“The hardest thing in deciding to move in one particular direction is to realize all the other potential paths that will likely never be traveled.” These words from his graduate school advisor made a lasting impression on Andre Sousa, PhD. As a graduate student at the University of Porto in Portugal, Sousa “liked too many things,” he says. That is until he found developmental neurobiology. “I was always fascinated by the brain and how this structure we have inside our heads is responsible for virtually everything we do – from controlling the most basic survival functions to our interactions within a very complex society.” He completed his PhD and postdoctoral training with Nenad Sestan, MD, PhD, at Yale School of Medicine.
This fascination with the brain led Sousa to the Waisman Center as the newest recruit in the Functional Genetics/Genomics of Neurodevelopmental and Neurodegenerative Diseases Cluster. He began as an assistant professor of neuroscience and Waisman investigator on February 1.
Sousa is the second hire in the cluster initiative that includes a biostatistician, a neuroscientist, and a geneticist. The cluster will serve as a nucleus to integrate research, training, and clinical services in the human genomics research area at the Waisman Center. Waisman director Qiang Chang says he is very happy to have Sousa join the Waisman team. “Andre is full of energy,” Chang says. “He creates an unprecedented view of the molecular and cellular details of early human brain development. We are thrilled to have him conducting such impactful research at our center.”
As a neuroscientist, Sousa fulfills the second of the three roles within the cluster. He joins Daifeng Wang, PhD, the biostatistician who was hired in 2019. Wang develops and uses machine learning and other innovative bioinformatic tools to understand genomics and other cellular mechanisms within complex biological systems. The Waisman Center is currently recruiting for a geneticist to round out the cluster.
“I think the Waisman Center is a great place for me and for my research goals,” Sousa says. “I think the work it does related to neurodevelopmental disorders – from research to treatment – is really outstanding.”
The evolving brain
Sousa describes a particular challenge of his work being the very organ he studies.
“The human brain is not amenable for direct experimentation,” he says. “Therefore, we have to create clever alternatives to study it. Only through the analysis of these modalities, we can reach a good understanding of what happens in the human brain during development.”
Those clever alternatives include a combination of mouse models, in vitro systems, and post-mortem human and primate brains. Sousa uses functional genomics – a field of biology that attempts to describe gene functions and interactions – to uncover genes in the brain that have human-specific expression patterns.
To do this, Sousa compares gene expression profiles in several brain regions to identify which genes are expressed differently and in which distinct developmental periods. He also profiles the same brain regions in non-human primate species.
This allows him to understand the processes that are conserved – or are similar in human and non-human primates and likely create the blueprint of a primate brain – and the processes that are specific to humans. The latter processes are more likely to be responsible for the differences we can observe in brain function between humans and other primates.
Once he identifies those differences, he tries to understand the evolutionary changes in our DNA that are responsible for these genes to be differentially expressed as well as the biological functional impacts of these differences.
“I am particularly interested in genes associated with neurodevelopmental and/or psychiatric disorders,” he says. “I therefore prioritize the study of how misexpression of those genes can lead to those disorders.”
Gene expression refers to the end product of what the DNA within a gene directs it to do – such as the production of a protein or other molecules. When a gene “misexpresses,” as Sousa puts it, it can cause some of the developmental disorders studied in many labs at the Waisman Center.
The goal of this research, he says, is to decipher the evolutionary changes that eventually led to making the human brain so, well, human.
Sousa’s research focuses neurons and how through evolution they have gained different purposes, and how connections among them are formed. “There are dozens of different types of neurons and most of them come from more or less similar progenitors or origins,” he says. “How and when do neurons gain their different identities?”
Focusing specifically on neurons may ultimately also open the doors to understanding neurodevelopmental and psychiatric disorders, Sousa says.
In addition to the difficulty of studying the human brain is the difficulty of discovering the function of brain processes – especially when those processes do not exist in other species’ brains. “How can we induce this process in a model so that we understand its impact on overall brain function?” Sousa asks. “We have been developing new ways to study these problems.”
Challenging as the work can be, though, that’s what keeps him coming back to it day after day. Sousa says he feels the most accomplished in his work when he realizes that he is creating “new knowledge. “That’s actually one of the most interesting things about science,” he says. “We find something and we realize that our finding leads to a dozen new questions that need to be answered.
“It’s really very exciting when we discover a new mechanism, or a new pattern of expression that only exists in the human brain. I continue to be surprised by how little we know!”
Much akin to the issues he faced deciding what to study in graduate school, Sousa says he probably has too many hobbies and interests outside of research. “Music would be the first one,” he says. “Until graduate school, I was not sure whether I would be a musician or a scientist.” He’s also an avid reader of history books and admires film for creating “entire realities that don’t actually exist.”
As a scientist, however, most of his time is currently spent on establishing his lab at the Waisman Center. Sousa describes his research as seated at the intersection of genomics, developmental neurobiology, and evolution. Because the work comprises multiple disciplines, he says the Waisman Center provides an ideal environment for him.
“I joined the Waisman Center because of my future colleagues,” he says. “It is a great scientific community with a complimentary set of expertise, which I believe to be essential in a thriving research center.”
Such collaborations and building off one another’s work are what Sousa believes will lead the field of neuroscience to some tremendous advances in the next couple of decades. “We have always studied what others discovered before our time and then we are the ones discovering things that future generations will study,” he says.
As exciting as this work is, though, the hardest part – as his graduate director said – is deciding in which direction to move.