Wu Tsai Institute: Making the right connections

Our first neurons form during the earliest weeks of development in the womb. As the brain takes shape, those neurons move about and cluster with others to create brain regions.

Then they begin the essential work of connection, following chemical trails to reach each other — sometimes stretching short distances, other times reaching far across the brain. Millions of these connections form every minute, as billions of neurons fasten together in trillions of ways.

Today, Yale’s Wu Tsai Institute (WTI) is following a similar developmental trajectory. Its researchers are settling and forming connections, crossing fields and forging networks, to help understand the most astounding product of the brain — human cognition.

Now nearing the fifth year since being founded with a historic gift from Joseph C. Tsai ’86, ’90 J.D., and Clara Wu Tsai, WTI was built for cross-disciplinary innovation. Made up of three symbiotic centers — addressing development and plasticity, cognition and behavior, and computation and machine intelligence — it acts as a metaphorical and physical bridge across scientific disciplines. 

Faculty members in WTI hail from more than 30 departments across Yale School of Medicine, the Faculty of Arts and Sciences, the School of Engineering and Applied Science, as well as the School of Public Health and Yale Law School. 

Through its core facilities, labs, classrooms, collaborative spaces, and intentional community building, WTI brings researchers together to find surprising avenues for exploration and discovery. And its interdisciplinary recruiting and mentoring efforts aim to expand the ranks of exceptional researchers who think differently about cognition.

“The advantage we have is that we can recruit faculty, postdocs, and students in support of an inherently interdisciplinary mission, not for an individual area of study,” said Nick Turk-Browne, the WTI director and the Susan Nolen-Hoeksema Professor of Psychology. “So we can get researchers at the ‘edge’ who are tapping into different fields to answer complex questions — using graph theory to understand brain networks, explaining behavior through brain-body interactions, engineering brains with synthetic biology.”

Collaboration in real time

Among the cohort of faculty recruited by WTI are Emilia Favuzzi and Shreya Saxena, with appointments in, respectively, the Department of Neuroscience at Yale School of Medicine and the Department of Biomedical Engineering in the School of Engineering and Applied Science.

“When I first started considering engineering as a major, I was more interested in machines and the way they work,” said Saxena, an assistant professor of biomedical engineering. “But during my undergrad, I started my journey into figuring out how the brain works, and it got me hooked in a way that nothing else really did.”

In her work, Saxena aims to reverse engineer the brain, building complex models of brain functions in order to see how the actual brain might be working. And she’s looking at how individual cell-to-cell communications lead to brain function and behavior.

Across her undergraduate, master’s, and doctoral training, she focused on mechanical, biomedical, and electrical engineering, respectively. When she was interviewing for the WTI position, it wasn’t entirely clear what department she should be affiliated with, she said.

“That’s partly because I’m at the interface of a lot of different fields,” Saxena said. “Even within biomedical engineering, which tends to be more clinically focused, I’m more on the basic science side, collaborating with experimental neuroscientists.”

One of those collaborators is Favuzzi, in an almost comically on-the-nose example of WTI’s goals working in practice.

“Emilia and I first started talking because we were the first new faculty here,” said Saxena. “It was mostly social but quickly graduated into what we could achieve collaboratively.”

As a graduate student, Favuzzi studied how different types of neurons connect with each other and how the specificity of those connections gives rise to the properties of a brain region. Then, as a postdoc, she started to ask similar questions about immune cells in the brain called microglia. Now she also studies how signals from the rest of the body affect these interactions.

“My research has always been very interdisciplinary,” said Favuzzi, an assistant professor of neuroscience. “And my approaches are very interdisciplinary, which is hard to maintain unless you’re embedded in an environment that promotes it.”

‘Different ways into a problem’

In addition to bringing together researchers whose disparate skills and areas of expertise can fuel new insights, WTI has been building resources and tools to help facilitate discovery.

Having now inhabited 100 College St. for two years, WTI’s core facilities have begun to take shape: BrainWorks, for non-invasive measurement of human behavior and brain activity; NeuroLux and The Plexus, with innovative tools for imaging molecules and cells in the nervous system; and the Matrix, for high-performance computing, experimental hardware, and data visualization. These facilities offer new tools and resources for Yale scientists to carry out boundary-pushing research.

Housed on the first floor of 100 College St., BrainWorks is operated by the Center for Neurocognition and Behavior, led by the center’s director, Kia Nobre, who is also the Wu Tsai Professor of Psychology in Yale’s Faculty of Arts and Sciences.

For research, Nobre says, two things need to be in balance.

“Specialization and focus on a particular area can be essential for developing mastery over particular methods, topics, and issues, and for building a common vocabulary with peers interested in similar questions,” she said. “But you also need to take a step back and look at different ways into a problem.

“Being able to come up for air and touch base with other specialists who have different perspectives is important for really cracking a problem.”

BrainWorks, directed by Roeland Hancock, offers extremely advanced technologies. But it is also designed to welcome researchers who may not yet use these tools or are just beginning to consider how they might benefit their research. Through community presentations known as PIPs — projects in preparation — Yale students, postdocs, and faculty share their current work and new ideas with colleagues. BrainWorks also hosts talks from invited speakers and bootcamps that offer training on specific methods and analyses.

“We’ve put processes in place that provide researchers with the best feedback and guidance on how to do the best science,” said Nobre. “And we’ve set up activities that support people who are in training and that enable a fruitful and constructive exchange of ideas.”

Then, of course, there are the tools.

BrainWorks has the full complement of workhorse tools for human neuroscience research, including a 3-Tesla magnetic resonance imaging (MRI) scanner, an essential piece of equipment for observing whole-brain structure and function; a transcranial magnetic stimulation (TMS) system, which uses magnetic pulses to stimulate targeted areas of the brain; and electroencephalography (EEG) setups, for recording electrical brain activity.

It also boasts more specialized equipment, including the first magnetoencephalography (MEG) systems at Yale. While EEG uses sensors placed on the scalp to measure electrical signals produced by active populations of neurons, MEG measures their corresponding magnetic fields. This approach provides better spatial resolution of where activity is happening in the brain, given that magnetic fields are less distorted by the skull and scalp. 

In one of BrainWorks’ MEG scanners, known as a SQUID (superconducting quantum interference device), participants sit still in a large machine that encircles the head — like a salon’s hooded hair dryer — while completing cognitive tasks, such as playing games, viewing movies, listening to narratives, or simply resting.

For researchers who want to measure brain activity while a participant moves around and performs more natural tasks, there’s another MEG scanner, known as OPM (optically pumped magnetometry). The OPM in BrainWorks was the first of its kind in North America — a major step toward measuring high-fidelity brain activity during real-world behavior.

“Developing OPMs is part of a big push to make our methods more immersive,” said Nobre. “By measuring the brain during natural and unconstrained behavior, we can ask new questions that connect better to how cognition unfolds in real life.”

To that end, BrainWorks has just launched two new experimental spaces. The Virtual Navigation Lab has an omnidirectional treadmill on which participants can walk in any direction while navigating through environments viewed through virtual reality headsets. With this technology, researchers can investigate how the brain uses and builds memories, orients itself in space, and controls body movements while navigating.

The Cave Automatic Virtual Environment (CAVE) is the second new space, delivering immersive multisensory experiences with motion capture to investigate how people behave freely in open but fully controlled environments. In addition to adult cognition, studies in the CAVE will investigate how children combine senses like sight and hearing and how they learn language. Both the Virtual Navigation Lab and the CAVE can be combined with wearable neurotechnologies to simultaneously measure brain activity.

Data streams and imaging technologies

While BrainWorks provides technology for measuring activity across the entire human brain, labs on other floors work on a decidedly smaller scale. The Center for Neurodevelopment and Plasticity — directed by Daniel Colón-Ramos, the Dorys McConnell Duberg Professor of Neuroscience and Cell Biology — hosts shared research facilities with advanced microscopes for viewing inside cells and communication between cells.

WTI’s microscopy core, directed by Lin Shao, has two components. The first, on the tenth floor of 100 College St., and known as The Plexus, is a sandbox where new ideas can be engineered and tested. It’s designed and equipped to foster the collaborations that generate innovative new instruments, and it makes those tools, which might not be commercially available for another decade, accessible to Yale researchers today.

For advanced equipment already available, there’s NeuroLux, across the bridge from 100 College St., in the Sterling Hall of Medicine. This facility houses commercially available, cutting-edge instruments that are transforming research. The first tool to arrive, earlier this year, was a super-resolution microscope that goes beyond the physical limitations of optics to image details 10-times smaller than a typical light microscope can detect. This exquisite precision enables researchers to view individual proteins within cells and the molecular machinery that powers thought.

All of the data collected in BrainWorks, The Plexus, NeuroLux, and at labs throughout WTI, need to be analyzed, and the Center for Neurocomputation and Machine Intelligence — directed by John Lafferty, John C. Malone Professor of Statistics and Data Science — is home to Misha and The Matrix, which offer new opportunities for data storage, processing, and visualization. 

Misha is a high-performance computing cluster driving the data-processing power of WTI. Named for Misha Mahowald, a pioneer in brain-inspired computing known for her work on the silicon retina, the cluster is housed in the Yale Center for Research Computing data center on Yale’s West Campus. It features a large collection of the kind of GPU chip technologies that power leading AI data centers around the world. These powerful chips are deployed in WTI to advance fundamental computational science and develop theoretical models of cognition.

On the eleventh floor of 100 College St., The Matrix — directed, along with Misha, by Ping Luo — contains a maker space as well as a video wall. This wall has virtual and augmented reality capabilities that can stream data from other WTI facilities, as it is collected, for visualization and interpretation.

For Saxena and Favuzzi, access to these resources have helped fuel their research and spark new ideas. Saxena uses Misha extensively in her work building complex models of brain functions and increasingly taps into the other resources offered at The Matrix.

And, Favuzzi says, she looks forward to using NeuroLux and The Plexus in her research on neuron interactions.

Favuzzi and Saxena ended up applying for a grant together before Saxena even officially arrived at Yale. They proposed combining Favuzzi’s neuroscience approach, in which she collects data on neuronal and microglial activity, with Saxena’s computational approaches to model these interactions. They can then, together, ask questions about how microglia regulate neuronal activity.

“This kind of collaboration enhances the type of questions we can ask and research we can do,” said Favuzzi. “And it happened immediately, enabled by the institute.”