vaccination ended when the virus was eradicated, we are

defenseless against it now.

Polio is another virus that has been virtually eliminated by

vaccination and very conscious activity on the part of the World

Health Organization. A few places in the developing world (India, in

particular) still have outbreaks of polio, but there hasn't been any

polio virus in the Western hemisphere for a couple of decades.

Because viruses multiply inside cells, they are faced with the

problem of exiting from the cell. They have found two solutions: they

can either break the cell open, or they can bud off the cell's

surface, carrying the outer membrane of the cell with them. In the

second mode, the virus modifies the cell's outer membrane by

insertion of one or more viral proteins. This protein is picked up by

the budding virus and endows the virus with the ability to recognize

new host cells and infect them. Both of these ways of escaping the

cell are pretty efficient, but the budding process is the most

insidious because it doesn't kill the cell and can continue for the

life of the cell.

Molecular biology of viruses

We know an enormous amount about many viruses today, but it was only

when molecular biology was born that they began to make sense. So let

me give you a very brief course in molecular biology. The nucleus of

a cell has chromosomes in it; the number varies from species to

species. If you unravel those chromosomes far enough, you see that

they contain supercoiled molecules of DNA. When you uncoil the DNA,

you see that it's a double helix, held together by cross bridges of

complementary chemical bases, which are paired up. That's almost all

the molecular biology you really need to know. When and Crick

published their famous paper in 1953 describing this structure, it

became obvious what was going on at the basic level: the DNA was

encoding the structure of proteins. And it also became clear

(although it took some time to prove it) that the way to duplicate

this molecule took advantage of the fact that the two strands are

redundant; they carry the same information, because a pairing rule

determines their structure. The duplication of DNA, therefore,

involved unwinding the duplex and duplicating each strand

individually.

The one other thing you need to know about molecular biology is that

it has a central dogma. That dogma says that DNA duplicates itself

(replication); that RNA is made from it (transcription); and that RNA

is the key material that directs which proteins are in the cell

(translation). The proteins do the work of the cell; they're the

muscles in the structure of the cell itself. That was the central

dogma until 1970, when Temin (PhD '60) and I did an experiment

that showed that you can also reverse-transcribe RNA back into DNA.

At the time, that looked like a particular characteristic just of

viruses, but we now know that it happens a lot in the life of cells,

especially over evolutionary time. In fact, about 50 percent of the

genetic material that we carry around in each of our cells arose by

reverse transcription.

Many of the discoveries in molecular biology depended on working with

viruses, particularly bacteriophage, a virus adapted to bacteria. The

great gods of bacteriophage research were Max Delbrück, here at

Caltech, and Salvador Luria, first at Indiana University and then at

MIT, where he was my mentor. It was with bacteriophage that A. D.

Hershey and Martha Chase at Cold Spring Harbor demonstrated that DNA

was the hereditary material, and that Seymour Benzer (now the Boswell

Professor of Neuroscience, Emeritus, at Caltech) showed that genes

had a fine structure that corresponds to the individual nucleotides

in the DNA. It was also at Caltech that experiments using bacterial

viruses showed that RNA carried the information from DNA to protein.

Mammalian viruses also played their role. Our discovery of reverse

transcriptase came from mammalian viruses, as did splicing, a process

by which the transcript RNA is cut up and certain sections are

removed. And plant viruses showed us that RNA is able to act as a

genetic material. We thought this was an oddity at the time; it

doesn't happen in any other class of organisms. But it was the first

clue to what was probably a very important stage in evolution, when

there was an RNA world in which DNA had not yet evolved. Life back

then depended on the genetic abilities of RNA, as well as on its

protein-like catalytic capability.

Equilibrium and nonequilibrium viruses

Let's get back to how viruses are adapted to individual species—to

us, in particular. These I call equilibrium viruses, because they

live in equilibrium with us. They know how to keep passing from

person to person, but they're not terribly lethal. They may kill a

few people (smallpox killed more than a few), but, in general, the

equilibrium viruses that occasionally give us colds are not a very

big danger to us. Many people, including me, think that part of a

virus's evolution is that it adapts to its host species in ways that

keep its host alive so that it can continue to infect the host's

children.

But when an equilibrium virus in one species jumps into another

species, it becomes a non-equilibrium virus. Such a virus will rarely

spread well in a population because it's not well adapted to the new

species' lifestyle. A few people may get it from an infected monkey

or rodent; it can be highly lethal, but it's not likely to cause an

epidemic in the overall population. It could become an equilibrium

virus in the new species, but only over a long time.

We guess that HIV first jumped into the human population in the 1930s

and certainly no later than the 1950s. Yet it's clearly not an

equilibrium virus. It is highly lethal, but only over a long time; it

is spread among people, but not efficiently, requiring either

injection or sexual contact. It and flu, which are the two

nonequilibrium viruses that most bother us, do not follow the rule of

poor spreading as a guest in the population, because they are able to

pass well enough from person to person that they can be a serious

problem.

Equilibrium viruses include polio, smallpox, measles, mumps, herpes,

most of the common cold viruses, and lots of others. Among the non-

equilibrium viruses are the influenza, HIV, SARS, Ebola, and Hantaan

viruses. Flu is the oddest, because it clearly passes around among us

as if it were an equilibrium virus. But one of the reasons it can be

so devastating is that it is constantly regenerating from a reservoir

in wild birds. We believe the birds infect domesticated ducks, they

in turn infect pigs, and the pigs infect people. This all generally

happens in China—until it finally breaks out of China by finding a

ship or an airplane or some other conveyance, and becomes a part of

our circulating pool of viruses. It's the only virus I know of that

can jump out of another species and adapt itself rapidly enough to

the human species that we pass it around as if it were one of our own.

SARS came from an as yet unknown animal, maybe a civet cat. It

originated in China and was carried out of that country by people

traveling to Canada and other places, where local epidemics then

began. The virus never started a serious epidemic in the general

population. Most cases occurred in hospitals or in medical personnel;

a couple of cases spread in an apartment house. But there was never a

real epidemic.

The amazing variety of viruses

Viruses come in an astonishing assortment of shapes and sizes and

have evolved some quite remarkable features. What I'd like to do now

is examine some individual viruses and look closely at what's

interesting about each of them. Some, like parvoviruses and

picornaviruses, are extremely small, only about 25 nanometers across,

just big enough to package an RNA or DNA molecule inside. The bigger

adenovirus can accommodate a much larger piece of DNA. Particularly

large RNA viruses include retroviruses like HIV and coronaviruses, of

which SARS is an example. All these are spherical in shape, but then

we have things like the bullet-shaped rhabdoviruses and the

complicated poxviruses. A poxvirus makes more than a hundred

different proteins and is much closer to being an actual organism

than most of the others.

Herpes simplex is a large, spherical virus, which I'd like to discuss

from the point of view of its structure. Herpes, related to the

viruses that cause chicken pox, infectious mononucleosis, and

shingles, is the virus of cold sores. (A close relative, herpes

simplex type II, causes genital herpes.) It has a way of passing from

person to person that most other viruses don't have. Its size enables

it to encode some special mechanisms, one of which is the ability to

sneak into nerve cells to hide and emerge later. The herpes virus

hides in the nerve cells in the brain and comes back out later to

cause cold sores on our lips, which can then pass the virus on to a

new host. Other kinds of herpes viruses hide in other parts of the

nervous system, emerging occasionally to cause problems such as

shingles.

The computer model of the inner core of the herpes virus on the next

page illustrates the answer to a very important question, raised

years ago by and Crick in another, not-so-famous, paper: Where

does all the information come from to make the viral protein that

coats the DNA or RNA with a complex protein shell? The answer lies in

the virus's symmetry, which allows one protein to be used over and

over again. This is the nature of viruses: they encode one or a small

number of coat proteins that know how to aggregate themselves into

beautiful shapes that enclose space—and the DNA or RNA is in that

space.

The nature of this symmetry is quite interesting. Most of the

proteins in the model are surrounded by six other proteins (top

arrow). But you can see some (bottom arrow) that have five neighbors.

So this is a funny kind of symmetry; it's not exactly the same over

the whole surface. Actually called quasi symmetry, it's made of fives

and sixes.

Buckminster Fuller didn't know anything about viruses when he

developed these principles himself. He realized that he could enclose

space with an elegant structure, one that is light and simple because

it uses the same parts over and over again. It's hard to see on the

actual geodesic dome above, but it's easier on the adjacent model of

the complete Fuller sphere. The top arrow indicates six units around

a point, and the bottom arrow points to one with five. (Most of them

are sixes; other fives are hard to find.)

Fuller's design is basically that of an icosahedron. Icosahedra have

20 triangular faces, either fives or sixes at the vertices. If you

place hexagons (sixfold symmetric objects) next to one another, they

form a flat surface, like old-fashioned bathroom tiles. But if you

try to do that with pentagons, it won't work. You have to tilt the

pentagons around to make the edges meet, and when you do, you get a

classic solid, the dodecahedron. So five is something that leads to

curvature, while six is flat. That's what is going on in the Fuller

dome: the curvature of the dome, which leads ultimately to a

spherical form, comes from the fivefold axes, while the sixfold axes

just tile a flat or slightly curved surface. Another well-known

example is the buckyball (named for Fuller), a natural chemical form

of carbon.

I'm very taken with this quote from Buckminster Fuller:

When I am working on a problem,

I never think about beauty.

I think only of how to solve the problem.

But when I have finished,

If the solution is not beautiful,

I know it is wrong.

That's not exactly a scientific proof, but when and Crick

published their structure of DNA, what convinced so many people it

was right was its beauty.

Viruses enclose space with this same elegant geometric symmetry.

Poliovirus, much smaller than herpes, also encloses its space on the

principle of icosahedral symmetry, as does Norwalk agent. But I'd

like to discuss Norwalk agent from the point of view of how it's

spread. Most viruses are unstable in the environment. If you sneeze

out a stream of droplets containing virus particles, and the droplets

have a chance to dry, the forces of drying are so great that the

virus is ripped apart and is no longer infectious. But this isn't

true of Norwalk, which is quite resistant in the environment. That's

why it has become known as the cruise-ship virus. It created a number

of mysterious illness outbreaks and headlines last fall, some of them

(62 people in a Canadian mounted-police academy, 74 at a wedding) on

land, but it's the cruise ships that give us the really impressive

statistics, where hundreds can be infected on a single cruise.

Norwalk infections are estimated at 23 million cases per year in the

United States, and most of these are actually on land. Most of them

are probably mistaken for something else, because the illness looks

very much like food poisoning. I'm not a physician or an

epidemiologist, but I think that a large fraction of people who get

what they think is food poisoning have actually come in contact with

Norwalk agent. Food poisoning comes from a bacterium, which causes a

fever along with the other disagreeable symptoms. Norwalk doesn't

cause a fever, and you get over it quickly. So, most of the cases of

overnight distress that you blame on the restaurant you just visited

may have had nothing to do with food but rather came from some other

infected individual you interacted with over the previous few days.

Plants also have a lot of different viruses, as many as animals do,

some icosahedrally symmetric, some helically. There are, for example,

more than 30 viruses of beets alone. Beet growers know all about

these viruses, but the rest of us fortunately are spared having to

acquire this knowledge. I don't know of any case of a plant virus

infecting a human, but they have been known to infect insects. Plant

viruses are, actually, responsible for one of the few good things

viruses do; they can cause beautiful streaking in flowers. In the

17th century, this led to the first widely known financial bubble,

when the Dutch became obsessed with ornamental tulips and were

willing to pay enormous sums of money for them. The most expensive

tulip bulbs were the virus-infected ones with streaked petals. So the

tulipmania bubble, which had many of the same properties and

craziness as the recent Internet bubble, was caused by a virus.

Influenza virus, which kills more people annually than any virus

besides HIV, has a very particular property. Rather than having one

long piece of genetic material, as most viruses do, it has eight

separate pieces. This gives it the ability to recombine itself with

other influenza viruses. So, human and bird influenza viruses can

infect the same animal, say a pig, and reassort their RNAs in that

animal. This reassortment is one of the reasons we get so many new

flu viruses. Since flu varies all the time, it never really reaches a

nice equilibrium, so we can't make a general vaccine that will

protect us against it once and for all. But we can make a vaccine

that varies from year to year by modifying just one piece of RNA. We

can also take advantage of the viruses' reassortment strategy to make

a vaccine by inserting a new RNA molecule that will interfere with

its multiplication.

The trick to making a flu vaccine for a particular winter flu season

is to be able to guess more than six months in advance the strains

that will circulate. In the winter of 2002–03 the Fujian strain that

circulated was a surprise, and the vaccine lacked representation of

that precise strain. The best guessers in the world simply guessed

wrong. The vaccine gave at best partial protection. The flu epidemic

started early and promised to be quite severe, but then it suddenly

diminished quite dramatically in early winter.

West Nile virus is interesting because, while it naturally infects

birds, it's carried by mosquitoes. Mosquitoes, in turn, can infect

humans (and horses). More than 99 percent of infected people are

asymptomatic and never know they had it, but there's no danger of

them passing it on to others, because it's a nonequilibrium virus.

Some fraction of people (and we don't know what's different about

them) develop a fever, and some cases even progress to infections of

the brain, which can be fatal. West Nile does cause a significant

number of deaths, and we don't yet know how to vaccinate against it.

The only way we know how to protect ourselves is to avoid mosquito

bites.

West Nile virus was discovered in 1937 in Uganda and spread widely in

Africa and the Middle East over subsequent decades. It's amazing that

it didn't reach the United States until 1999, when a few cases were

discovered around New York. Then it began to spread. In 2003 there

were 9,136 cases and 228 deaths. The year 2002 saw 284 deaths. But

the frightening thing about it is that it's now permanently

established here. No one believes that we can eradicate it with

anything we know about today, because it winters in an animal

reservoir, particularly mosquitoes. At least it's good for the

mosquito-repellent industry. And even though it has spread widely,

there are still very few cases west of the Rocky Mountains. I don't

know if that's because the virus finds it difficult to maintain

itself in the West, or if it's just a matter of time before we have

as big a problem as the East and middle of the country.

Ebola is a virus of helical symmetry, long and convoluted because

it's not rigid. It looks aggressive and is aggressive. Like other

viruses, Ebola is not one fixed virus but a complex family of

viruses. We can get the complete RNA sequence from each outbreak and

construct a tree that shows how closely related they are. For

example, the Ebola viruses isolated in Gabon in 1994 and 1996, and in

Zaire in 1995 and 1976, are very similar, indicating that there must

be an animal reservoir in that part of Africa. No one can find it,

although they've looked very hard. It's probably an equilibrium virus

in some rodent living in the forest or bat living in a cave, and it

may not much bother the animal species that maintains it in

equilibrium. It's always the same virus coming out again and again.

Other Ebola viruses, slightly different in their RNA, have broken out

farther away, in the Ivory Coast and Sudan, where they must reside in

other reservoirs—different but related. Then there's a very strange

set of Ebola viruses that appeared in Reston, Virginia, and starred

in the book and movie The Hot Zone. Interestingly, these viruses

infected monkeys, not humans, but because of its reputation in

Africa, the fear was that it would spread to humans. Still another

Ebola-like virus, Marburg agent, very different from all the rest,

erupted in Germany in 1980, killing a significant fraction of the

people it infected before it was quickly contained.

HIV, the world's most serious health challenge

HIV (human immunodeficiency virus) has a beautiful, very unusual

internal structure. For unknown reasons, it's asymmetric. HIV is not

known for its beauty, however, but for its relentless and lethal

effects. The horrifying statistics from the end of 2003 show 40

million people infected with HIV/AIDS worldwide. This past year

brought 5 million new cases and 3 million deaths, more deaths than

tuberculosis and malaria, which were the two greatest infectious

killers in the world until HIV came along. In some African countries,

life expectancy has been reduced by more than 20 years. This is an

epidemic on a scale that we have not seen in modern times, and we

should be doing a lot more about it than we are.

What kind of response can we make? We have been very good at making

drugs to combat it. The pharmaceutical industry rose to the occasion

and makes a lot of money selling drugs that slow down the infection's

development enormously, even if they don't cure it. Many people are

living today who would have been dead 10 years ago without these

drugs. It's a great success story, but not a perfect one; these drugs

are very expensive, and they require a lot of attention from the

patient. So they have not been transferred into the developing world

with any efficiency. This may be changing now with the money coming

from the Gates Foundation, the U.S. government, and elsewhere to make

these drugs more available.

Education has also worked. Educating people about a sexually

transmitted disease is a very difficult job, but the programs in

Uganda and Thailand have been very effective, reducing transmission

by 60 to 80 percent. But education, also employed in the United

States, requires constant vigilance. For instance, new cohorts of

young men entering a gay lifestyle must continuously be taught to

protect themselves.

But the right answer for protection against a virus is a vaccine. A

vaccine preprograms your immune system so that the memory protects

you forever, without your having to be exposed to the virus. The

scientific community has been trying to make a vaccine against HIV

since the day the discovery of the virus was announced. Margaret

Heckler, then secretary of the Department of Health and Human

Services, got up in front of the press in 1984 and said, " We've

discovered the virus; we know what it is; we'll have a vaccine in a

year or two. " She could not have been more wrong, but I can

understand why she said it. We had been so successful making vaccines

against smallpox, polio, measles, mumps, and lots of other viral

diseases. But, while the immune system controls all the other viruses

pretty well, it can't control HIV, for a set of complex reasons. That

makes a vaccine very difficult. The truth of the matter is that we're

not even sure we can make a vaccine. We can vaccinate monkeys against

a related virus, and we can show that in certain cases people can be

protected by their immune system, but there has been no successful

efficacy trial of any vaccine against HIV.

HIV, oddly enough, may give us a way of doing the only other good

thing viruses can do (besides striped flowers). Viruses, as we've

seen, are able to bring genes into cells. And if we can splice good

genes into a virus, we can get those genes into cells in place of the

damaged ones (gene therapy). In my lab and in laboratories around the

world, we are trying to use genes to turn the HIV viruses on

themselves and actually make them valuable. The idea is to use a

stripped-down version of the virus to carry into cells genetic

components that can interfere with the growth of the real virus. It

works in the lab, but it will be a while before we can know if it

works in people.

Last but not least of our headline-making viruses is SARS, a

coronavirus, so called because the proteins, strung on a long stalk

surrounding the virus, resemble a halo. Thanks to modern molecular

biology, the SARS genome was sequenced within weeks after the virus

was discovered. Comparison to other known coronaviruses showed that

it was on its own branch of the genetic tree, which told us instantly

that this was a virus we had never seen before. It was something

brand new. The sequence also told us about all the proteins the virus

makes. Many of them turn out to be quite unusual, and it will take

years to figure out what they all do.

SARS (severe acute respiratory syndrome) started in China in November

2002. The last case was found in June 2003 (with the exception of two

separate cases in laboratory workers who were infected from lab

samples). The number of cases topped out at 8,098, with 774 deaths,

none in the United States. There is no evidence that there was a

large number who were infected but not symptomatic (as, for instance,

with West Nile virus). This is fortunate, because it means that the

8,000 is not really 800,000. Some experts claim there's a reservoir

somewhere, probably in humans, and predicted that it would come back

again in the fall of 2003. This is the standard thing viruses do—come

in November and leave by June, like flu or the common cold. In

October my forecast was that SARS would not reappear, that it's gone,

and that the only place it exists now is in some unknown animal

reservoir in China. Could it come out again? Yes, it could, but the

Chinese should be ready for it next time, and it should be quickly

contained. So far my prediction has held up.

The bottom line is that it's these non-equilibrium viruses that we

need to be concerned about. They emerge from a huge pool in nature to

cause havoc among us. Although I don't see SARS in our future, we

have to expect that more viruses will emerge. This huge reservoir is

not going to just sit there and stay in its species; some of the

viruses are going to jump over to our species. We should consider

this at least as much of a challenge as bioterrorism. In fact, it's

sort of nature's own bioterrorism and, fortunately, similar. We can

employ the same public health skills that have been put on alert to

deal with bioterrorism to watch out for viruses coming out of nature.

SARS was a good rehearsal.

Baltimore, Caltech's president since 1997, has good reason to

appreciate viruses; he's been studying them for a long time. He won

the Nobel Prize in 1975 for his discovery of reverse transcriptase,

an enzyme that allows a strand of RNA to copy itself back into DNA—

work published in 1970 that came out of his research on how cancer-

causing RNA viruses manage to infect a healthy cell. The discovery

added significantly to scientists' understanding of retroviruses such

as HIV. Baltimore earned his BA in chemistry from Swarthmore College

in 1960 and his PhD in biology from Rockefeller University in 1964.

He was founding director of MIT's Whitehead Institute and spent most

of his professional career at MIT (except for a few years at

Rockefeller University, as a professor and president) before coming

to Caltech. From 1996 to 2002, he has chaired the National Institutes

of Health AIDS Vaccine Research Committee. This article was adapted

from Baltimore's Lecture last fall.

http://pr.caltech.edu/periodicals/EandS/articles/LXVII1/viruses.html