Regenerative Medicine: Where the Genetic and Info Revolutions Converge
William Haseltine, one of Americas leading
molecular biologists, is chairman and chief executive officer of Human
Genome Sciences, the firm that is developing a variety of gene-based pharmaceutical
products. He is also editor in chief of E-BIOMED: The Journal of Regenerative
Rockville, MD The completed mapping of the human genome is an historic
feat comparable to sending men to the moon. But the actual feat will have
little practical impact on our lives unless we can characterize and isolate
the useful genetic information in the genome. After all, there was little
utility in the moonlanding itself; so far that has come from the associated
advances which enabled todays satellite communications.
Genes are stored in fragmentary form in the human genome. Three percent
of the genome is genetic information; 97 percent is packaging. The cell
is smart enough to assemble that three percent for you to build and maintain
When we know, in effect, what our cells know, health care will be revolutionized,
giving birth to "regenerative" medicineultimately including
the prolongation of life by regenerating our aging bodies with younger
Thanks to the convergence of the information and genome sciences revolution,
we are already on the threshold of isolating and characterizing virtually
all useful genes. The enormous advances during the last decade of the
20th century in molecular biology, laboratory instrumentation and computational
capacity have made this possible.
In molecular biology we have learned how to utilize genes by moving them
from one organism to another, by altering them and changing the effect
of their protein products. Instrumentation advances have allowed us to
manipulate genes in parallel and then to create assembly lines, speeding
up the rate of biological discovery 10,000 times. Finally, the advances
in both computer software and hardware have enabled the storage, retrieval
and quick interface of very large amounts of data essentially what
the Internet does for information at large.
Already under way for about four years, is the development of new and
more efficient drugs to treat disease based on genetic knowledge. Up to
this point, pharmaceutical treatment had been a little like Wild Cat oil
prospectingdigging hopefully for knowledge about migraine headaches
or cholesterol based on the extant medical literature. Finding a starting
point for drug development was always a hit and miss proposition.
Now, by isolating and characterizing human genes and the way they are
actually used in different states of cancer or heart disease or schizophrenia,
a systematic means to identify where and when to intervene with drug treatment
has been opened up.
This does not mean curative drugs will be available over the counter tomorrow.
The process is long and difficult. First, the gene and what it does has
to be identified. Then, it has to be shown that, when you perturb that
gene, you get the desired effect and only the desired effect. The drug
has to be compatible with your body, it has to get in, get around and
get out of your body and only stay for the right amount of time. We have
to cope with the complication that the body metabolizes the drug you take
in, like a rocket that bursts into fireworks, and spreads it all around.
All this has to be taken into account and tested through trials that prove
the drug safe and effective. But the experience so far is positive. Within
six to seven years, we will see a whole range of new drugs for diseases
that have no other treatment today.
Our company, to take one exciting example, has discovered a "receptor"
on a protein on the surface of cells that is important for the functioning
of the immune system. If you dont have this receptor, it appears
you are less susceptible to inflammation and viral infections. Based on
our discovery, a study by the National Institutes of Health has shown
that people who are defectivethat is, who lack this receptornot
only dont seem to have any adverse health consequence but, indeed,
are not infectible by HIV. A further study in 1999 showed that an unusual
form of the Herpes virus, like AIDS and probably other viruses, uses this
handle to infect a cell.
With this new information in hand, drugs can be developed to inhibit inflammation
for viral infectionpossibly even to stop AIDS.
It is the action of genes on a single cell and within that cell that leads
to the fertilized eggs production of every organ and tissue in our
whole body. We are formed by the action of our genes and, as a mature
organism, we maintain ourselves for a long time. Under ideal circumstances,
that would be 120 years or more.
And we dont do this statically, but by replacing our parts. Everyone
knows that the skin we have today is different than our skin tomorrow.
And that is true for almost all parts of our bodies, including, we now
realize, the brain as well.
Though there are defects, such as among those who cant clot their
blood, our bodies are reasonably effective at repairing themselves.
This understanding is key to the regenerative medicine of the future.
Once we have full knowledge of the signals that make this process work,
we can create a new medicine.
I see four phases of the development of regenerative medicine:
1. Gene Drugs. The use of our genes, proteins and antibodieshuman
components themselvesas the new pharmaceuticals. In this way we
will be able to use our bodys own substances to rebuild, repair
and permanently restore ourselves rather than rely on some chemical crutch.
If you now take a pill every day to lower your cholesterol, wouldnt
it be much better to have a treatment of your own proteins that permanently
lowers the cholesterol level?
As a result of the first revolution in bioengineering we already have
medicinessuch as insulin, which is a tiny human part made from the
gene of a person and used as a drugthat are essentially body parts.
The remarkable fact about insulinone persons can be used by
everyoneis that it shows how humans are essentially interchangeable
at the gene and protein level.
Knowing this, the first phase of regenerative science will be to use our
own genes, proteins and antibodies as medicines to rebuild our bodies
from the inside out. All we are doing, really, is stimulating the bodys
inherent regenerative capacity.
An example: We are testing methods of using a natural protein to enhance
the healing of skin for patients with large open wounds or for chemotherapy
patients with ulcers in their mouths. This treatment is based upon the
cell signal to repair damaged skin (when cells know they don t have
a neighbor, they turn on a receptor that grows new cells). A normal, healthy
body doesnt have these receptors; they only appear when there is
We will see the first set of these new drugs emerging in two to three
years. By 10 years, it may be 15 percent of our medicine. In 20 years,
it will be at least half of all our medicines.
DRUG DELIVERY | A parallel revolution is taking place in delivering
such drugs to our bodies. The full power of modern materials science.
Already underway are technologies enabling drug inhalation for large molecules
that look like miniscule whiffle balls, enabling the prescribed drugs
to reach into the deep recesses of the lungs. And there are microchips
implanted in your body that will release the right dose of a given drug
2. Organ Replacement. The next phase of regenerative medicine, already
with us in early form, involves engineering organs outside the body so
they can be implanted. This has already been done for bladders.
If a person has bladder cancer, the bladder can be removed. A matrix made
of material similar to cat-gut is used as a kind of scaffolding to which
snippets of the cancer patients own cells are attached. These cells
grow into a thin sheet of muscle and lining cells that are stretched over
the scaffolding, where they take hold and grow as the cat-gut like material
disintegrates. That new bladder can then be implanted in the patient with
out any danger of rejection because it is an "auto-transplantation."
In this way arteries, ligaments, new pieces of bone and tracheas are being
Within 5 to 10 years replacement kidneys will be possible; within 10 to
15 years liver replacement will be a reality. Eventually, entire hearts
can be made for reimplantation. In 20 to 30 years, organ replacement will
be a major part of medicine.
3. Resetting the Genetic Clock. The ultimate transgenic medical treatment,
only now a gleam in the eyes of scientists made possible by the cloning
technology begun by Ian Wilmut and Dolly the sheep, is resetting the genetic
This involves supplanting aging adult cells with younger cells grown from
"stem cells"the originating cells for all body functions.
There is one stem cell, for example, for blood. Another for the skin,
the brain and so on.
It will be possible in the future to take a cell from a person, reset
its genetic clock and then move it to stem cell status for brains or musclesin
effect enabling our bodies to rebuild themselves in a younger form. The
fundamental process that drives aging is the aging of stem cells that
replace tissues worn down by livingreactive oxygen interacting with
DNA changing its chemical nature.
The average life of an essential gene in an essential stem cell is about
50 years. But there is nothing intrinsic in that age; it is a result of
our bodys evolutionary response to its environment. If we can regenerate
stem cellsand get rid of the old cells that turn into cancerthen
we can prolong life.
The current medical practice of bone marrow transplants shows that this
idea is not at all far fetched. In that process, an older person with
cancer whose ability to form new blood cells has been damaged by chemotherapy
often receives marrow donated from someone younger. In effect that person
is an age-hybrid, with 50 to 60-year-old bodies, but with blood-derived
tissues that are only 20 or 25 years old.
In short, rather than continually regenerate our body with aging stem
cells, in the future we can regenerate them with our own younger cells.
I expect this third wave of regenerative medicine to come into being no
sooner than the year 2050.
4. Integrate Non-Biological Substances with Our Bodies. Already, an older
person is a bit of metal with a joint in his leg, a bit of plastic with
a valve in his heart, a bit of nylon with a new blood vessel, a bit of
an electronic device with a pacemaker or hearing aid.
Miniaturization and nano-technology (molecular-sized machines) will further
enable the creation of prosthetic devices fully compatible with our bodies.
One exciting field in rapid development today is neuro-prosthesis where
brain implants pick up mental intent and can translate that signal into
the movement of muscles independent of the spinal chord.
Already, implants in the brains of monkeys enable them to move robots
in the next roomor it could be the next continent. This will make
it possible for people to move through bypassing the spinal chordwhich
may have been ruptured or otherwise injuredaltogether.
Though less than a decade in the works, it is already clear that the combination
of the genetic and information revolution will change medicine within
the next 50 years more than in the past several centuries.
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