Susan Lindquist believes that if “personalized medicine” for complex neurodegenerative disorders is to become a reality then scientists must begin developing more rigorous approaches to identifying and validating promising new therapies.

Susan Lindquist believes that if “personalized medicine” for complex neurodegenerative disorders is to become a reality then scientists must begin developing more rigorous approaches to identifying and validating promising new therapies.

Although personalized medicine offers tremendous promise for developing new medical treatments that are tailored specifically to a patient's genes, researchers moving in to this nascent field face formidable challenges: For example, some scientists feel they still know too little about the molecular underpinnings of diseases to begin designing personalized treatments. And although scientists have discovered many candidate genes for diseases, the research to validate those genes as legitimate drug targets has proceeded very slowly.

We may fail. But HHMI is confident that even if we do, we're going to learn an awful lot and generate information that's important.

Susan Lindquist

Undaunted by those challenges, Howard Hughes Medical Institute investigator Susan Lindquist is using a new Collaborative Innovation Award from HHMI to forge ahead. Her team's goal is to discover new strategies to target the biological mechanisms that break down in Parkinson's disease and other neurodegenerative disorders. “The idea behind our project is to transition to a new era in medicine,” says Lindquist, who is also a member of the Whitehead Institute for Biomedical Research.

Lindquist and her collaborators have developed an action plan that will exploit the powerful tools available to study gene function in three different model organisms (yeast, worms and mice) and integrate genetic data from large-scale studies of people who have Parkinson's disease. Their plan also calls for using new stem cell technology to generate cellular and animal models that can be used in screening for new drug therapies to treat neurodegenerative diseases.

Even if they fail to bring personalized medicine closer to reality, Lindquist says the risk of inaction is far greater. She prefers to take the long view: “We may fail,” she concedes. “But HHMI is confident that even if we do, we're going to learn an awful lot and generate information that's important.”

Her bold proposal unites top experts from multiple disciplines—a sort of “scientific dream team.” As independent researchers, Lindquist and her collaborators have made important discoveries about the basic biology of diseases ranging from neurodegenerative disorders to cancer to sickle cell anemia and diabetes.

Lindquist, an expert on protein folding, will join forces with Rudolf Jaenisch, a stem cell and cloning pioneer who is also at the Whitehead. Other members of the dream team are: Richard Myers, who studies the genetics of Parkinson's disease at Boston University School of Public Health; Guy Caldwell at the University of Alabama, Tuscaloosa, who has developed roundworm models of dopamine neuron degeneration; and Jean-Christophe Rochet of Purdue University, whose research probes how the buildup of misfolded proteins damages nerve cells.

Parkinson's disease is one of the neurodegenerative diseases at the top of the group's “to study” list. The disease causes progressive deterioration of dopamine neurons in the brain, leading to muscle rigidity, tremors, balance problems and mental decline. The scientists will also tackle Huntington's, amyotrophic lateral sclerosis, and other diseases that are still to be determined, says Lindquist.

Over the years, various research teams have shown that improper protein folding plays a major role in severe neurological disorders, including Huntington's disease and Parkinson's disease. Lindquist and others have shown that a neurotoxic form of the alpha-synuclein protein causes a lethal buildup of proteins inside dopamine-producing neurons. Her team developed a model of alpha-synuclein toxicity in yeast and used that model system to identify dozens of genes that affect protein folding. Some of these genes help cells cope with the surfeit of misfolded proteins and may therefore provide blueprints for the design of new drugs to treat neurodegenerative disorders.

Building on those studies, Lindquist's group will first do chemical and genetic screens in yeast to identify additional genes and small molecules that can be validated as new drug targets and/or potential therapies. Validation is a tedious but crucial part of drug discovery: Researchers use a variety of assays to determine whether a molecule plays a key role in the onset or progression of a disease. In those studies, they also assess whether interfering with or enhancing the activity of that molecule has an impact on disease symptoms and progression.

Lindquist notes that the collaborative HHMI project “will take the validation process to an entirely new level” by testing potential drug compounds in yeast, nematode worms, cultured rat neurons, and in both mouse cells and in mice derived from mammalian embryonic stem cells. For expertise in new cloning and stem cell manipulation techniques, Lindquist will turn to Jaenisch, a leader in the pursuit of patient- and disease-specific stem cells designed for research.

Jaenisch will use a relatively new technique to reprogram both mouse and human adult fibroblast cells back to near-embryonic status. Those reprogrammed cells, called induced pluripotent stem (iPS) cells, can then be further tweaked to differentiate into desired populations of cells, including the dopamine-producing neurons that are attacked in neurodegenerative diseases.

The scientists believe that if they are successful, their work will provide much needed new animal models for testing therapies for other neurodegenerative diseases and complex multifactorial diseases. Lindquist and her collaborators will use these mice to test the neuroprotective effects of specific genes that she and others have been putting through their paces in yeast and cultured rat neurons.

The mice will also give researchers an unprecedented opportunity to learn how misfolded proteins, aberrant protein trafficking and environmental factors interact to produce devastating neurodegenerative disorders. “The long-term goal is to develop personalized therapeutic interventions for very complex diseases,” said Lindquist.

For someone who has spent her career on the frontline of basic research, Lindquist is invigorated by the chance to work on such a promising translational project—something she has long avoided as “too hard.”

“To me the thought that people could actually be living better lives because I've done something—that is really exciting,” she says.

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