Give Me Immunity or Give Me Death
By Jason Socrates
Bardi
Having
been among the early converts, in this part of the globe,
to [smallpox vaccine's] efficiency, I took an early part
in recommending it to my countrymen. I avail myself of this
occasion of rendering you a portion of the tribute of gratitude
due to you from the whole human family. Medicine has never
before produced any single improvement of such utility.
———Thomas
Jefferson, from a letter to Edward Jenner, 1806
When Meriwether Lewis and William Clark began planning their
mission of exploring the American West, they received a special
package from President Thomas Jefferson, who had commissioned
Lewis to lead the expedition.
Jefferson instructed Lewis to carry with him Jenner's smallpox
vaccine and distribute it to the Indian tribes throughout
the West, many of which had already sustained outbreaks of
smallpox. Variola, the virus that causes smallpox, had continued
its expansion into the new world.
"Inform those of them with whom you may be, of it's efficacy
as a preservative from the smallpox & instruct & encourage
them in the use of it," said Jefferson.
Jefferson was hoping that the vaccine—which contained
live cowpox virus—could possibly stave off smallpox epidemics
among the immunologically naïve western tribes, whose
landmass isolation had allowed them to escape the devastating
disease.
Sadly, though, the vaccine did not survive the journey west.
And within a few decades, smallpox outbreaks with mortality
rates as high as 90 percent would devastate many of the western
tribes.
"The history of these things is quite interesting," says
Michael B. A. Oldstone, a professor in the Department of The
Scripps Research Institute(TSRI), who is equally interested
in viruses themselves.
Small, Significant
The smallpox virus belongs to a family of nature's most
ruthless killers—the RNA viruses, which are among the
oldest and most notorious adversaries the human species has
ever had, and which Oldstone has spent a career studying.
They range from measles, mumps, and rubella virus to the
viruses that cause foot and mouth disease, polio, hepatitis
A and C, yellow fever, human immunodeficiency virus, and the
"Spanish Flu" influenza virus, which killed more Americans
in World War I than died in combat.
In this day and age of solving genomes and mapping the expression
of thousands of genes to particular tissues, RNA viruses are
somewhat of a paradox. On the one hand, they can bring societies
to their knees. Smallpox killed more people in the 20th century
than died in all the century's wars combined.
On the other hand, RNA viruses are rather unassuming. They
are like the old VW bugs of the pathogen world—small,
simple, and seemingly able to run forever. An RNA virus can
have as few as four genes. Nearly all of them have under 10
genes. The largest RNA virus has only 12 genes.
Yet, RNA viruses are able to alter cell function and profoundly
affect the complex, eukaryotic life forms that they infect.
An RNA virus with only four genes can cripple or kill a mammal
with 40,000 genes.
Take the choriomeningitis virus, for instance, one of the
viruses that Oldstone has studied for several years. Its genome
is segmented into two separate pieces of RNA that are packaged
together. They are packaged inside a compact virion, an infectious
virus particle. And together, the entire genome is only a
few thousand bases—six orders of magnitude smaller than
the cells it infects—and has only four genes. Yet it
can easily persist for the lifetime of that organism.
"Everything the virus needs is in these four genes—it's
amazing," says Oldstone, adding that, by comparison, herpes
virus has 250 genes.
This leads one to ponder—as it led Oldstone to puzzle
over years ago—how, with so few genes, these RNA viruses
are able to do what they do. At the outset of his career,
Oldstone decided to ask, specifically, what are the host factors
that are involved in the infection? What proteins and other
molecules in the infected organism are the viruses interacting
with? And how can we use the tens of thousands of genes in
our brains to stop those handful of viral genes? His work
in this area since he began his career at TSRI has led to
recognition and many awards, including the J. Allyn Taylor
International Prize in Medicine for the study of host–virus
interactions.
The Most Contagious of Them All
One of the viruses that Oldstone has studied for a number
of years, measles, is the most contagious infectious agent
known to humankind.
With an infection rate of 98 to 99 percent, measles is a
highly infectious virus that causes a maculopapular rash,
fevers, diarrhea, and, one to two times out of a thousand,
death. Measles is also highly contagious, and until the advent
of mandatory vaccination programs in the United States, there
were an estimated three to four million cases annually. Some
90 percent of the U.S. population had had measles by the age
of 15.
There has been a commercially available vaccine for measles
in use since 1963, and, though effective, this vaccine must
be kept refrigerated for the duration of its one-year shelf
life. This is problematic in tropical climates like southern
Asia and sub-Saharan Africa, which continue to support endemic
measles infection. The World Health Organization (WHO) estimates
that in 2001 there were 30 million cases of measles worldwide
and over one million deaths.
The measles virus has eight genes and gets a lot of use
out of them, infecting lymphocytes, dendritic cells, and cells
of the nervous system. The viral receptors that facilitate
the entry of measles into cells are known, and one of these
receptors, called CD46, is of particular interest to Oldstone.
The measles virus has a hemagglutinin glycoprotein that binds
to a single, broad surface on one side of CD46, which is expressed
on virtually all cells in the body, and as a result, measles
virus can infect multiple organs, including the brain.
Cases of measles can be severe when the virus infects the
brain, because the body's immune response can cause massive
damage to the central nervous system, and about one out of
every million cases results in a chronic, progressive, fatal
neurological disease.
However, mortality from measles is usually much higher than
this because the disease is immunosuppressive—it infects
cells of the immune system—and if "opportunistic" infectious
agents like Mycobacterium tuberculosis or Staphylococcus
are present, the immunosuppression can lead to a secondary
infection, which is often fatal. Measles mortality can be
is as high as 33 percent.
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Michael Oldstone, professor at TSRI, is also the author of
a historical narrative, Viruses, Plagues, & History.
Measles, the most contagious infectious
agent known to humankind, has afflicted many societies, as
this drawing by a sixteenth-century Aztec shows. Drawing
from the C—due Florentino.
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