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LE Magazine July 2002
William
Haseltine, Founder, Chairman of the Board and CEO, Human
Genome Sciences
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| Dr. William Haseltine on
Regenerative Medicine, Aging and Human Immortality |
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What would it take to be able to
engineer an unlimited human life span? Although nobody knows
for sure, being able to manipulate the complete "parts list"
of all the molecular building blocks of the human body would
be a nice resource to draw on. Human Genome Sciences claims to
have something very close to that-a copy of almost every human
gene in test tubes, and the ability to use them as drugs. Dr.
William A. Haseltine is the Founder, Chairman of the Board and
Chief Executive Officer (CEO) of Human Genome Sciences, a
powerhouse biotechnology company that claims to have
discovered over 90,000 human genes and to have filed patent
applications on many of the most useful ones. Human Genome
Sciences (ticker symbol, HGSI) aims to create a new era in
medicine, in which its gene-based products are used as
specific, non-toxic, non-allergenic medicines that replace
many drugs. Along these lines, Dr. Haseltine coined the term
"regenerative medicine," and then a newer term, "rejuvenative
medicine," to describe the expected medical revolution that,
in his view, could lead to human immortality. Dr. Haseltine
talked to us in an exclusive interview conducted by Gregory M.
Fahy, Ph.D. on Sept. 10, 2001.
Life Extension Foundation
(LEF): Can you tell us how big Human Genome Sciences
is?
William Haseltine (WH): We
have about 1,000 employees. We have about 450,000 square feet,
including about 350,000 square feet of manufacturing space. We
have six products in clinical trials. Our income is about 25
million dollars a year from transactions. We have income from
interest of about 100 million dollars per year. We have about
1.7 billion dollars in cash assets. We are very well
capitalized.
LEF: How did you happen to
become the founder of Human Genome Sciences?
WH: I was a professor at
Harvard Medical School from 1975 until 1993. During that time
I was, essentially, Chairman of two departments, both of which
I founded: the Laboratory of Biochemical Pharmacology, which
worked on cancer treatments; and the Division of Human
Retrovirology, which conducted AIDS Research. From about 1980
on, I started creating biotechnology companies. The first was
Cambridge Bioscience. I have now founded seven biotechnology
companies, the most recent one being Human Genome Sciences. In
addition, giving advice to HealthCare Ventures was
instrumental in helping me create another 20 companies.
In 1992, I realized that the time was right to bring together
technologies developed for the Human Genome Project that could
generate a revolution in medical science. I realized that
rather than completing the sequencing of the human genome in
10 to 15 years, one could obtain working copies of most human
genes in useful form in two to three years. This could be done
by focusing on messenger RNAs (mRNAs), the active products of
genes, rather than on the genes themselves. Information about
human mRNAs could be used to start a new pharmaceutical
company based upon the use of human genes, proteins and
antibodies as drugs. That is what we did with Human Genome
Sciences.
LEF: So the method involves
extracting mRNAs from human cells and then translating them
into proteins in the laboratory. Is that the basic idea?
WH: Yes. This approach offers
a number of advantages. First, it is a way of reducing the
complexity of finding genes by more than a hundred-fold. Only
one one-hundredth of the genome gives rise to messenger
RNAs.
Second, if a messenger RNA exists, it means the cell has
transcribed the corresponding part of the genome [actually
used a gene to make an active mRNA; see sidebar-Ed.] and is
ready to use it to make a protein. In other words, there is no
doubt that the information in the messenger RNA is relevant to
the cell.
Third, because we can isolate messenger RNAs from specific
tissues, we can gain some idea of where in the body and under
what conditions those messenger RNAs are being used. That
gives us a clue about the roles they may play in the body.
Fourth, we can copy a specific messenger RNA into DNA
[thereby making "complementary DNA," or cDNA, which has the
same information content as the mRNA being copied-Ed.], and
then we can use that DNA to program a cell to make more copies
of the original mRNA and therefore, more copies of the protein
it normally produces.
One cannot do that from genomic information alone. We knew
in 1992 that genomic information would not easily lead to
whole genes, because the genes cannot be read from the genome
in a direct way.
Between 1993 and 1995 we isolated at least one copy of what
we believe to be more than 95% of all human genes. There is
still a dispute over how many genes humans have. We think
there are close to 100,000, and we have actually isolated
90,000 unique genes. About 60,000 genes remain to be found by
others analyzing the human genome.
LEF: Have you isolated all
those genes from adult tissues?
WH: We have also looked at
fetal tissues, embryonic tissues, tumor tissues and other
diseased tissues. We have looked at more than 1000 primary
human tissues.
LEF: How sure can you be that
the RNAs you've isolated are full-fledged RNAs and not just
fragments or pieces of bigger mRNAs that are being recycled?
You might translate meaningless fragments into proteins, but
they might not be proteins that are actually made in
cells.
WH: We have tested that
possibility thousands of times. Typically, we look at the
longest messenger RNA in our collection, then analyze it. In
most of the cases we were able to make fully functional
proteins, the same as those found in cells and tissues.
LEF: What about different
alleles [variations of given genes, like brown and blue as
variants of the eye color gene]? Is that a problem? Do you get
all of these?
WH: For the most part, we
ignore allelic variation. Alleles usually represent minor
variations in function. We often have a choice of which
alleles to take. We usually make proteins from the predominant
allelic type.
LEF: If you were to give that
dominant version of the protein as a therapeutic agent to a
patient who did not make that version of the protein, is there
a chance of an allergic response or an attack on the foreign
protein?
WH: Generally, no. That is
why insulin works for most people. That is why human growth
hormone, g-CSF, gm-CSF [bone marrow related proteins] and many
other proteins, work for most people. Humans tolerate proteins
with non-self allelic variants. The moment we stop tolerating
the alleles of others, we will no longer be members of the
same species.
Even human antibodies can be used as drugs. Antibodies are
created by individuals in response to a particular set of
circumstances. Today those antibodies can be created in the
test tube. They are extremely well tolerated when injected
into the body. One might expect the body to make antibodies
against the injected antibodies, but this does not appear to
happen.
LEF: As you know, what we
generally hear these days is that there are only 30,000 to
40,000 human genes, not 90,000 to 100,000.
WH: One of the first human
genome publications said there were 26,000 genes. And another
publication said there might be 30,000 genes. Then a paper
(Genome Biology 2001 2(7):
research 0025.1-0025.18) reported that most of the genes
referred to in those publications were not the same. The new
paper estimated that there are 65,000 to 75,000 human genes.
So are we to believe there are 26,000 genes? Or 70,000 genes?
The detection of different numbers of genes by different
groups shows just how poor the methods of identifying genes
from chromosomal DNA really are.
LEF: I've heard it said that
there may be an average of three different splice variants of
[different ways of using] each gene, and that might amplify
the total effective number of genes.
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We are focusing on genes that
control external signaling pathways. Those pathways
instruct our cells, from the outside, to perform one or
more
of several simple actions. |
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WH: Such analyses fail to
consider that almost all splice variants have the same
function. That means it is still usually true that one gene
corresponds to one function. Most of the time, for drugs based
on human genes, the rule to remember is still one gene, one
protein, one drug.
LEF: Are you personally
responsible for the mission of Human Genome Sciences? Is the
company fulfilling your dream?
WH: I am the one who shaped
its formation and direction.
Our original mission was (and still is) to improve human
health by bringing a wide variety of new products to patients
and to treat diseases that could not previously be treated.
Specifically, we seek to bring new protein and antibody drugs
to market. Our goal is to become an independent global
biopharmaceutical company. From the outset, we established
four specific objectives.
First, to be the first in finding most human genes in
useful (that is, in cDNA) form. We accomplished that objective
in mid-1995.
Second, to create systematic means to turn knowledge of new
genes into medical uses. We wish to do that both for
ourselves, so we can create new human protein and antibody
drugs, and for our partners, so we can enable them to create
new small-molecule drugs.
Third, to share our newfound knowledge with large
pharmaceutical partners, which we have done.
We had a seven-year relationship with a group of
pharmaceutical companies led by Glaxo-SmithKline. During that
period, our partners used our technology to initiate about 460
different drug discovery programs. The most advanced of these
is the first small-molecule drug developed through genomics to
enter human trials, a drug that Glaxo-SmithKline is using to
attempt to treat heart disease. The drug inhibits an enzyme
called PLA2 that creates inflammatory reactions in blood
vessels.
Part of the third objective was to obtain substantial
payments from pharmaceutical companies to support our own
research, as well as to participate in the sale of products
after they are developed. Human Genome Sciences is entitled to
a substantial portion of the sales of drugs developed by our
partners.
The final objective was to build the infrastructure
necessary to discover and bring to market our own human
therapeutic protein and antibody drugs. We are well along on
that path. So we have executed plans to accomplish all our
original objectives.
LEF: I understand that you
have singled out a subset of genes that you consider to be
particularly interesting for patenting.
WH: We are focusing on genes
that control external signaling pathways. Those pathways
instruct our cells, from the outside, to perform one or more
of several simple actions.
The signaling proteins can be on the surface of cells or
can leave the cell surface and circulate. Such proteins
generally are exported from cells by a common pathway, which
involves the use of "signal sequences." We have used that
common pathway to isolate (in cDNA form) about 10,000 human
messenger RNAs that have the ability to make proteins with a
signal sequence. We believe that these 10,000 human proteins
comprise most of the proteins that will be useful as
drugs.
These proteins signal the cell to grow or to remain static,
to differentiate or to remain unspecialized, to live or to
die, to stay stationary or to move. Those are the basic
functions that cells perform.
This set of proteins also includes the targets of most
antibody drugs. Antibodies work on the outside of cells, not
on the inside, and therefore must recognize structures that
are either in the blood or other body fluids, or on the
surface of cells. Proteins that can be targets of antibodies
almost all have signal sequences.
That's why we have focused on this subset of about 10,000
genes. In their cDNA form they are stable, and we can use them
to make proteins. We are systematically analyzing their
functions through biological experimentation.
LEF: One of the things I
understand you've done is to use a sort of robotic system to
proceed from simply finding the original proteins to getting
information about what their functions are. How can you do
this when there are so many possible functions?
WH: We do analyses for one
disease at a time. In one case, we were interested in diseases
that could be treated by stimulating the immune system-either
cell-mediated or antibody immune responses. We examined the
ability of our set of 10,000 proteins to influence those
processes. We have found several proteins that influence
immune system function, which then became candidate drugs. One
example is a drug we call B-Lymphocyte Stimulator, which
stimulates cells that make antibodies. We have initiated two
safety trials in patients with serious immunological disorders
that leave them susceptible to a variety of infections. One
group suffers from Severe Combined Immunodeficiency Disease;
another group has Immunoglobulin A deficiency. B-Lymphocyte
Stimulator might boost the immune system in ways that are
beneficial in patients with AIDS. We believe that this protein
has the ability both to boost the immune system's ability to
fight ongoing infections and to potentiate vaccine activity.
It seems to be the most potent stimulator of antibody
production the body has.
LEF: So you simply search
through the proteins until you find the best ones for
accomplishing various predetermined tasks?
WH: Yes. We concentrate on
substances with activities that fit a medical need.
LEF: In the past you've also
talked about using genes as drugs. How do you make a gene into
a therapeutic product?
WH: We view genes as
specialized delivery vehicles for proteins. Genes, when
injected into cells, can induce those cells to produce
proteins. If one wishes a protein to persist for a longer
period, one might inject a gene for that protein into a
tissue. To date, the only tissue that works is muscle.
Typically, a muscle cell will produce the protein for several
weeks. Eventually, the injected gene will be degraded or
otherwise inactivated, and production of the protein will
stop.
We licensed one such gene to a company called Vascular
Genetics, Inc. The company has attempted to create
micro-vasculature in heart muscle by direct injection of DNA
into that muscle. In preliminary experiments, the gene seems
to have had some beneficial effect on cardiovascular disease
in about 100 patients. There do not seem to be serious side
effects associated with the use of this drug.
LEF: Are you using temporary
rather than permanent gene transfer just in case something
goes wrong?
WH: No. One does not
necessarily need a protein to persist for a long
time. Once new microvasculature has formed, the purpose of
having the protein there disappears. Our blood vessels seem to
maintain themselves for as long as they are needed.
LEF: Are you also working on
permanent insertion of genes?
WH: We are not pursuing that
strategy. We think that for a variety of reasons, our purposes
are best served by focusing on proteins and antibodies as
drugs. The technologies and methodologies for gene therapy
have not yet been adequately developed, in my opinion.
LEF: Even limiting yourself
to therapeutic proteins, can 10,000 proteins really be
exploited within the 20-year life of a patent?
WH: That number is not
achievable even by the entire pharmaceutical and biotechnology
industry working in concert. But we already have partners who
are developing 460 drugs based on genes, and typical drug
sales today for large pharmaceutical companies are $500 to
$700 million per year.
Continued on Page
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