, Research Paper
Diseases: Sex Linked and Sex Influenced
by Richard Nixon
Honors Biology
Mrs. Linda
December 19, 1994
There are thousands of cases of sex linked and sex influenced diseases
worldwide. These diseases can range from a social inconvenience, to a fatal
ailment. In sex linked diseases, like Muscular Dystrophy, hemophilia and color
blindness, only males are affected. When a man infected with a sex linked
disease has children, all his sons are normal, but all of his daughters are
carriers. When a carrier woman and an uninfected man have children, half of the
sons are normal, and half of the sons are affected; half of the daughters are
carriers and half of the daughters are normal. Only males are affected because
the sex linked diseases affect the X chromosome. Males have one X chromosome
and one Y chromosome, so they need to use that X, whether it is flawed or not.
Females on the other hand, have two X chromosomes, so if one is defective, they
can use their second X chromosome. Duchenne’s Muscular Dystrophy(DMD) is
defined as “a genetic disease characterized by defective muscle cells that can
not produce a protein called dystrophins (Science News 380). In patients of
hemophilia, there is a deficiency of a protein needed for blood clotting,
causing this hereditary bleeding disorder. In red/green color blindness, the
broadest form of color blindness that affects six percent of the population, the
cones in the retina that receive green light do not function properly. Unlike
sex linked diseases, sex influenced diseases are not reserved solely for the
male. However, the diseases occur in males much more frequently than in females.
This is because sex influenced diseases occur from imbalances in testosterone,
much more highly concentrated in males. Baldness and gout are two diseases that
are a result of these hormonal imbalances. Baldness is defined as the lack or
loss of hair. Permanent baldness strikes on a hereditary basis because the
hormonal imbalances tend to be passed from generation to generation. Gout is a
hereditary metabolic disorder that involves recurrent acute attacks of severe
inflamm ation of joints.
Sex linked diseases are born when sex genes, that compose two of the 46
chromosomes, are mutated by an error in copying genes in reproduction. One of
these sex linked diseases is Duchenne’s Muscular Dystrophy. DMD is a disease
that has rightfully been gaining some headlines recently, as the disease is
taking the lives of young children. Several cures have been brought up recently
in the medical society, but none have paid any dividends. According to the
Muscular Dystrophy Association, one in every 2500 boys are infected with
muscular dystrophy. The defective gene is found at the top of the X chromosome.
This gene is the largest known to exist. In patients of DMD, this gene is
either missing or severely mutilated. The symptoms of DMD are fatal. By age
eleven, the victims weaken fast. Normally, muscle deterioration begins in the
lower legs and then moves up the body of the patient. Generally, victims are in
their early twenties when they die from either heart failure or diaphragm
failure.(The diaphragm is the muscle that makes breathing possible.) One mother
of a Duchenne’s Muscular Dystrophy patient says succinctly, “Eventually these
kids get bedridden and then they die.”(Grady 87) It is imperative to find a
cure for Duchenne’s Muscular Dystrophy so we can save the lives of thousands of
innocent children.
One of the major researchers working on a cure for DMD is Dr. Peter K. Law
of the Cell Therapy Research Foundation. Law has been in the field for over
twenty years and has made many discoveries. In 1972, Law’s doctoral thesis
proved that dystrophic muscle cells have abnormal cell membranes. This showed
that the disease was caused by a muscle defect, not a nerve defect as was
previously thought. Since it was clear that it was a muscle defect, Law tried
to transplant both whole and minced muscle into mice. The minced muscle proved
to be too damaged to operate, and the whole muscle was so large that it died
before an adequate blood and nerve supply was developed. At this point, since
the whole muscle was too large but was the only feasible solution, he decided to
transplant whole muscles of a baby mouse into an adult mouse. This muscle was
not damaged, because it was not minced, and it was not too large, because the
baby muscle is considerably smaller than an adult muscle. Not only did the
mouse survive, but normal function was restored to diseased adult muscle. Since
the transplantation of muscle in mice was so successful, Dr. Law tried to find
something along those lines that would work in a human. He found a solution;
myoblasts. A myoblast is a mature muscle cell. It is a long thin fiber that
can be more than an inch long. Unlike cells of other types, myoblasts have over
200 nuclei. When they are damaged, the myoblasts call upon a reservoir of
satellite cells; small immature cells that nestle inside the muscle fiber’s
outer sheath. Satellite cells are the key to muscle repair and regeneration.The
satellites leave the fiber, divide and then flatten into spindle shaped forms-
the myoblasts. Myoblasts repair muscle cells by fusing with the injured cell and
they share their nuclei with the injured cell’s nuclei. When these two
myoblasts fuse completely, new cells are formed.
In 1970 Law thought of a procedure that would fuse healthy myoblasts with
the dystrophic one, hoping that the resulting hybrid would have some function.
However, Law had to perfect this procedure. One of the main problems was that
when the healthy myoblast cells were fused, the immune system would treat them
as alien and attack them. According to Law, another thing they had to do was
“… to design and perfect a culture medium to mass-produce myoblasts and weed
out other cells.”(Grady 90) Law explains yet another problem encountered,”If
you cram too many cells in the same spot, they might not survive.”(Grady 90)
While Law was working on his myoblast experiments, another door was opened
by the discovery of the exact gene that caused the dystrophy. Many scientists
thought that this gene therapy, rather than Law’s cell therapy, was the future.
But Law dismissed gene therapy saying, “To me, in reality, that science will not
work in our lifetime. First you must make a normal copy of the defective gene,
which is enormous, and somehow insert it into a small virus to carry it into the
host. Then you must hope that the virus will attack the right cell in the body,
get through the cell membrane, break into the nucleus, and splice itself into
place inside the cell’s DNA. And then you expect that cell to function as
normal? Are you kidding me?”(Grady 91-92) Law also made it clear that in gene
therapy you have to replace the exact right nucleus in the exact right gene. In
cell therapy, it doesn’t matter which is the exactly right one that needs
replacement because all of the cells are being replaced.
Just two years after he wrote off the gene therapy, in 1988,when the
problems were weeded out, Law injected healthy myoblasts into 19 dystrophic mice.
The results of these tests were encouraging; 11 mice fared extremely well, 3
showed moderate improvement and 5 rejected the myoblasts. Another encouraging
fact was that the life span was increased from nine months to nineteen months in
the mice that fared extremely well. With the success in the mice, Law decided
to launch phase I of his human experiments . Each of three boys received four
injections of myoblasts from either their brother’s body or their father’s body.
In two of the boys, these injections, which were given in the foot, were matched
in the other foot by placebo saline solutions so nobody except Law’s assistant
would know which foot the real injections were placed. At the end of the
experiment, all three boys said that they felt that one foot was stronger than
the other. The foot that felt stronger was the same foot that was injected with
the myoblasts in all three cases, and all three feelings of greater strength
were backed up by muscle strength tests administered by Law.
Although the results of Phase I seemed ideal, Law received some criticism
from his peers. They said that he rushed too quickly into the human experiments
without gaining complete assurance that it would work to perfection. Some
scientists were concerned that the myoblast injection would have side-effects.
The criticism was not publicized to a wide extent, and it went virtually
unnoticed after Law made a statement in which he said, “We have to move the
research forward as quickly as possible. These are dying children. We have no
time to lose.”(Grady 88)
In May 1991, after Phase I was considered to be a success, Law lunched
Phase II. As of July 24, 1992 Law had treated the major leg muscle of 32 boys,
ages 6 to 14. For this process, Law removes an eraser-sized piece of muscle
from either the patients father or brother. Then, he grows the muscle in the
lab until he has 5 million myoblasts. At the time of treatment, the patients go
under general anesthesia for 10 minutes, and receive 48 injections of myoblasts
in 22 muscle groups. All patients take cyclosporin, an immune system
suppressive for six months to prevent the boys from rejecting the myoblasts.
The muscle strength of each patient is recorded 3 months before treatment, at
the time of treatment, and three months after treatment. This test was also
successful. Muscle strength was reported to improve in 43% of the muscles by an
average of 41% when compared to muscle strength before treatment. 38% of the
muscles stopped deteriorating after treatment and 19% completely failed to
respond.
However, as in Phase I, Law’s success was accompanied with criticism. The
major problem his peers had was that there were no controls. Says Robert H.
Brown Jr. of Massachusetts General Hospital in Boston during one meeting session,
“I am astonished that you haven’t controlled for cyclosporin.(Thompson 473) Law
counters, “We have a perfect control, strength before and after transfer on the
same muscle.”(Thompson 473) Law also says that the upper body of the patient
acts as a control. Law says that another reason he does not use controls is
because the saline solution is shown to speed up deterioration, and that would
not be ethically correct. His opposition, however says that since he only had
two patients with the placebo solution, so those results could not be verified.
Another thing that was criticized was the use of muscle strength to measure the
effectiveness. The three major components of the criticism is that the children
may not be using full exertion, that when you get older your strength gets
greater, and third, how do you know dystrophin produced this strength; what
about the cyclosporin?
The work done by Peter Law has been exemplary. He has found a method
for prolonging the life of young DMD patients. Although the way Law went about
his trials were controversial, moving as fast as possible is imperative because
thousands of children are having their ability to walk, and eventually their
lives taken away by this disease. If Law had waited, it may have been too late.
Although there is a large controversy concerning Peter Law, the Muscular
Dystrophy Association should support him and encourage him to perfect a cure for
this disease.
Another sex linked diseases that is similar to DMD in makeup, not in
symptoms is hemophilia. In hemophiliacs, a protein that clots blood is missing
or abnormal due to a gene mutation that was formed in the duplication of sex
genes. The protein missing in hemophilia victims is antihemophilic globulin
(AHG). Like in all sex linked diseases, only males can show symptoms, and
females are the only carriers. The father of a hemophiliac may or may not be
infected, but the mother must be a carrier. A hemophiliac has received his
mother’s bad X chromosome and his father’s Y. The same couple can also have a
normal son who received his mother’s good X and his father’s Y. If the couple
has daughters she can receive her father’s X and her mother’s bad X, or mother’s
good X. So, the chance of a hemophiliac boy being born when the mother is a
carrier is one in four. Therefore the incidence of hemophilia is familial, as
in the Russian royal family. In hemophiliacs ,the tendency to bleed becomes
noticeable at a young age and leads to severe anemia or even death.
Hemophiliacs often have large bruises and soft tissue of the skin from incidents
as small as lightly bumping into something. This bruising is much like the
bruising of the elderly. Not only will bruises form, but bleeding will often
occur for no reason in the mouth, nose and gastrointestinal tract. Once the
victim grows out of childhood, hemorrhages in knees , ankles, elbows and other
joints occur frequently. These hemorrhages result in swelling which impairs the
victim’s function. Hemophilia patients are generally advised to refrain from
physical activity . When hemorrhages occur, local application such as thrombin
are applied that serve as a blood clotting mechanism, or blood is transfused.
A third type of a sex linked disease caused by a defective chromosome is
color blindness. Red/green color blindness, the most common type that affects
six percent of the population, is caused by defective green cones in the retina.
People with red-green color deficiency see blue and orange very clear and bright.
Other colors, although different from the colors that normal people see, are
always the same to them and suit most victims fine because they have nothing to
compare the colors they see to(USA Today 16). Like hemophilia, Duchenne’s
Muscular Dystrophy and all sex linked diseases, only males suffer the symptoms,
and the females are the carriers. Although color blindness is a disease that
affects thousands of people, it is not a life-threatening disease. Most color
blind people do not suffer, because they do not know that the color should be
different. Few problems, like traffic lights, hinder color blind people, and as
Cynthia Bradford, an opthamologist at the University of Oklahoma Health Science
s Center says, “With many people, you might not even know they’re color blind?
unless they tell you”(USA Today 16)
Unlike sex linked diseases, sex influenced diseases do not affect one
sex solely. Baldness, the lack or loss of hair, is caused by an imbalance of
testosterone. Since it is caused by testosterone, much more concentrated in
males, sex influenced diseases are much more common in males.This imbalance
causes the destruction of hair follicles which causes the baldness to be
permanent. The largest type of baldness is male-pattern baldness that affects
forty percent of some male populations(Norton 2:826). Male-pattern baldness is
hereditary, and varies in degree from generation to generation. Ironically,
people with male pattern baldness have a higher percentage of body hair than
most, and those Aborigines with male pattern baldness generally have bald calves
as well. Although this disease is not life-threatening, baldness is a social
problem. Almost every other man is a victim, and those who do suffer the
disease are prejudiced. Solutions, not cures to baldness to exist. The first
obvious option is the wig. Secondly, hair transplants are becoming more and
more frequent, and topical solutions such as minoxidil have helped to prevent
further balding in many cases, and reinitiate hair growth in a much smaller
percent of users. The important thing to remember about sex influenced diseases
is that they are hereditary, but only to the extent of the amount of
testosterone produced. The genes tell the offspring the amount and
concentration of testosterone, not whether or not to lose hair. If the amounts
of testosterone relayed are not normal, baldness may occur.
A second sex influenced disease is gout. Gout is the “hereditary metabolic
disorder that is characterized by recurrent acute attacks of severe inflammation
in one or more of the extremities”(Norton 5:392). This inflammation is caused
by an excess deposition of uric acid in and about the joints. Like baldness,
this condition strikes men predominantly, but can also be found in women. The
exact cause of gout is not yet known, however, it is logical to believe that it
is caused by the same hormonal imbalances as baldness, and that is why it is
classified as a sex influenced disease. Gout is inborn, however the symptoms do
not occur until middle age. Before the attacks, small amount of uric acid build
up in the joints. All joints, especially the big toe, are susceptible.
Symptoms such as heat, redness of the skin, and extreme tenderness and pain
accompany the affected joints. Numerous gout attacks can cause knobby bumps on
the affected joints. Acute cases of gout may come and go in a matter of a week
for no apparent reason. Some circumstances , however, inhibit the symptoms of
gout. These circumstances include: emotional upset, diuresis, surgery, trauma,
and the administration of certain drugs. Cochicine is the classic treatment
for gout, but new medicines have surfaced recently.
Sex linked and sex influenced diseases are a problem that hurts our society.
Although many of the diseases are just an inconvenience, others are fatal.
There is no fathomable way of preventing any of these diseases, unless genes can
be altered. The only medicine to treat theses diseases acts as a suppressant,
not as an end to the diseases’s life. Hopefully, cures can be found to save the
lives of young, innocent people who are affected with hemophilia, Duchenne’s
Muscular Dystrophy and other fatal diseases.
Works Cited
“Color Blindness Misconceptions.” USA Today 120 (1992):16 “Foot Feat:
transplant treats dystrophy.” Science News 16 June 1990:380 Grady, Denise.
“One foot forward.” Discover September 1990:86-93 Massie, Robert., and Massie,
Suzanne. Journey. New York: Alfred A. Knopf, 1961. Norton, Peter B.
“baldness.” The New Encyclopedia Britannica. 1994 ed. Norton, Peter B. “gout.”
The New Encyclopedia Britannica. 1994 ed. Norton, Peter B. “hemophilia.” The
New Encyclopedia Britannica. 1994 ed. Thompson, Larry. “Cell transplant results
under fire.” Science 257 (24 July 1992) 472-474