Eric Wang, Senior Photographer

A group of Yale researchers at the School of Medicine has received a $4.5 million grant to study bipolar disorder. The team will use a combination of patient observation, advanced brain imaging techniques, stem cell research, mitochondrial analysis and cutting-edge genetic studies to investigate bipolar disorder and its underlying biological mechanisms. 

The Yale team joins groups from Harvard, Stanford and the New York Genome Editing Center in receiving funding from fund BD²: Breakthrough Discoveries for Thriving with Bipolar Disorder. The Yale group is led by psychiatric neuroscience professor Hilary Blumberg and will focus on how mitochondria, the parts of the cell that turn food into cellular fuel, generate energy and on how differences in mitochondrial structures and energy productions pathways might play a role in bipolar disorder.

“Researching bipolar disorder has been my life’s work, motivated by wanting to reduce the suffering and high rates of suicide associated with the disorder,” said Blumberg, who is also the director of Yale’s Mood Disorders Research Program. “The field has made great progress, but it’s been very challenging to try to understand the causes of bipolar disorder when disciplines research pieces of the puzzle separately.”

According to Blumberg, many individuals with bipolar disorder report symptoms related to energy levels and their sleep — which are often linked to mitochondrial function. Genetic studies and other previous research have also suggested that mitochondria are key players in the disorder’s biological underpinnings. The Yale researchers believe that disrupted pathways in the mitochondria could play a major role in the development of bipolar disorder.

“What I think is really exciting and important, and is being facilitated by BD², is that pieces of a puzzle are now being brought together,” Blumberg said, “so now we can start to be asking the important questions like, what are the genetic and molecular mechanisms that underlie cellular changes and contribute to brain changes, and identify new treatment targets across these levels of scientific translation.”

Blumberg explained that the Yale team hopes to connect those puzzle pieces from different scientific fields to generate a multi-level understanding of bipolar disorder; she added that their research is divided into four aims.

Blumberg will lead the first aim, which focuses on the clinical features, symptoms, behaviors and brain circuitry of individuals diagnosed with bipolar disorder. Employing several brain scanning techniques, the researchers plan to examine differences in brain circuitry functioning and how mitochondria may be involved. 

Using a combination of magnetic resonance imaging techniques, including functional MRI, and a new imaging technology called broadband near infrared spectroscopy — or bNIRS — the researchers will be able to observe brain activity and mitochondrial activation in the same patient. 

In the second aim of the study, genetics professor and stem cell expert In-Hyun Park, will analyze blood samples collected from the participants who were scanned. Park’s lab will use these samples to generate cells called induced pluripotent stem cells (iPSCs), which can be used to create brain organoid models consisting of real neurons and other brain cells. 

This approach, Park said, provides a unique opportunity to explore the functioning of live brain cells and how they respond to medications.

 “From the stem cell, we can generate a brain-like structure called the brain organoid, which mimics the structure and function of the human brain,” said Park. “Using this model, we can compare the overall structure and neural activity and total gene expression and function between the healthy control and [bipolar disorder] patient.”

Directed by medicine and neuroscience professor Elizabeth Jonas, the study’s third aim will take a deep dive into the biochemistry of mitochondria using Park’s brain organoid models. Jonas’s research focuses on a protein in the mitochondria called ATP synthase, which contains a channel that ordinarily carries small charged particles — ions — across the mitochondria’s membrane during the process of generating cellular energy.

However, through her research, Jonas discovered a leak in the ATP synthase channel — one that lets ions escape. That leak can disrupt the delicate balance of ion concentrations on both sides of the mitochondria’s membrane — a balance that mitochondria use to moderate their energy production. As a result, Jonas explained, brain cells with the ATP synthase leak can be “hyperexcitable.”

Jonas’s research has previously shown evidence of this leak in the cells of individuals with bipolar disorder. Their brain cells, she’s also found, can be hyperexcitable. Through the new grant, Jonas hopes to tie everything together: understanding how the ATP synthase leak can play a role in causing bipolar disorder.

Cellular and molecular physiology professor Hongying Shen and psychiatry professor Kristen Brennand will oversee the study’s final aim. This research phase will focus on genetics of bipolar disorder, using advanced gene-editing tools like CRISPR Cas-9. The team aims to replicate earlier findings about bipolar disorder at the genetic and molecular levels. 

“What is especially powerful is performing this combination of research and integrating the work across the aims; for example, being able to look at someone’s brain scanning and in that same person studying their neurons,” said Blumberg, “And still more powerful will be performing the research in the context of the highly collaborative overall BD² research network.”

While the scientists are optimistic about their four-fold approach to studying bipolar disorder, they still face challenges during the research process. 

According to Jonas, one major complication stems from the limitations of brain organoids, which cannot fully replicate the intricacies of the human brain. The process of translating information from these organoids to the human brain is a complex endeavor, Jonas said.

“They’re not real brains,” said Jonas, “so we know that the brain organoids may tell us something about which cells in the real brain are abnormal, but they won’t tell us everything.”

But Blumberg said she remains hopeful about what the research represents and what it can produce.

She told the News that the grant they received represents growing support for new and highly collaborative efforts to study bipolar disorder. 

“We’re going to find out new things about bipolar disorder that will bring better help to people who are suffering with it,” Blumberg said. 

The Yale School of Medicine is located at 333 Cedar St.