Biology JOURNAL

5.4
The Gene Hunters
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The road to scientific achievement is a challenging one that requires scientists

to have determination, perseverance, and innovation. This is well illustrated
by the history of our studies of Huntingtons disease. This deadly genetic
disorder strikes people in midlife and does not yet have any effective cure
or treatment. Motivated by personal tragedy, and supported by advances in
DNA technology, Dr. Nancy Wexler was a pioneer in the hunt for the faulty
gene. These efforts not only led to the discovery of the Huntingtons disease
gene (and many others) but also opened up avenues of future research that
offer hope for possible treatments and a cure.

Introduction
Huntingtons disease (HD) is a devastating neurological
genetic disorder. Inherited as a dominant autosomal trait,
this late-onset disease has symptoms that do not usually
appear until individuals are between 30 and 50 years of age.
Symptoms include uncontrollable movements, intellectual
and emotional deterioration, and other health complications that may lead to death.
First described as early as the sixteenth century, the unusual
symptoms were thought by some to be evidence of demonic
possession. Tragically, ignorance of genetics and such beliefs
likely led to the execution of many HD sufferers during the
witch trials of the Middle Ages. It was not until 1872 that
American physician George Huntington provided the first
detailed description of the disease and established it as an
inherited disorder.
By the early twentieth century, Mendelian laws of
inheritance had become widely accepted in science, and
researchers had learned that HD causes parts of the brain
to degenerate. Unfortunately, with no understanding of
the molecular basis of inheritance, the genetic cause of HD
remained a mystery to scientists.
Venezuelan physician Americo Negrette unknowingly
made a major contribution to unravelling the mystery. He
studied two villages on Lake Maracaibo, Venezuela, that
had a very high incidence of a neurological disease known
locally as el mal (the bad). His findings, published in 1955
in Spanish, went largely unnoticed for more than a decade,
until a young researcher discovered them while searching
for answers to her own questions.

her family. With great determination, she graduated

from university at the top of her class and became a
researcher for the National Institutes of Health in the
United States.

The search for Answers

Wexler believed that the first step to finding a treatment or
cure for HD would be to discover the gene responsible for
the disease. In 1981, after obtaining vital federal funding,
she headed to the shores of Lake Maracaibo.
Wexler studied family histories and prepared pedigrees
of thousands of individuals in the Lake Maracaibo communities (Figure 1). In 1983, using pioneering advances in
DNA technology, researchers were able to identify a section
of DNA near the tip of chromosome #4 that is a marker
for the HD gene. A marker for a genetic disease is a DNA
sequence that is associated with a specific gene and is found
in the same position on a chromosome in people who have
or are predisposed to having that disease. The discovery of
this marker meant that, for the first time, there was a conclusive test for people at risk of inheriting the disorder.

Personal Motivation
In 1968, at the age of 23, Nancy Wexler became very
interested in geneticsher mother had started to show
the symptoms of HD. Wexler maternal grandfather and
three uncles had already died of the disease. Fighting
the disease became the primary focus for Wexler and
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Chapter 5 Mendelian GeneticsPatterns of Inheritance

Figure 1 Since the early 1980s, Nancy Wexler has compiled a

community pedigree of over 18 000 individuals.

nel

Innovations and Advances

In 1983, modern genetics and the ability to analyze DNA

were still in their infancy. It took the efforts of many scientists more than a decade before the actual gene for HD was
identified. The discovery of the HD gene in 1993 was monumental. The gene is abnormally long and prone to repeated
mutation events (changes in the DNA code as it replicates).
These mutations result in large numbers of copies of a very
short portion of the gene. This discovery led to an understanding of an entire family of genetic diseases caused by
similar abnormal repeat sequences of DNA.
By 1996, advances in genetic technology had enabled scientists to begin conducting research on the HD gene in living
organisms. Genetically modified mice were created that contained the actual human HD gene. These model organisms
could be used to conduct experiments and study the activity
of the gene. The mice were also useful for preliminary testing
of new drugs without putting human patients at risk.
A number of other scientific and technological innovations have contributed to our understanding of Huntingtons
disease. Positron emission tomography (PET) scans produce detailed nuclear images of areas of the body. Other
technologies are used to monitor and study the progression
of the disease in the brain and changes in body chemistry
and metabolism. Stem cell research has been conducted in
tissue cultures and animal models. Human stem cells containing the HD gene can now be grown and used to study
the effect of treatments on the development of the disease
directly within human cells (Figure 2).

The Challenges Ahead

Even with tremendous strides in understanding, scientists
still do not know exactly how the protein produced by the
Huntingtons gene actually causes cell deterioration and death.
There are not yet any truly effective treatments or a cure.

Figure 2 In the future, stem cells may be able to replace cells that
have the defective Huntingtons gene.

Still, researchers and patients remain hopeful as advances

in science continue. Perhaps an effective drug will soon be
found. Perhaps some day a patients own stem cells will
be used to regrow and replace defective or lost brain cells.
Perhaps some day we will have the ability to actually correct
or replace the defective gene using gene therapy.
Meanwhile, the villagers on the shore of Lake Maracaibo,
and other people with Huntingtons around the world,
remain the subject of intense scientific investigation as they
continue to suffer from this horrific disease.

Further Reading
Quarrell, O. (2008). The Facts: Huntingtons Disease. New
York, NY: Oxford University Press.
Wexler, A. (2010). The Woman Who Walked into the Sea.
Ann Arbor, MI: Sheridan Books.
go to n els on s c i en c e

5.4 Questions
1. Prepare a brief chronology of events leading to our current
understanding of HD. C
2. Nancy Wexler could not have accomplished her goals on her
own. Use examples from this article to describe how the
discipline of science builds up a knowledge base over time. A
3. Use the example of Huntingtons disease to illustrate how
advances in one area of science can be applied to others.
A

4. Why would Dr. Nancy Wexler look at family pedigree charts

of the people of Lake Maracaibo as a starting point for her
search for the Huntington gene? T/I

5. Nancy Wexler has a strong affinity for the villagers of Lake

Maracaibo. She said, The Venezuelan families have given us
many gifts. . . . It is important that the world understand how
much they have given. It would be fitting if they could be the
T/I
C
first to reap the benefits of all future therapies.
(a) Use the Internet and other resources to investigate the
latest therapies that are being researched for future
implementation. Report back on two that you think
sound promising.
(b) Do you agree with Dr. Wexler that the people of Lake
Maracaibo should be the first to receive a successful
treatment? Why or why not?
go t o n elson s c i en c e

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5.4 Biology Journal: The Gene Hunters 203