Arches. Photo by Daniel Chia
HOPES: Huntington's Outreach Project for Education, at Stanford
Jun
26
2010

Drs. James Gusella and Marcy MacDonald

Drs. James Gusella and Marcy MacDonald
Molecular Neurogenetics Unit, Massachusetts General Hospital
Charlestown, MA

Introduction^

This summer two HOPES team members, Taylor Altman and Shawn Fu, spent several days with Drs. James Gusella and Marcy MacDonald at their laboratories in the Molecular Neurogenetics Unit of Massachusetts General Hospital (MGH) in the Boston area. HOPES would like to thank Gusella and MacDonald for taking the time to share many valuable insights with us.

The Molecular Neurogenetics Unit, under the direction of Gusella, is dedicated to using molecular genetic techniques in humans and mice to understand and treat neurological disorders. Gusella and his colleagues pioneered the use of DNA sequence polymorphisms as genetic markers and mapped the Huntington gene to chromosome 4 in 1983 (please click here for more information about this breakthrough). He and his fellow researchers have since applied this genetic mapping approach to numerous neurological diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Batten disease, and familial dysautonomia (FD) in an effort to pinpoint the chromosomal locations of the disease genes and/or the nature of the genetic defect itself. In 1993, Gusella, MacDonald, and their colleagues, as part of an international collaboration, identified an expanded, unstable CAG trinucleotide repeat in a novel gene as the cause of Huntington’s disease.

Both Gusella and MacDonald are currently trying to understand the pathogenesis of HD and find ways to interfere with the disease cascade in order to halt its progression. According to the webpage of the MacDonald laboratory, she and her colleagues follow three interrelated steps in order to investigate the complex biology behind HD and other neurological disorders:

  1. The use of polymorphic DNA markers in genetic family studies to isolate gene defects that cause inherited disorders of the nervous system and test loci that alter the disease phenotype in some way.
  2. The creation of model systems (such as the mouse model of HD) in order to understand and clarify the functions of the products (essentially, proteins) of the abnormal gene at the whole animal, cellular, and biochemical levels.
  3. The use of model systems to explore novel gene therapy based strategies, which aim to intervene in the disease process.

MacDonald uses knock-in mice that carry human mutations, such as the gene defects in HD and Batten disease, to identify early cellular and molecular events in the disease pathways. She is also in the process of identifying cellular partners (the parts of the cell that a chemical or molecule interacts with) and pathways for the HD and Batten disease proteins, huntingtin and battenin.

Fig AH-1: The MacDonald lab

The MacDonald lab

What’s special about HD research?^

Altman and Fu sat down with Gusella and MacDonald to discuss their passion for investigating HD. What’s special about HD research? Both stated that they have the opportunity to do a great service for those with HD and, at the same time, learn about the biology behind the disease.

“HD, in particular, gets scientists interested,” said MacDonald. “What makes [HD research] fun is the discovery part, being in the middle of nowhere and finding new biology.” Take, for example, the mutant huntingtin protein: “We have no clue what it does, but we can connect it with old things and see things that are brand-new.” When studying the biology behind non-genetic (traditional) disease, researchers learn from what they already know, which is “not great for discovery,” according to MacDonald. Conversely, when studying HD, researchers do not know what they are looking for, which sets the stage for some amazing new findings.

“What’s disturbing is that the more you know about how something works, the less interesting it is,” Gusella said, pointing out a negative aspect of scientific discovery. “But working on HD is different”, MacDonald asserted. Unlike other degenerative disorders of the nervous system like Alzheimer’s and Parkinson’s disease, whose “ etiologies are myriad” (meaning that there is a wide range of possible causes), everyone who develops HD has the same mutation. The hypothesis that things will be found that counteract the effects of the single mutation in the single gene that triggers the disease in everyone is exciting to work on because it still poses new and interesting questions and challenges for the scientists who work on it. (For a comparison of Alzheimer’s, Parkinson’s, and HD, please click here.)

Although MacDonald, Gusella, and their colleagues are interested in many aspects of the Huntington gene and related proteins, the overarching purpose of their work is finding a way to treat HD sufferers. “The ultimate goal of our research is a treatment, not understanding HD completely,” said Gusella. MacDonald added, “If you know how the disease starts, there will be a solution.” However, Gusella believes that an actual cure will not be possible until the HD allele vanishes from the population – something that is not likely anytime in the foreseeable future (he defines “cure” as the disappearance of the HD allele from the gene pool). (For more information on the distinction between a treatment and a cure, please click here.)

Conceptualizing HD^

MacDonald drew a diagram of the disease (please see Figure AH-2: “HD pathogenesis and progression” below), its original CAG repeat mutation, and the age of onset. She and Gusella are currently looking for genes that interact with the original mutation. They conceptualize the disease in the human body as a series of steps in time from the HD CAG mutation to the onset of nerve cell death, to clinical symptoms and then the progression of the symptoms with factors that can effect each step (modifiers) determining the rapidity of each step and the age of onset of symptoms. Their labs are working to produce information about the genetic factors that determine the age of onset in the HD-MAPS (HD Modifiers in Age of Onset in Pairs of Siblings) study, coordinated by Dr. Richard H. Myers of the Boston University School of Medicine. By understanding the biological modifiers of onset, researchers may be able to develop methods to delay the onset of HD. Similarly, in the Huntington’s Disease PREDICT-HD (Neurobiological Predictors of Huntington’s Disease) study, conducted by Dr. Jane S. Paulsen of the University of Iowa, individuals who are known to have the gene expansion for HD are continually being recruited for a brief study examining changes in the DNA (genetic factors) that influence the age at onset of the disease.

Fig AH-2: HD pathogenesis and progression

Figure AH-2: A conceptual diagram of HD

Approaching HD^

How do scientists go about studying HD? Gusella and MacDonald explained the approach they take to their research. They look at HD from a genetic angle, choosing to study the basics – in other words, the root cause(s) of the disease – not just the symptoms and pathology (the clinical aspect that interests doctors). If we envision the disease cascade as a timeline, Gusella and MacDonald work at the very beginning, understanding the various mechanisms that trigger the disease, including the early biochemical and metabolic changes that take place. Clinicians, on the other hand, work near the end of the cascade, looking not at the cause(s) of the disease, but rather at the consequences (the movement, cognitive, and psychiatric symptoms). Whereas clinicians generally try to intervene toward the end of the disease cascade with drugs or other therapies, Gusella and MacDonald attempt research that aims to intervene at the start of the cascade via experimental methods on the level of RNA, most notably RNA interference (RNAi), which will be discussed later. The researchers even anticipate that someday they may be able to change the slope of the cascade so that the age of onset is later and the symptoms are less severe. (As you may already know, the later the age of onset, the less severe the symptoms.)

Genetic disease is fundamentally different than non-genetic disease in that it has a definite starting point, even if symptoms are not yet apparent. In contrast, non-genetic disease usually has apparent symptoms that clinicians try to block, but not always an easily identifiable starting point. In the study of HD, researchers like Gusella and MacDonald have the broadest definition for the “disease” part of Huntington’s disease. They define it as the genetic mutation present at the time of conception all the way to the last stages of the cascade near the end of the person’s life. Neuropathologists (professionals who study diseases of the nervous system) define the disease as nerve cell death. Clinicians, who have the narrowest definition, consider it to be the visible symptoms in the last stages of the cascade.

MacDonald argues that huntingtin protein aggregation and eventual nerve cell death are not the causes of the disease, but rather the consequences. She and Gusella, therefore, strive to discover the things that happen before, without worrying about integrating the results of their experiments into the HD “story.” For a decade, the HD story has sounded the theme of huntingtin aggregation as a cause of HD. Here the term “story” describes a paradigm created by the scientific community – something of an umbrella idea under which many subsequent research findings huddle. While a story of this kind may one day be proven false, the scientific community has a hard time letting go or changing the paradigm. Similar to the HD story, the Alzheimer’s story emphasizes the buildup of amyloid plaques in the brain as the cause of the disease (the events that start the disease cascade). This story, too, may turn out to be inaccurate. Protein clusters may not cause either disease, but are considered to be the result of events that occur further upstream in the disease cascade. In other words, once the original trigger (as yet unidentified) sets off the disease cascade, it often takes a long time for protein clumps or tangles to form.

To hypothesize or not to hypothesize?^

“The first step [of experimentation] is observation, not a hypothesis”, Gusella said. The scientific community has been so focused on having a hypothesis, he said, that getting funding without one was almost impossible because research projects that appeared purely descriptive (that is, projects that seemed to merely describe a phenomenon rather than answer a research question) were rarely awarded grants in the recent past. The scientific establishment’s penchant for storytelling may still prompt some researchers to formulate questions that they already know the answers to (“I can map and clone this gene”, for instance) simply to get funding for experimental research that may inhibit the careful observation necessary to formulate a meaningful hypothesis.

“Unfortunately”, said Gusella, “scientists must tailor their results to fit a hypothesis, which then must fit the overarching story that the research community is trying to tell.” This need for storytelling often results in unnecessary hype over a “rediscovered” discovery. For example, Alzheimer’s researchers have presented the same or similar findings about amyloid plaques over and over again, and the scientific community treats these findings as new discoveries. The way MacDonald views it, “It’s like mentioning Wilt Chamberlain to today’s great basketball players, and they say, ’Who?’”

Gusella and MacDonald think of science as a field in which researchers must continually build on the past, or else they run the risk of repeating the past (as in the Alzheimer’s example) or even losing it (as in the Wilt Chamberlain example). Gusella, though, cited an example of a scientific endeavor that did not have a hypothesis but was ultimately successful – the Human Genome Project, a thirteen-year effort coordinated by the U.S. Department of Energy and the National Institutes of Health to determine the complete sequence of the DNA in the human genome. The project gathered genetic information and developed a hypothesis later. Thankfully, said Gusella, the scientific community is beginning to come around; nowadays, more value is placed on descriptive research.

“Regardless of the type of research one is doing,” Gusella concluded, “the results can be interpreted in various ways, but one must select the correct interpretation.” Scientists must be willing to rule out certain hypotheses, as well as present failed hypotheses to their peers and to the public. Negative results are just as important as positive results because the data from a failed experiment may be useful in future research.

Accomplishments^

Gusella, MacDonald, and their colleagues in the field of HD research have accomplished much in their careers. As mentioned earlier, Gusella mapped the Huntington gene to chromosome 4 in 1983. Dr. Gillian Bates of King’s College, London, cloned the tip of the chromosome, where the Huntington gene is located, and with Gusella and MacDonald, made a road map that pointed to the location of the gene. From there, researcher Christine Ambrose narrowed down the search for the gene to the two most promising segments of the tip, IT15 and IT16 (IT is lab lingo for “Interesting Transcript”). She discovered that these ITs were actually one gene, the Huntington gene. (Several neighboring ITs are now known to be inherited together with this gene.) Then, with her colleague Mabel Duyao, Ambrose made an assay that found that excess CAG repeats on the HD allele of the Huntington gene cause HD.

MacDonald got involved in the research effort in 1985, discovering new pieces of DNA on chromosome 4. In 1987, enough pieces of the chromosome were cloned to show various gene recombination events. Recombination events occur when genes lying farther apart on the same chromosome are often not inherited together due to the transfer of segments of DNA between homologous chromosomes during meiosis, the reproductive process by which sperm and egg cells are made. A haplotype study (a study describing the genetic makeup of an individual with respect to a specific pair of alleles or genes) was published in 1992. The objective of the study was to find out if the chromosomes on which the Huntington gene resides looked similar at a particular region in different people who had HD (in other words, the researchers wanted to know if the same mutation causes HD in everyone who has it). Through linkage studies (for more information, please click here), the researchers found that there was more than one mutation in ancestral populations (the predecessors of various groups of people who suffer from HD today). Interestingly, they also found the same mutation at the same spot in chromosome 4 in unrelated people with HD, so the same type of mutation in the same gene causes the disease in all people.

MacDonald’s Masterminds^

Altman and Fu were fortunate enough to get a behind-the-scenes look at where HD breakthroughs are being made. They attended a lab meeting, where several of MacDonald’s postdoctoral (post-PhD) research fellows and interns gave presentations about their individual research projects. “Presenting research and sharing results is an important part of science,” said MacDonald.

Research fellow Julie Woda discussed her work on huntingtin normal function. Past research has shown that the protein is quite large and contains 36 HEAT-like repeats. The acronym HEAT comes from four proteins in which these repeated sequences have been found. These HEAT repeat sequences, which fold up into a spiral structure (alpha helix-loop-alpha helix), may serve as docking sites for other proteins. Most huntingtin partner proteins (“binding partners”) bind to one of its end segments. Based on its binding partners, huntingtin is involved in a variety of processes in the cell, including signal transduction, regulation of transcription (a big step in the process of turning DNA code into a protein), trafficking of molecules and other materials within the cell, maintaining the function of the cell’s cytoskeleton, and gene splicing.

Woda believes that the normal huntingtin protein is essential for the development of the human embryo. Studies conducted in the past have revealed that inactivating the Huntington gene (which produces the huntingtin protein) in a mouse results in abnormal embryo development. Supplying the mouse with either the altered (mutant) or wild-type (normal) huntingtin protein can rescue the non-huntingtin phenotype, meaning that the mouse can be brought back to a normal state. This phenomenon occurs because altered huntingtin acts like wild-type huntingtin, but gains some kind of new functions, such as a kind of “stickiness” that might make it more likely to interact inappropriately with another protein.

While touring the MacDonald lab, Altman and Fu spoke with some other postdoctoral research fellows about their research projects. Each trainee approaches HD from a different angle. For example, research fellow Elisa Fossale and intern Sony Mysore work together to prepare tissue cultures (a technique used to grow body tissue outside the body on a culture medium, a liquid or gel-like substance containing nutrients). The tissues kept in the culture medium are from the striatum of the brains of mice that carry the Huntington gene homolog (the mouse version of the gene). This brain region is known to deteriorate during the course of HD. The researchers are currently looking at differences in energy metabolism in mutant and wild-type striatal nerve cell clones. Preparing the cells for experimentation is a laborious process, generally taking about four to six hours. After this preparation, they can operationalize the changes in energy metabolism as changes in levels of the cell’s major energy carrier, ATP. These researchers have observed that ATP levels decrease in mutant cells, suggesting that metabolism is sluggish. Therefore, the cells are weakened through decreased efficiency in producing energy for their own survival. This information may be important to other researchers who use these types of cells for screening drugs that have the potential to combat decreases in energy metabolism.

Fig AH-3: Intern Sony Mysore learns how to perform a tissue culture.

Intern Sony Mysore learns how to perform a tissue culture.


Fig AH-4: HOPES team member Shawn Fu looks at striatal nerve cells under a microscope.

HOPES team member Shawn Fu looks at striatal nerve cells under a microscope.

Other researchers and technicians work on a type of tissue culture called cell lines. Cell lines represent generations of a primary or original culture, such as a bacterial colony that arose from a single cell. Cell lines are “immortalized” biochemically so that they continue to reproduce themselves and can subsequently be used to develop tests called screening assays for potential drugs that are available from biotechnology companies and academic laboratories under contract. Once researchers have figured out the appropriate target for a drug (such as mitochondria that make ATP or nerve cell transportation machinery slowed by the effects of mutated huntingtin), they can test these chemical compounds to see which one of them really goes after the target.

Fig AH-5: Cell lines in cold storage in the MacDonald lab

Cell lines in cold storage in the MacDonald lab.

Alex Lloret, another research fellow in the lab, studies sections of the brains of transgenic mice with different genetic backgrounds to observe the formation of huntingtin in the nucleus and later formation of neuronal inclusions (NI) in the nuclei of nerve cells. Neuronal inclusions are clumps of mutated huntingtin protein fragments that result from having HD. There is generally one inclusion per nucleus in mutant mice (those with excess CAG repeats).

Lloret also looks for proteins that interact with the normal huntingtin protein. He has found that huntingtin’s function is similar to that of a scaffold, or facilitator, because it organizes groups of proteins that play various roles in signal transduction in nerve cells. He is currently in the process of mapping one end fragment of the huntingtin protein in order to understand how other protein complexes bind to it. He is also looking at HEAT repeat sequences in huntingtin and trying to determine how these sequences interact with many protein complexes.

Fig AH-6: Researcher Alex Lloret prepares sections of transgenic mouse brains for experimentation.

Researcher Alex Lloret prepares sections of transgenic mouse brains for experimentation.


Fig AH-7: Sections of transgenic mouse brains are mounted on slides for viewing under a microscope.

Sections of transgenic mouse brains are mounted on slides for viewing under a microscope.

Other methods of investigating HD include the genomic, RNA interference (RNAi), and biochemical approaches. The genomic approach entails screening various genes in a human or mouse’s body for genetic markers, measuring the transcription level (amount of transcription) of each gene, and measuring the amount of RNA produced. The RNAi approach consists, in part, of describing the normal function of the huntingtin protein. Working with HD cell models, researcher Songshan Jiang uses short interference RNA (siRNA) to stop the translation of the huntingtin protein. Nerve cells treated with siRNA do not contain huntingtin at all. Jiang then examines the phenotype of the cells, looking at the way in which they are affected by the lack of huntingtin. This kind of observation can tell him what huntingtin’s regular function is within the nerve cells.

The biochemical approach involves understanding and describing how the structural and physical properties of biological molecules (such as proteins) influence the functions of those molecules. To study these molecules, they must first be purified. One of the biggest breakthroughs in biochemistry was the introduction of chromatography, which made it possible to separate and isolate different kinds of molecules quickly and efficiently. In the MacDonald lab, a technique called gravitation chromatography is used to compare the mass of the mutant and wild-type huntingtin protein. Researcher Ihn-Sik Seong has found that mutant huntingtin is in large complexes that are even bigger (have more mass) than the complexes with normal huntingtin. They also regularly use high pressure liquid chromatography (HPLC) when studying changes in the biochemical molecules that are due the presence of mutant huntingtin in cells. Generally, protein molecules are separated according to their physical properties such as their size, shape, and affinity for other molecules. HPLC facilitates the separation of molecules under high pressure in a stainless steel column filled with a special chemical substance called a matrix. A computer controls both a pump and a means of collecting data. By using HPLC, researchers can describe various properties of mutated and wild-type huntingtin. Knowing more about the characteristics of wild-type huntingtin will give the researchers a basis of comparison for mutant huntingtin since they each have different properties.

Fig AH-8: High pressure liquid chromatography (HPLC) machines in the MacDonald lab.

High pressure liquid chromatography (HPLC) machines in the MacDonald lab.

Debunking the Myths^

For those of us who are not familiar with the ins and outs of the scientific community, Gusella and MacDonald believe that there are many misconceptions about researcher work because then many different activities that are necessary to attack a disease like HD tend to be lumped together. In reality, these activities require quite different skills, levels of funding, and working environments.

  • Myth #1: All labs are the same.Reality: There are important distinctions between academic labs (like the MacDonald and Gusella labs), industrial labs, pharmaceutical labs, clinical research labs, and clinical testing labs. All carry out different kinds of activities that are important to HD research. Generally, academic labs are responsible for discovering the biology behind a disease. Well-funded industrial and pharmaceutical labs are responsible for developing drugs that treat the disease and testing them on animals raised for that purpose. Clinical research labs are responsible for conducting clinical trials of treatments and drugs using consenting human subjects. Clinical testing labs do not do research, but instead conduct diagnostic tests for disease, in a government-approved manner, that are ordered by physicians.
  • Myth #2: Researchers spend all their time researching.Reality: In fairly large academic labs like MacDonald’s, the principal researcher does little or no actual lab work (often referred to as “bench work” because the lab tables are called benches). Rather, MacDonald hires postdoctoral students and technicians to do the bench work, dividing up the different tasks and projects among them and spending time to direct their efforts. MacDonald herself spends much of her time interpreting results, strategizing for future projects, and doing administrative work, such as writing and reviewing grant proposals and sitting on scientific committees.
  • Myth #3: Researchers are paid by the hospitals they work for.Reality: Researchers like MacDonald rent lab space from their institution, such as a hospital, and must do their own fundraising to obtain money for equipment and employees’ salaries. This fundraising is accomplished by applying for grants.
  • Myth #4: Treatments that work on mice will usually work on humans.Reality: Most experimental drugs and treatments tested on mouse models of various diseases do not work on humans. Mice are often used to test the toxicity of the chemical compounds involved in various treatments before drugs are developed and approved for human consumption. The process of testing treatments on mice, developing drugs, getting government approval for the drugs, and putting them on the market is quite slow, has many steps, and involves making enough of a particular compound for large groups of people.Some scientists think that a larger animal model may be a promising alternative to a mouse model of HD in terms of shortening the clinical trial timeframe. A large animal model may be physiologically more similar to a human, which will give scientists a better sense of what kinds of treatments may work on humans. MacDonald mentioned that a researcher named Russell Snell at the University of Auckland in New Zealand is currently developing a sheep model of HD. Because researchers will see much more nerve cell death in sheep than in mice or rats, they might be able to get a more accurate picture of the progression of the disease in people. It will thus be easier to study the pathology of the disease in its final stages. Not only is the physiology of a sheep is closer to that of a human than a rodent’s, but a sheep model can provide other benefits in terms of HD experimentation. For example, living experiments (experiments conducted in the living animal), transplantation of cells and tissues, and protection of the nerve cells against deterioration (a process called neuroprotection) will be easier to perform.
  • Myth #5: The nerve cell is healthy, and then it changes and gets sick after the onset of HD.Reality: The nerve cell in a presymptomatic person with HD is never normal. If a genetic mutation is present, then the cell is abnormal from the start. It is a common misconception that if a cell is not presently sick, it is normal. Yet, according to MacDonald, the cell merely gives the appearance of being normal by trying its best to remain healthy for as long as possible.
  • Myth #6: There is one big, important change that occurs in the body to make a person sick with HD.Reality: There is certainly more than one big, important change; in fact, there is a whole series of changes! Visualizing HD in terms of a timeline allows us to think about the changes sequentially (i.e. what happens, when, and in what order during the disease cascade). MacDonald says that one of the earliest changes involves the RRS1 gene. RRS, which stands for regulator of ribosome synthesis, directs the production of this small organelle that, in turn, directs the synthesis of nuclear proteins (proteins found in the nucleus of the cell). At the beginning of the disease cascade, more RRS1 is made, perhaps because the cell needs to change its protein synthesis. Other subsequent changes take place, leading to “derangements;” for example, in energy metabolism, which lead to other changes, and so on.
  • Myth #7: Scientists will find a “magic bullet” to cure HD.Reality: MacDonald thinks that it is highly unlikely that one chemical compound will work well in all people with HD. Yet she believes that HD researchers may, as a first step, be able to develop a drug to delay the onset of disease symptoms for about five years, which is the size of the effect in some individuals with a certain version of the GRIK2 (Glu6) gene. The GRIK2 gene is a genetic modifier in HD, meaning that its expression in different people can have an effect on age of onset. For instance, by manipulating this gene in a certain way, scientists can perhaps stall the onset of HD and thus shift the disease cascade in such a way that when onset actually does occur, the symptoms will be less severe.

Toward a Treatment: The future of HD research^

What big questions remain in the field of HD research? Gusella said that the question, “How does mutant huntingtin trigger the disease cascade?” is, by far, the most important one because learning about the root cause of the disease will help researchers intervene early in the cascade before the onset of symptoms. Secondary questions include:

  • What is the normal function of the huntingtin protein?
  • Is there a point at which the disease pathway becomes independent of its trigger?
  • What are the phenotypes in tissues other than the brain of a person with HD?
  • Why are cancer rates lower in people with HD?
  • What is the overall effect of HD on metabolism (not just in certain fat cells)?
  • What is the origin of the chromosome that gives rise to new mutations?
  • What produces the long length of the HD allele?
  • Why don’t nematodes (a type of worm) have a Huntington gene? (Nematodes are multicellular – made up of many cells – just like humans and mice.)

MacDonald discussed what she believes will be an important future discovery: the development of a biomarker to measure the progression of HD in a patient. She thinks that a rating scale that measures the functional decline (the physical deterioration) of people with the disease may prove to be important. She would also like to see a quantitative test that reflects the state of a person’s disease – not just for HD, but for Parkinson’s and cancer, as well. Unlike MacDonald, Gusella thinks that a biomarker would not be particularly meaningful; rather, he would like to see researchers direct their efforts toward developing a marker that could indicate a reversible disease state.

What level of specificity within the body will be targeted by a breakthrough treatment – the cell, gene, protein, DNA, or RNA? After a drug, which would be their first choice, MacDonald and Gusella said that RNA, but not DNA, is a promising level for a treatment. RNA is promising in terms of delivery to nerve cells (siRNA is delivered to the cells via the RNAi technique). At the protein level, it is possible to deliver normal huntingtin to the nerve cells in a similar way. However, the only drawback is that the technology involved in these processes is relatively unknown and underdeveloped. On the bright side, scientists and doctors can target the mutant huntingtin with small-molecule pharmacological drugs that are already available. At the level of the nerve cell, it seems promising to target treatments to nerve cell-nerve cell interactions at a distance from the trigger of the disease cascade. Unfortunately, this may be difficult due to the fact that the trigger is still unknown. On the other hand, targeting drugs to genetic modifiers would be a faster route than targeting nerve cell-nerve cell interaction – if such a route were available.

Conclusion^

Gusella, MacDonald, and their fellow researchers in the United States and around the world will continue to work diligently to find a treatment for HD. Much has already been accomplished by dedicated research teams, and many more breakthroughs are soon to come with advances in technology and the development of more accurate animal models of the disease. Once researchers identify the trigger, they can develop an effective treatment that stops the disease cascade early enough to prevent the onset of symptoms.

In the meantime, how can people with HD help the researchers in their quest for a breakthrough? MacDonald said that they can ask their doctors if they can participate in ongoing research, such as clinical trials, genetic studies, or observational studies. To learn more about current research, people with HD should read informative websites like the Huntington Study Group site. MacDonald added that newly diagnosed people should ask their doctors for something to read (a booklet or pamphlet) about managing the symptoms of HD, such as A Physician’s Guide to the Management of Huntington’s Disease, Second Edition by Drs. Adam Rosenblatt, Neal G. Ranen, Martha A. Nance, and Jane S. Paulsen.

“Research is a winding journey from the starting point to where you want to end up,” MacDonald said of the experience of working on HD (or any scientific phenomenon). It has been a long road, and she and Gusella still have miles to go, but they can see their destination – a much-anticipated treatment – on the horizon.

Fig AH-9: L-R: HOPES team member Shawn Fu, Dr. Marcy MacDonald, and HOPES team member Taylor Altman

L-R: HOPES team member Shawn Fu, Dr. Marcy MacDonald, and HOPES team member Taylor Altman

-T. Altman, S. Fu, M. Stenerson, 12/07/04