Paola Arlotta holds up a vial of clear fluid swirling with tiny orbs. When she shakes her wrist, the shapes flutter like the contents of a snow globe.
“Those small spheres swirling around are actually tiny pieces of human cerebral cortex,” said Arlotta, the Golub Family Professor of Stem Cell and Regenerative Biology, “except instead of coming from the brain of a person, they were made in the lab.”
Those minuscule shapes may represent a giant opportunity for breakthroughs into bipolar disorder, a mental health condition that affects about 8 million people in the U.S. These lab-grown “organoids” — brain-like tissue engineered from blood cells of living patients — offer a means to discover more effective drugs and develop more personalized treatments for bipolar patients.
Paola Arlotta.
Harvard file photo
The research effort is just one example of the diverse array of projects funded by the Bipolar Disorder Seed Grant Program of the Harvard Brain Science Initiative, a collaboration between the Faculty of Arts and Sciences (FAS) and Harvard Medical School (HMS). Over the last decade, the program has funded more than 90 projects across the University and affiliated hospitals and hosted five symposia. In some cases, the grants have enabled researchers to develop innovative approaches that subsequently won larger grants from major funding agencies and to publish their findings in prominent journals such as Nature.
“The goal for this grant program has always been to help creative scientists in our community initiate new avenues of research related to bipolar disorder,” said Venkatesh Murthy, co-director of the Harvard Brain Science Initiative and Raymond Leo Erikson Life Sciences Professor of Molecular & Cellular Biology. “New directions, as well as new thinkers, are vital for understanding and eventually curing this damaging disorder.”
The program began in 2015 with the first of a series of gifts from the Dauten Family Foundation and recently expanded thanks to a new gift from Sandra Lee Chen ’85 and Sidney Chen. Kent Dauten, M.B.A. ’79, and his wife, Liz, took up the cause after two of their four children were diagnosed with bipolar disorder despite no known family history of the illness. “The field is terribly underfunded and for too long was a discouraging corner of science because of the complexity of these brain disorders, but in recent years has become an exciting frontier for discovery,” said Kent Dauten. The Chens had similar motivations. “Bipolar disorder has touched our family,” said Sandra Chen. “Our experiences drive our commitment to help advance understanding of what causes this disruptive disorder.”
The program now provides each project with $174,000 spread over two years. The 11 projects funded this year will investigate bipolar disorder from perspectives including genetics, brain circuitry, sleep, immune dysregulation, stress hormones, and gut bacteria.
The seed grants seek to nurture “outside-the-box ideas,” Murthy said. He added, “Many of our grantees have made significant discoveries with this support.”
An unsolved problem
Bipolar disorder usually begins in adolescence and on average patients suffer from symptoms for nine years before they are diagnosed. It brings recurrent episodes of mania and depression — most often the latter.
The typical treatment involves mood stabilizer medications such as lithium. Some patients also are prescribed antipsychotic medications, but these can cause weight gain.
The disorder often brings other health challenges such as cardiovascular diseases, Type 2 diabetes, metabolic syndrome, and obesity. Patients have a life expectancy 12 to 14 years lower than average, and high rates of suicide.
The causes of bipolar remain unknown, but the disorder appears to arise from a complex mix of genetic, epigenetic, neurochemical, and environmental factors.
Basic science: When brain signaling goes awry
Extreme mood swings are a hallmark of bipolar disorder. Patients often veer between manic episodes (characterized by grandiosity, risky behaviors, compulsive talking, distractibility, and reduced need for sleep) to depressive periods (sullen moods, joylessness, weight changes, fatigue, inability to concentrate, indecisiveness, and suicidal thoughts).
Nao Uchida, a professor of molecular and cellular biology, suspects that one driver of this volatility is dopamine, a neurotransmitter that plays a key role in learning, memory, movement, motivation, mood, and attention.
Uchida studies the role of dopamine in animal learning and decision-making. Dopamine often is described as the brain’s “reward system,” but Uchida suggests it is better understood as an arbiter of predictions and their outcomes. Mood often depends not on the result itself, but instead on how much the outcome differs from expectations — what scientists call the reward prediction error (RPE).
A few years ago, Uchida became interested in how dysregulation of the dopamine system might offer insights into the swings of bipolar disorder.
“We had not done research related to these diseases before, so this seed grant really let me enter the field,” said Uchida.
The funds allowed his lab to test how manipulation of depressive or manic states altered the responses of dopamine neurons in mice. The team incorporated new revelations about how synapses became potentiated or depressed to make certain pathways stronger or weaker. Some of their early findings will soon be published in Nature Communications.
Uchida posits that the disorder may be linked to skewed signaling of the neurotransmitters involved in prediction and learning. When the dopamine baseline is high, the person may become biased to learn from positive outcomes and fail to heed negative ones — and thus become prone to taking dangerous risks or entering manic states. In contrast, when the dopamine baseline is low, people pay too much attention to negative outcomes and ignore positive ones — and this pessimism pushes them toward depression.
“A lot of our future predictions depend on our experiences,” said Uchida. “I think that process might be altered in various diseases, including depression, addiction, and bipolar disorders.”
Nao Uchida (left) and Louisa Sylvia.
Harvard file photo; courtesy photo
Clinical research: Reducing obesity
Louisa Sylvia got an intimate glimpse of bipolar disorder in her first job after college. Working as a clinical research coordinator in a bipolar clinic, she witnessed patients struggling with anxiety, depression, and other symptoms. Again and again, she saw patients gain weight after being prescribed medications.
“I quickly became disappointed by the options that were out there for individuals with bipolar,” recalled Sylvia, now an associate professor in the Department of Psychiatry at Mass General Hospital and HMS. “It was really just medications — medications that can have really bad side effects.”
Sylvia has devoted her career to finding better options. (She also is the author of “The Wellness Workbook for Bipolar Disorder: Your Guide to Getting Healthy and Improving Your Mood.”) Even with the best current medications and psychotherapy, many patients continue to suffer from depression and other side effects. To supplement standard therapies, she has sought to develop interventions involving diet, exercise, and wellness.
One promising strategy is time-restricted eating (TRE). Restricting meals to a limited window — say 8 a.m. to 6 p.m. — can result in weight loss, improved mood and cognition, and better sleep.
With the seed grant, Sylvia plans to conduct a trial to evaluate the effects of TRE on bipolar patients. The study will investigate how the regulation of eating habits affects weight, mood, cognition, quality of life, and sleep patterns. She will work with Leilah Grant, an instructor at HMS and researcher at Brigham and Women’s Hospital who specializes in sleep and circadian physiology.
“For individuals who are depressed or have difficulty with motivation or energy, TRE is actually considered one of the easier lifestyle inventions to adhere to,” said Sylvia, who also is associate director of the Dauten Family Center for Bipolar Treatment Innovation at MGH. “We’re basically just saying, ‘Don’t focus as much on what you eat, but rather when you are eating.’”
The seed grants seek to nurture promising approaches that might not get funded through other channels. Sylvia can attest to the value of this opportunity; she had two TRE grant applications for federal funding rejected.
“I look at it like an innovation grant to try something that’s a little bit different but won’t get funded by the normal channels,” she said.
Translational research: Brain avatars
Despite decades of research, the success rate of drugs for treating bipolar disorder remains frustratingly low. Lithium, the mainstay first-line treatment, fully benefits only about 30 percent of patients — but three-quarters of them also suffer from profound side effects.
Animal models do not always translate to human medicine. Among humans, responses vary greatly; some individuals benefit from drug treatments while others do not.
To address these shortcomings, Arlotta is developing an innovative method to test drugs on brain cells of people with bipolar — without putting the humans themselves at risk.
Her team has spent more than a decade developing human brain organoids. They begin by taking a single sample of blood from a person. Because blood cells carry copies of our DNA, they hold the instruction manuals that guide development from fetus to adult. With a series of biochemical signals, these blood cells are reprogrammed to become stem cells. The team then uses another set of signals to mimic the normal process of cell differentiation to grow human brain cells — except as cell cultures outside the body.
“You can grow thousands and thousands of brain organoids from any one of us,” said Arlotta. “If the blood comes from a patient with a disorder, then every single cell in that organoid carries the genome, and genetic risk, of that patient.”
These “avatars” — each about five millimeters in diameter — contain millions of brain cells and hundreds of different cell types. “That is the only experimental model of our brain that science has today,” she said. “It may not be possible to investigate the brain of a patient with bipolar disorder, but scientists might be able to use their avatars.”
In pilot studies, the Arlotta team created brain organoids from stem cells from two groups of bipolar patients: “lithium responders” who benefit from the drug and “lithium nonresponders” who do not. The researchers will test whether these organoids replicate the differences seen in living patients — and then use them to develop more effective therapeutic drugs.
But Arlotta knows that no single approach represents a panacea. Because bipolar disorder remains so mysterious, the seed grant program is valuable because it promotes many promising lines of research across disciplines.
“The program has the modesty of understanding that we know very little about bipolar disorder,” said Arlotta. “Therefore, we need to have multiple shots on goal.”
