The Scientific Approach

A Layperson's Guide

Genetic Research at Massachusetts General Hospital (MGH)

The MacDonald lab is located in the brand-new Richard B. Simches Research Center, just up the street from the main MGH campus. Designed to facilitate communication between the various research groups, the building features wide hallways, open spaces, and meeting rooms equipped with audiovisual equipment for presentations. A spiral staircase, representing the double helix structure of the DNA molecule, connects the fifth and sixth floors, which make up the Center for Human Genetic Research (CHGR), through to the seventh floor, which houses the Molecular Biology Department.

One of five new thematic centers launched at the Hospital, the CHGR strives to facilitate the genetic research cycle, which begins with basic research, driven by scientists’ interest in questions pertaining to the biology behind a genetic disease. In basic research, biologists try to make new discoveries about the disease. For example, by studying animal models relevant to a given disease, scientists can try to observe new phenotypes in animals (that is, observable properties, particularly those associated with gene effects) that can then be looked for in human patients as well. Or researchers may try to use these new phenotypes to develop novel assays (chemical analyses) that can be used to discover drug compounds that may prevent the disease-associated phenotype.

The next stage of the cycle is the applied, or engineering-type, research, which puts the discoveries of basic research into practice. For example, researchers, usually in biotechnology or pharmaceutical companies, may use a variant of the assay discovered in the academic research lab to test a wide variety of drug compounds to see which of them effectively alter the outcome. Then, they may give the effective ones to animals and evaluate the outcomes, modifying the compounds by changing the chemical structure and retesting them, in successive rounds, to make them perform better, with fewer untoward side effects.

At this stage, researchers often look for drug targets, or molecules that can be expected to enhance or inhibit the disease. The best drug targets provide a direct route to what should be changed in a patient on the molecular level. Testing drugs in animal models helps researchers to identify targets and prioritize the best ones for further testing.

The third stage of the research cycle is clinical research, in which physicians and clinical researchers administer drugs to patients in government-approved clinical trials. Observations made at this stage often give rise to hypotheses at the basic research stage, and the cycle begins again, as illustrated in the diagram below.

Fig. 2. The genetic research cycle.
The cycle begins with basic research in academic labs, continues with applied research in biotech or pharmaceutical labs, and ends with clinical research in hospitals. Observations from the clinical phase may be used in basic research, and the cycle begins again.

Genetic research, or research of any kind, is therefore not monolithic; there are various stages of the research effort that operate in different facilities, with different kinds of people, and on different timelines for completing experiments and trials. Because each type of research has different goals, it requires funding from different sources.

The HD researchers at the CHGR are among the many people at MGH working to facilitate the genetic research cycle for HD. The MassGeneral Institute for Neurodegenerative Disease (MIND), directed by Dr. Anne Young, Chief of Neurology, makes discoveries in the basic realm and aims to translate them into prevention and treatments of neurodegenerative diseases like HD and Alzheimer’s. MIND, therefore, serves as a bridge between basic and clinical research. On the clinical side, the Department of Neurology helps HD patients to manage their symptoms through medical treatment, such as drug regimens, some of which may be experimental, in the cadre of clinical trials.

The study of HD at Massachusetts General Hospital via the scientific method can be compared to what scientists call a "fractal," a geometric pattern that is repeated at ever-smaller scales, as in the diagram below. Whatever the size or scale of the problem—whether a researcher is looking at a molecule, an organism, or an entire population—the process has a regular structure (derived from the scientific method) and resembles the greater whole.

Fig. 3. "Construction of a Fractal Snowflake." (from MSN Encarta.)

The basic triangle shape is reflected at every stage in the process of forming the larger design, just as the scientific method is reflected at every level of research from the smallest to the biggest detail.

As part of the CHGR, the MacDonald lab performs basic research and takes a molecular genetic approach to understanding HD. The researchers examine the DNA sequences of genes—the HD gene, in particular—to understand how changes in gene expression and protein structure are affected by the HD mutation. Gene expression is the process by which a gene’s DNA sequence is converted into proteins that are involved in cellular processes both structurally and functionally.

Studying the genetic expression of the HD gene (both the HD and non-HD causing alleles) can provide scientists with clues about how the nerve cells stay healthy or get sick. Determining the temporal order of the early steps in the disease pathway will eventually lead to the development of drug compounds that prevent these steps from occurring. As biological models for the disease, the MacDonald lab uses genetically altered mice and cells derived from them. Because the mice have high numbers of glutamine repeats in the huntingtin protein, as a result of the same HD CAG mutations that cause HD, they are likely to reveal the earliest presymptomatic changes to manifest with HD in humans.

Last Modified: 07/07/2007

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