HDSA 20th Anniversary of Gene Discovery Symposium

Dr. Francis Collins, MD, PhD, Director of the National Institutes of Health (NIH)^

The day started off with a presentation by Dr. Francis Collins, director of the National Institutes of Health (NIH). While at the University of Michigan, Dr. Collins was an instrumental member of one of the teams invested in finding the location of the HD gene.

Dr. Collins declared the month of April to be one of many celebrations. Sixty years ago, in 1953, the paper describing the structure of the double helix in DNA was published. Thirty years ago, in 1983, scientists successfully mapped chromosome 4. (Mapping means the scientists were successfully able to determine the location of the genes on that chromosome.)Twenty years ago, the location of the HD gene on chromosome 4 was discovered. Finally, only ten years ago, under the direction and leadership of Dr. Collins as director of the NIH, the human genome was finally sequenced.

The NIH is a part of the U.S. Department of Health and Human Services and is the “nation’s medical research agency making important discoveries that improve health and save lives” (NIH.gov). The NIH is the largest supporter of biomedical research in the world. Their goals for improving the lives of millions are ambitious, but necessary. Dr. Collins stated that the NIH is working on re-engineering the drug discovery pipeline while removing bottlenecks in the process. The National Health Service formed the National Center for Advancing Translational Sciences (NCATS) whose work is to advance projects that will remove bottlenecks in the drug discovery process, such as a chip that screens for the toxicity of certain drugs using induced pluripotent stem cells. The chip will assist in determining whether or not a drug will pass the blood-brain barrier prior to beginning clinical trials. The NIH is also a major funder of various areas of Huntington’s disease research, such as mitochondrial DNA maintenance, huntingtin protein biology, translational therapeutics, and Sirt 1/BDNF metabolism.

The BRAIN Initiative, recently announced by President Obama, will invest $100 million into mapping the systems of the brain beginning in fiscal year 2014. Essentially, mapping means scientists will have a better understanding of how and why the brain is connected. This will theoretically help researchers develop better treatments and cures based off of this information.

Tracing Our Roots: Nancy Wexler, PhD^

Dr. Nancy Wexler is an iconic figure in the world of HD research. After watching her mother suffer from the disease, Nancy’s entire family invested their lives into the search for a cure. Nancy Wexler’s father met with Marjorie Guthrie, Woody Guthrie’s widow, and decided to create the Hereditary Disease Foundation. The mission of the Hereditary Disease Foundation, at the time, was to seek out and create collaborations amongst the world’s brightest scientists dedicated to curing HD. There were many complex challenges. At the time, it was believed that humans didn’t have biological markers, or indicators of a biological state that highlights certain genetic abnormalities, which would make it nearly impossible to discover what was causing genetic disease. However this did not stop the scientists.

Dr. Wexler first ventured to Venezuela in July of 1979. Venezuela contains one of the largest HD families in the entire world. Wexler and her team made the treacherous journey to Lake Maracaibo where they studied over 18,000 people. After collecting blood samples and family lineages, Dr. Wexler discovered that HD was first brought to this region by a woman in the 1800’s, potentially a slave or mistress of a European.

With a combination of the information collected from this Venezuelan family, as well as that of the American family that Dr. Collin’s lab studied, many new developments followed. The Venezuelan information led to the discovery that the CAG repeat length corresponds to age of onset of disease symptoms and indicated that environmental and other genetic factors can affect the age of onset. The combination of research findings led the scientists to chromosome 4, and more specifically, the mutation responsible for HD in 1993.

Dr. Wexler described not only her scientific efforts, but her humanitarian ones as well. The Venezuelan family members affected by HD were extremely poor. Many lived in huts and slept on dirt floors. There was no Western medical care whatsoever. When Dr. Wexler returned to the United States, the Hereditary Disease Foundation donated funds to create Casa Hogar, a home for families affected by the disease. Since 1979, the Hereditary Disease Foundation has donated over $17 million to bettering the quality of life of Venezuelans afflicted by this disease.

Dr. Nancy Wexler finished her talk by stating her belief that the cure lies in tackling the disease progression via the silencing of the mutant gene.

Current Affairs: James F. Gusella, PhD^

Dr. Jim Gusella was another gene hunter who was instrumental in finding the location of the gene. He concentrated his talk on various HD basics.  With the discovery of the HD mutation in 1993, scientists were able to determine the genetic difference between a normal person and HD person at any age. While we may take this achievement for granted twenty years later, at the time the development was a huge boost to understanding the underpinnings of HD. The “trigger of this entire process of genetics is now known.”

Huntington’s disease affects compounds that control the manifestation of the disease. Symptoms can be determined before genetic diagnosis as specialized doctors now have enough information to understand the cognitive, psychological, and physical features of the disease.

Dr. Gusella finished his talk with the same message as Dr. Wexler. He said that it is best to think of this disease as a process that must be stopped before any damage is done. Preventing disease progression before it starts is a guiding mission of his research group.

The Promise of the Future: Marcy MacDonald, PhD^

The last gene hunter to speak was Dr. Marcy MacDonald. Dr. MacDonald began her talk with what was becoming the theme of the symposium: Interventions must be made during, but ultimately before, a life-long disease progression.

The “big goal” of researchers is to discover a way to cut or reduce the number of CAG repeats to a normal count (individuals with 35 repeats or higher will almost assuredly have symptoms of HD in a normal lifespan). Every human being needs the huntingtin protein to function, so reducing the total levels of the huntingtin protein is likely to be detrimental. We each have two copies of the HD gene (just like all of the other genes in our bodies). For most HD patients, one copy produces a version – or allele – of huntingtin that has a normal CAG length, while the other produces the mutant version of the protein with the expanded CAG region. It is crucial to control the mutant expression and not touch the normal huntingtin protein.

Dr. MacDonald advocates that scientific research needs to shift to discovering the earliest features of disease progression, as current methods primarily analyze only symptomatic individuals. Understanding how the earliest effects of the HD mutation differ or concur in various HD populations would allow scientists to make great strides in targeting the mutant protein expression.

HD is systemic. The brain is the most important organ affected, but many more types of cells throughout the body are impacted as well. This concept has been confirmed by a study of induced pluripotent stem cells (iPS) in HD patients. This study allowed scientists to use multiple lines of iPS cells (which function similar to embryonic stem cells) to re-create and study various cell types. Dr. MacDonald stressed the need to move away from research approaches aimed at a single target in the brain, as these methods have been ineffective and cost a large amount of money. Instead, it is important to discover various cell networks and functions affected in patients at the earliest age possible and research how environmental factors can affect disease progression.

Dr. MacDonald ended by discussing how HD is a “pioneering vanguard disease.” The research produced in the last 20 years has changed the way other neurological disease and therapeutic approaches are viewed by the scientific community. Emphasizing the need to find cures not just for HD, but all neurological illnesses, creates a collaborative paradigm that allows for a successful exchange of information and research.

Question & Answer^

The day finished with a question and answer session in which attendees could inquire about certain points the scientists had made during their talk. Many of the people in the audience were personally affected by HD, whether they were caregivers, loved ones, or living with the disease. One of the overarching questions involved the fear that scientists are only realizing how much more complex this disease is, making it even harder to find the cure. Many of the attendees wondered if this meant discoveries were further down the road than previously thought. All of the scientists responded with the idea that “complexity is an opportunity” (Gusella). The more complexity, the “more possibility for solutions” (MacDonald). What was stressed to the audience, especially by Dr. Wexler, was the idea that the silencing of the mutant gene and early intervention along with potential therapies are the greatest opportunities we have for a cure.