Solving the mysteries of Parkinson’s disease

When Clemens Scherzer, MD, was in high school in the 1980s in South Tyrol, an idyllic mountain region of Italy bordering Austria, he decided to do something big and bold with his life. “The most exciting journeys of discovery are space exploration or a voyage into the unknown of the human brain. I chose the brain,” says Scherzer, the Stephen and Denise Adams Professor of Neurology and director of the Stephen & Denise Adams Center for Parkinson’s Disease Research at Yale.

Scherzer was a student at the Medical University of Vienna in the early 1990s when he had the epiphany that centered his work as a brain researcher on an enigmatic neurodegenerative disease: Parkinson’s disease. He attended a lecture by the neurologist Thomas Brücke, MD, PhD, that featured a diagram of the circuit of the basal ganglia—a group of nuclei in the brain that are responsible for motor control. Brücke spotlighted the role that the basal ganglia play in Parkinson’s disease. Scherzer was enthralled. “I wanted to understand and map the molecular circuits of brain cells and correct the glitches that cause diseases,” he says.

After Scherzer earned his medical degree, he came to the United States to work with the creators of that diagram: Anne B. Young, MD, PhD, and the late John B. Penney, Jr., MD, researchers at Harvard Medical School; and with the late Mahlon DeLong, MD, former chair of neurology at Emory University and the pioneer of deep brain stimulation.

Now, as director of the first Parkinson’s research center focused on precision medicine, Scherzer is making a much more expansive brain map of his own. The Adams Center, housed partially in temporary space, will occupy areas of three floors at 100 and 101 College Street, the built-for-purpose medical laboratory buildings that span the old Route 34 Connector in New Haven.

The center, which is expected to grow to about 70 scientists over the next few years, combines expertise in genomics and machine learning with a huge data trove. The goal is to map the RNA of brain cells—the genetic software that programs a cell—in Parkinson’s patients and in people without the disease. At the core of the enterprise is the Parkinson’s Cell Atlas, a database that Scherzer and his colleagues launched at Harvard to track the role of RNA in brain cells.

“We’re going to use the revolutionary tools of genomics and AI to find the specific disease drivers in each patient, and to develop tailored medicines,” says Scherzer. “We will then take those precision therapeutics all the way into proof-of-concept clinical trials.”

Parkinson’s disease is named after James Parkinson, a 19th-century physician who called it “shaking palsy” in an essay published in 1817. Parkinson’s is a long-term neurodegenerative disease that mainly strikes people after age 60. About 1 million people in the United States are living with Parkinson’s disease, and an additional 90,000 new cases are diagnosed each year.

The earliest symptoms of Parkinson’s include constipation, a loss of sense of smell, and sleep disorders, such as acting out dreams. When motor symptoms develop, they include tremor, stiffness, and slowed movements. Over time, people may experience mood swings, hallucinations, and dementia. Decades ago, researchers believed that Parkinson’s was caused by exposure to pesticides and certain metals, but they now recognize that the disease is caused by multiple genetic risk factors in combination with these environmental influences.

There is no cure for Parkinson’s, but a wide range of treatments, including dopamine-replacement medications such as L-Dopa (levodopa), deep brain stimulation, and focused ultrasound help control motor symptoms. These therapies don’t address dementia and other disabling complications, however, and the disease will continue to progress.

Scherzer’s goal is to help produce medications that prevent motor symptoms from developing and—for people who already have them—to stop the disease’s progression. “We’re focusing on disease-modifying medicines that actually slow or halt the disease progression,” he says.

Inspired by his time at medical school in Vienna, where L-Dopa treatment was pioneered, Scherzer wanted to learn from the giants in the field. He applied for a research fellowship at Harvard and Massachusetts General Hospital, where Young was then chief of neurology. He remembers the day when the phone rang in his sparse room in Vienna, which had little more than a mattress, a desk, and an oil heater. It was Young, offering him a position. He was thrilled.

At Harvard, Scherzer gained experience as a laboratory researcher. He learned a method called RNA in situ hybridization, which allows researchers to explore gene expression in the human brain one gene at a time. It was, however, slow work.

After about two years at Harvard, Scherzer did his clinical residency at Emory. One of his mentors there was DeLong. Near the end of Scherzer’s clinical training, he joined a lab exploring the use of microarrays, which are chips carrying printed microscopic spots of DNA designed specifically to analyze the expression of thousands of genes in parallel. In a breakthrough, the researchers discovered that the activity of a gene called SORL1 (LR11) is markedly reduced in Alzheimer’s disease. Indeed, SORL1 (LR11) turned out to be one of the most important Alzheimer’s genes.

Then it was back to Harvard, where Scherzer joined the faculty in 2001 as a clinical and research fellow in movement disorders. He established his own lab in 2003 with the goal of using the gene chips to analyze Parkinson’s and Alzheimer’s cells, spotting genes whose expression was too high or too low, which indicated potentially troublesome mutations.

“It’s a different way of doing science,” Scherzer says. “Traditional research is serial. It places a risky bet on one molecule at a time, often based on little more than a hunch with limited information. In our lab, we make discoveries based on massively parallel quantitative data. This provides a genome-wide view and allows nature to tell you what is truly important.”

Around 2005, advances in high-throughput sequencing made it possible for researchers to sequence an individual’s entire human genome (all genes) and transcriptome (all RNAs produced by the genome) quickly and cost-effectively. Genetic analysis could be done on an even more massive scale by using sequencing instead of microarrays. In the Scherzer lab, researchers extracted RNA from brain cell samples, created libraries, sequenced the libraries, and measured the expression of all active genes to spot potential trouble.

Only 1% of the human genome encodes proteins, meaning that everything we know about the brain comes from this very thin slice of information. When sequencing the RNA content of brain cells, however, Scherzer and his team made an astounding discovery: they found that a whopping 64% of the human genome is active in brain cells. “This is ‘dark matter’ RNA,” Scherzer says.

The team began exploring the vast universe of both protein-coding RNAs (so-called messenger RNAs) and regulatory RNAs (so-called non-coding RNAs). Scherzer believes this network of RNA molecules encodes the genetic “software” of brain cells, providing vital information about human brain diseases, including Parkinson’s. One of the lab’s most important discoveries is that there are two types of genes related to Parkinson’s. Some are connected to susceptibility, others to progression. (A few do both.) This finding changed the way Scherzer thinks about drug development.

Traditionally, pharmaceutical companies designed drugs to target susceptibility genes. Scherzer’s research, however, suggests that for patients who already have the disease, progression genes are the logical targets to prevent the disease from worsening.

These advances were made possible, in part, by the lab’s vast biobank containing hundreds of thousands of human biosamples—including DNA, RNA, and plasma—collected over the past 15 years from more than 3,000 patients.

The Scherzer lab’s 20-year run at Harvard came to an end earlier this year when Yale School of Medicine lured him away with a strong institutional commitment and support from Stephen and Denise Adams for an endowed, interdepartmental center. Stephen Adams, a businessman and private equity investor, suffered from Parkinson’s and died in March at age 86. “Yale and Stephen and Denise Adams offered this once-in-a-lifetime opportunity to develop precision neurology for Parkinson’s and other brain diseases,” says Scherzer. “We are committed to making major headway toward solving these diseases.”

The Adams Center is a large and complex project. It spans multiple domains of expertise—including genomics, high-powered computing, AI, big data analytics, clinical knowledge, and drug development.

The biobank samples are stored in New Haven in 12 laboratory freezers, kept at -80°C, and in tanks chilled with liquid nitrogen. Additional samples will now be added from patients across New England—with a goal of including 10,000 patients. The center will also expand efforts to build a Parkinson’s Discovery Engine that maps the entire biology of Parkinson’s and to develop search algorithms to identify disease drivers and match them precisely to each patient. Scherzer calls this the “Google of Parkinson’s disease.”

Taking this project a step further, Scherzer envisions a Parkinson’s clinic of the future in which a patient will give a few drops of blood for genome sequencing. Then, the data analytics engine behind the scenes will identify that patient’s disease drivers and suggest precision medicines to correct those genetic defects.

A major element of the Adams Center is drug development. Scherzer and his colleagues are following two parallel tracks. One is using computers to screen massive health datasets to identify already-approved drugs that might be repurposed to combat Parkinson’s. So far, they have identified asthma medicines that might be useful. The second track is new drug development: the researchers want to develop therapeutics that can directly recode the RNA defects. Scherzer expects to form drug-development partnerships with pharmaceutical companies and biotech startups—and even plans on setting up a startup incubator space at the center.

Scherzer believes that we are at a turning point in the effort to make precision medicine a reality. His lab at Harvard accomplished a great deal, including discovering susceptibility and progression genes, establishing the biobank, and launching the Parkinson’s Cell Atlas. Now at Yale, he looks forward to bringing together clinical neurologists, scientists, and engineers from across the university’s departments who share his passion for solving the riddle of Parkinson’s.

“This is the right time to aim for a ‘Mars landing’ for Parkinson’s: precision medicine that targets the genetic disease driver in the right patient at the right time and prevents disease from ever progressing,” Scherzer says. “With the exceptional ingenuity, brain power, and partners at Yale, I am confident we will make important advances toward this awesome mission.”