|
B |
y 2020, the biomolecular revolution may also
bring another class of ancient diseases under control: hereditary diseases.
Stephen Hawking, one of the world's great cosmologists, suffers from ALS
(amyotrophic lateral sclerosis), the same hereditary disease which took lives
of
baseball player Lou Gehrig, Senator Jacob
Javits, and actor David Niven.
Although Hawking's thinking is as sharp and
penetrating as ever, he has totally lost control of his hands, arms, legs,
tongue, even his vocal cords, and communicates with the world via a voice
synthesizer while sitting completely helpless in a wheelchair. He performs all
his complex mathematical manipulations entirely in his head.
Throughout history, horrible genetic defects such as ALS have tormented
the human race. Frédéric Chopin may have suffered from cystic fibrosis, Henri
de Toulouse-Lautrec from pycnodysostosis, Vicent van Gogh and King George III
from acute intermittent porphyria (causing intermittent bouts of insanity),
songwriter Woody Guthrie from Huntington's disease, and Niccolò Paganini from
Ehlers-Danlos syndrome.
There are about 5,000 human genetic diseases, including muscular
dystrophy, hemophilia, cystic fibrosis, sickle-cell anemia, and Tay-Sachs
disease. Genetic disease take a particularly heavy toll among the young,
resulting in one-fifth of all infant mortalities, half of all miscarriages, and
80 percent of all cases of mental retardation. Genetic disease afflict perhaps
15 percent of the general population, but if one considers disease which are
polygenic or have a strong genetic component (such as cancer, Alzheimer's
disease, diabetes, and cardiovascular disease), then they account for fully 75
percent of all deaths in the United States.
Although medicine was helpless for thousands of years against these
ancient diseases, molecular medicine
promises us new therapies and strategies in the battle against them, and possibly
even cures. However, it is a battle that must be waged indefinitely, because
there is a never-ending struggle
between evolution (which gradually eliminates these harmful genes by natural selection) and mutations (which are
constantly being replenished by random errors, cosmic rays, toxins, environmental
contaminations, etc.). In each generations, a few hundred mutations occur in
the DNA of each one of us. If we assume that a small percentage of these are
harmful, then perhaps two or three harmful genes creep into our bodies by mutation.
Thus perhaps 10 billion new harmful genes enter the human gene pool every
generations. As a result, the battle against genetic disease will never end.
|
O |
nly in the last ten years or so, with the
coming of biotechnology, have these genetic diseases finally been understood at
the molecular level. But some genetic diseases have been recognized for
millennia. Hemophilia, a rare blood disease which prevents the blood from
clotting normally, was known as far back as biblical times. The Talmud excused
male babies from circumcision if the child had siblings who bled
uncontrollably; it also recognized that the disease was hereditary, passed from
the mother to the son. These diseases have even altered the destiny of nations,
often because of intense inbreeding within the ruling monarchies of Europe.
In the eighteenth century, King George III of
England suffered from periodic bouts of madness brought on by acute
intermittent porphyria. It was, apparently, during one of these episodes of
dementia that his Prime Minister, Lord North, mismanaged his American colonies,
thereby triggering the American Revolution and the birth of the United States.
In the nineteenth century, one of his successors, Queen Victoria of England,
was a carrier of hemophilia; when many of her nine children married, they
spread the hemophilia gene into the royal courts of Europe, creating havoc.
(Three of her daughters were carries, like herself, and her son Leopold was a
hemophiliac.) "Our poor family seems persecuted by this disease, the worst
I know," she lamented. In Russia, Victoria's gene was passed on to her
granddaughter Alexandra, who married Czar Nicholas II. Their son Alexis had
hemophilia, and the unscrupulous but charismatic monk Rasputin used his
hypnotic powers to control his bleeding and thereby exert enormous power over the royal family. Some historians claim
Rasputin paralyzed the Russian royal court, delayed
badly needed reforms, and helped set the stage for the Bolshevik Revolution of
1917. As geneticist Steve Jones of University College, London, writes: "
It is odd to reflect that both the Russian and the American Revolutions may
have resulted from accidents to royal DNA."
Many
of these diseases have heartbreaking symptoms which lead to a slow, painful
death. Some of them are truly bizarre, like Lesch-Nyhan syndrome, which affects
2,000 people in United States, in which young patients literally chew off their
fingers uncontrollably in fits of self-mutilation. Other genetic diseases can
be horribly disfiguring, such as neurofibromatosis, affecting one person in
4,000, in which the victim's skin is covered with scores of tiny brown
tumors. (The most famous victim of this disease
may have been John Merrick, the celebrated "elephant man" of the late
nineteenth century.)
Historically, the most feared hereditary disease is Huntington's
disease, which has long been associated with witchcraft and devil worship
(including the famous Groton witch of 1671). Families of victims were
mercilessly harassed and exiled into camps as if they were lepers. Patients
with Huntington's gradually lose control of their muscles and the mind. The
body often undergoes violent convulsions and bizarre dancing movements until it
is covered with black-and-blue spots. Many die of respiratory problems or
starvation, because their violent flailing is so fierce they cannot be
physically fed. In the United States, it affects some 30,000 people and 150,000
more at risk.
Some
genetic diseases, such as muscular dystrophy, have become well known because of
televised fund-raisers. Many genetic diseases affect specific races and ethnic
groups:
Cystic fibrosis. This is the most common genetic ailment
affecting Caucasians. CF is potentially a widespread problem, because as many
as one in every 25 Caucasians is a carrier. In the white population, it affects
one in 1,800 babies and strikes 35,000 young people in the United States and
Canada. About 1,000 new cases of this disease are recorded each year in the
United States. CF is a parent's nightmare: the disease thickens the mucus in
children's lungs, which weakens the lungs and clogs the pancreatic ducts, so
the body cannot digest nutrients well. One of the earliest records of this
disease dates from the Middle Ages, when there was a common adage among the
people of Northern Europe: " Woe to that child which when kissed on the
forehead tastes salty. He is bewitched and soon must die."
Tay-Sachs. Fortunately, screening for certain diseases
has brought some genetic defects under control, even without gene therapy.
Tay-Sachs is one example. It affects one in 3,600 Jewish children of mainly
Eastern European descent. Within this population, as many as one in 30 is a
carrier of this disease. Tay-Sachs attacks the nervous system; children appear
normal at birth, but then suffer progressive mental retardation, blindness,
loss of muscle control, and usually death before age four.
Sickle-cell anemia. This disease strikes 4,000 children per year in the United States,
mainly African-Americans. Roughly one in 500 African-Americans has this disease,
but as much as 10 percent of the entire African-Americans population are
carriers. It is a chronic disease in Africa, where 120,000 children are born
with it each year. In South Africa, as many as 40 percent of the people have
the gene.
|
B |
y 2005, when the first human DNA is completely
decoded, scientist will have a broad map on which to locate the genes of our
bodies. By 2010, we should have a genetic list of almost all 5000 genetic
diseases.
At
times, searching for these defects can be slow. As Francis Collins has said,
locating a particular gene from scratch, without any guideposts, is like
“trying to find a burned-out light bulb in a house located somewhere between
the East and West coasts without knowing the state, much less the town or
street the house is on.” Imagine, for the moment, assembling all the telephone
books listing the people in the United States. Let us say that we are looking
for just one misspelled name out of 3 billion letters. Possessing the complete
collection of phone books for the country does little to identify the single
misspelled letter.
So
far, in decoding the mystery of hereditary diseases, the bio molecular
revolution has already revealed some surprises. In general, the defective genes
found are extraordinarily long, which vastly increases the probability of
error. In many cases, a hereditary disease is caused by a single error. Other
times, it is caused by strange repetitions of certain genetic fragments.
Here is a brief listing of some of the genetic errors that have so far
been isolated, which reveal how even the tiniest of misspellings within the
human genome can cause unending suffering.
Huntington’s
disease. Located on
the short arm of chromosome 4, the Huntington’s gene IT-15 is 200000 base pairs
long. This gene is involved in producing two brain neurotransmitters,
acetylcholine and gamma aminobutyric acid. In normal people, there is a
repetition of the triplet CAG, which may repeat up to 11 to 34 times. In a diseased
patient, the CAG repeats far more than that, sometimes more than 80 times, and
causes dramatically reduced production of these two chemicals. The longer
triplet repeats beyond a total of 40, the more serve the disease.
Cystic fibrosis. In 1989, the gene was finally
identified by Francis Collins and Lap-Chee Tsui on chromosome 7. It is 250,000
base pairs long. CF can be caused by the omission of as few as three base
pairs, an infinitesimal fraction of the total. The mutation is caused by the following
deletion of nucleotides:
ATCTTT ----- ATT
This, in turn, triggers cystic fibrosis by
deleting just one amino acid (phenylalanine) out of the 1480 amino acids for
which the gene encodes.
Lesch-Nyhan syndrome. This disease is caused by a single mutation which renders a key gene
on the X chromosome, which stretches for 50,000 base pairs, incapable of
producing the enzyme HGPRT (hypoxanthine guanine phosphoribosyl
transferase).
Duchenne’s muscular dystrophy. In 1986, scientists finally isolated the gene
for Duchenne’s, which produces a protein called dystrophin. It’s one of the
longest gene so far isolated, stretching across 2.5 million base pairs. In
fact, its extraordinary length explains its high rate of mutation.
Unfortunately, although we should have a good listing of the
precise mutations causing thousands of genetic diseases by 2010, it may take
until 2020 or before we have cures for many of them.
“The
gap between the ability to diagnose and the ability to treat genetic diseases
could well be five to twenty years or more,” states Leroy Hood of the
University of Washington.
In this
never-never land before gene therapy becomes a reality, how can the information
we have learned be applied? Nancy Wexler, who helped to track down Huntington’s
disease, notes that some people ,upon being told that they have an incurable
genetic disease,“end up hospitalised – not for the disease, but for depression.
“
Ultimately ,the most promising strategy to combat genetic diseases
is to directly intervene via gene therapy.
|
G |
ene therapy is the
path advocated by W. French Anderson of the University of Southern California,
the leading pioneer in the field. Anderson is tackling a rare hereditary
disease called SCIDS (severe combined immunodeficiency diseases),which the
press has dubbed the “bubble boy syndrome.” The most famous case was “David,” a
child born without a normal immune system, who could be killed by the common
cold. David spent his life imprisoned in a sterilized plastic bubble; even his
mother could hug him only through special plastic gloves. Without healthy white
blood cells capable of warding off diseases, children with SCIDS usually
succumb to disease in childhood. Before he died in 1984, David became a symbol
of the terrible hereditary diseases which have stalked the human race.
Curing defective genes is no trivial task,
the body contains 100 trillion cells. However, millions of years of evolution
have created perhaps the most efficient “vector” for altering these cells: the
virus. By first neutralizing a virus (so it cannot make the patient sick),
scientists can insert the correct gene into the virus, and then insert the
virus into the patient.
Anderson’s experiments may prove to be the prototype for gene therapy in 2020. He first extracted blood from his young patients, and then infected the blood with the modified virus. After the virus infected the blood and inserted the correct gene into the blood cells, the blood was injected back into the patient. The world’s first such gene therapy patient was a four-year-old girl, Ashanthi DeSilva. In 1995, Anderson’s team claimed that 50 percent of the child’s white blood cells had their genetic mechanisms corrected.
After seven intensive years of gene therapy experiments, however, many of the results are still disappointing. One frustrating problem is that the body’s immune system sometimes attacks the virus and the modified cells, thereby preventing the corrected genes from proliferating in the body. The entire field was reeling from the impact of a scathing 1995 report to the NIH, which stated that gene therapy was “oversold” to the American people and that most of the experiments had failed to show any significant medical progress.
David Rimoin of the Cedars-Sinai Medical
Center, echoing the skepticism of the report, has said, “You need a smart bomb
to get the DNA to the right place, and a smart detonator to set it off at the
right time, and for the most part, those mechanisms are not yet available.”
People with cystic fibrosis in the trials,
for example, suffered complications when their immune system reacted negatively
with the injected virus, the “smart bomb” which was carrying the correct gene.
The report was a sober reality check to
gene therapy, but certainly not a deathblow. Yes, experiments were overblown.
Yes, the experiments have in the main failed to show much progress. But that
does not dampen the optimism of scientists and victims of genetic diseases.
As Francis Collins says: “This is a new
field. Would you criticize a baby while still in its cradle for not getting up
and quoting Shakespeare? Come on, give us a break here!
Since that 1995 report, there have been a
number of partial successes. The University of Texas group found tumors reduced
in size or even eradicated totally when gene therapy with p-53 was carried out.
The NIH’s Michael Blaese, a collaborator
of Anderson’s, has stressed that the progress of gene therapy can be compared
to the initial flights of the Wright brothers. Although there were those who
snickered at the strange experiments conducted by these bicycle makers, their
logic and science was sound, and within a few decades the air was filled with
flying machines.