A Vaccine Factory Inside Each Cell
By Jason Socrates Bardi
When Edward Jenner fired his magic bullet into the arm of
eight year-old James Phipps, it kept traveling. Inoculation,
a new paradigm for controlling diseases, had arrived. He had
lifted a cowpox scab from the hand of milkmaid Sarah Nemes
to see if it would protect the Phipps boy against smallpox.
It worked. And in the 200 years since, nothing has been as
effective at combating, controlling, and in some cases eradicating
infectious diseases as vaccines.
Smallpox, tetanus, measles, polio, diphtheria, pertussis,
and several other once pandemic viral and bacterial pathogens
are now gone or all but eliminateddestroyed through
widespread application of Jenners basic technique of
stimulated immune response. Inoculations have become widespreadin
some cases universal. Its no secret that vaccines are
the best way to treat many epidemics.
And its certainly no secret for Bruce Torbett, associate
professor of molecular medicine, who says his scientific outlook
is deeply influenced by his background in public health. Trained
in epidemiology, Torbett has seen first-hand how successful
vaccines can be, and he regards vaccines as the logical approach
to controlling those epidemics that rage in our society todayAIDS
Only, the vaccines on which he is working arent
really vaccines at all.
At least, theyre not vaccines in the sense of being
shots that challenge the immune system to produce specific
antibodies against something bad or foreignsuch as an
HIV virion or a cancer celland target it for destruction.
His vaccines work by changing genotypes that make cells susceptible
in the first place.
Torbetts laboratory is developing and testing a gene
delivery technique that may someday be used to deliver genes
into cells, providing a high level of protection against HIV
or cancer. The technique involves treating hematopoietic stem
cells (HSC). These are the pluripotent granddaddy of all blood
cells, located in the bone marrow, that develop into lymphocytes,
platelets, erythrocytes, and red blood cells.
The basic idea is to give these cells genes that will allow
them to resist an HIV infection, then implant them into tissue
where they can freely grow, develop, and resist HIV infection.
The same approach may be used to inhibit cells from becoming
"I view [the therapy] as a general vaccinesomething
that provides protection for particular cells," says Torbett.
"Protection is prevention," he adds. "And prevention is
the best form of disease control."
Take Them Out, Change Them, and Put Them Back
Several years ago, researchers noticed that against the
apparent odds, some people who had had unprotected sex or
shared needles on numerous occasions with multiple HIV-positive
partners continued to test negative for the virus. Somehow,
despite repeated high-risk exposures, they had remained uninfected.
Even more stunning was the result that cells isolated from
these individuals were resistant to HIV in vitro, even though
the cells had normal expression of the CD4 surface receptor
that HIV envelope glycoproteins bind to and use to gain entry.
It turned out that HIV virions require a coreceptor for
entry into a cellthe chemokine receptors CCR5 and, to
some extent, CXCR4, present on the cell surface. Individuals
who are homozygous for a mutation that knocks out the CCR5
receptor are highly resistant to infection with HIV, and individuals
who are heterozygous for this mutation produce less CCR5 and
tend to be among the more healthy people with HIVthe
so-called "slow progressors."
Because the mutation confers some level of resistance from
initial infection, provides a better prognosis for the course
of their infection, and has no otherwise ill effect, Torbett
felt that the coreceptor would make a good candidate for a
gene therapy vaccine approach.
To do this he enlisted Carlos Barbas's support. Barbas has
experience producing specific immunoglobulins, or antibodies,
which are normally released into the bloodstream by B-cells
to target antigens during an adaptive immune response.
Barbas and his group isolated an antibody, and its gene,
that is specific for CCR5 and then designed a peptide "anchor"
on one end that keeps it retained in the endoplasmic reticulum
in the cell. These intracellular antibodies have been termed
"intrabodies." Once the intrabody gene was incorporated in
a cell, the cell would express the intrabody that would then
grab the CCR5 and keep it from getting to the surface of the
Thus, the cells would then be protected from infection.
This sort of therapy could prove useful as a way of treating
people who are already infected with HIV. Torbett and Barbas
would like to be able to deliver it into patients stem
However, the trick is to effectively "deliver" the intrabody
genes, or for that matter any therapeutic gene, into stem
or selected cells. For this approach Torbett has been working
with the very virus that causes the diseaseHIV.
Using a crippled version of HIV as a gene delivery vector/vehicle
that can no longer spread in human cells and cause disease,
Torbetts group has shown that human stem cells can be
given the gene for green fluorescent protein from jelly fish,
and all cells developed from these stem cells express this
"Our first generation gene delivery vectors were useful
for proof of concept to get a gene into stem cells and show
that it made a product, but we are now developing newer generation
gene delivery vectors," says Torbett. The newer vectors may
be useful for targeting stem and other selected cell populations.
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