By KERMIT PATTISON | Harvard Gazette Research

4 min read

A ball-like structure under a microscope. One side is mostly green and the other mostly magenta.
Human brain organoid showing integration of excitatory (magenta) and inhibitory (green) neurons of the cerebral cortex. Image: Arlotta Lab

Work described in this story was made possible in part by federal funding supported by taxpayers. At Harvard Medical School, the future of efforts like this — done in service to humanity — now hangs in the balance due to the government’s decision to terminate large numbers of federally funded grants and contracts across Harvard University.

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, except instead of coming from the brain of a person, they were made in the lab,” said Arlotta, the Golub Family Professor of Stem Cell and Regenerative Biology at Harvard University.

Those minuscule shapes may represent a big opportunity for advances in the understanding and treatment of bipolar disorder, a mental health condition that affects about 8 million people in the United States.

Get more HMS news

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.

The research effort is 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 Harvard Faculty of Arts and Sciences and Harvard Medical School.

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 the Raymond Leo Erikson Life Sciences Professor of Molecular and Cellular Biology at Harvard. “New directions, as well as new thinkers, are vital for understanding and eventually curing this damaging disorder.”

Promo to Earn a Master's degree from Harvard Medical School. Applications are now open, apply today

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 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 program now provides each project with $174,000 spread over two years. The 11 projects funded this year — 10 of them headed by HMS faculty — will investigate bipolar disorder causes and treatments 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.

Projects to advance bipolar disorder research and care

This year’s awardees are:

  • Paola Arlotta: “Human ‘Brain Organoids’ As Avatars To Understand Individual Variation in Treatment Response in Bipolar Disorder”
  • William Carlezon, HMS professor of psychiatry at McLean Hospital: “Induction of Mania-Like Signs in Mice by Perinatal Immune Activation via TLR7, a Gene Implicated in Bipolar Disorder”
  • Catherine Dulac, the Samuel W. Morris University Professor at Harvard and faculty steering committee member of the Kempner Institute for the Study of Natural and Artificial Intelligence at Harvard University: “Neuroimmune Interactions Underlying Bipolar Disorder”
  • Susan Dymecki, professor of genetics in the Blavatnik Institute at HMS: “A Brain Circuit and Cell Behavior Contributing to the Seasonality Patterns of Affective Disorders”
  • Jordan Farrell, HMS assistant professor of neurology at Boston Children’s Hospital: “Hypothalamic Control of Manic-Like States”
  • Michael E. Greenberg, the Nathan Marsh Pusey Professor of Neurobiology at HMS: “Aberrant Astrocyte Glucocorticoid Receptor Signaling in Bipolar Disorder”
  • Christopher Harvey, professor of neurobiology at HMS: “Multiplexing Measurement of Neural Activity and Neuromodulation in Bipolar Disorder”
  • Daniel Hochbaum, HMS assistant professor of medicine at Beth Israel Deaconess Medical Center: “Thyroid Hormone Modulation of Dopamine Signaling as a Molecular and Circuit Mechanism Underlying Mania and Depression”
  • Jun Huh, associate professor of microbiology and immunobiology at HMS: “How the Immune System and Gut Bacteria May Influence Bipolar Disorder”
  • Bernardo Sabatini, the Alice and Rodman W. Moorhead III Professor of Neurobiology at HMS and co-director of the Kempner Institute: “Investigating the Function of all Identified Bipolar Disorder Risk Genes in the Mouse Brain”
  • Louisa Sylvia, HMS associate professor of psychiatry at Massachusetts General Hospital: “Impact of Time-Restricted Eating on Weight Loss, Mood and Circadian Rhythms in Patients with Bipolar Disorder”

A case study: 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 those 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.

The researchers begin by taking a single sample of blood from a person, using chemical signals to reprogram them to become stem cells, and then using another set of signals to mimic normal cell differentiation and grow human brain cells — 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 so-called avatars — each about five millimeters in diameter — contain millions of brain cells and hundreds of different cell types.

Avatars are the only experimental model of the brain that science has today, Arlotta said.

In pilot studies, Arlotta’s team created brain organoids from two groups of patients with bipolar: “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. If they do, the team will try to use them to develop more effective therapeutic drugs.

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, she said.

“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.”

Adapted from an article in the Harvard Gazette.