SANTA CRUZ — In a groundbreaking study published last week, UC Santa Cruz biomolecular engineering assistant professor Tal Sharf and other researchers have shown that developing brain tissue exhibits spontaneous activity and structure without receiving any sensory information, suggesting that the brain comes prewired to understand physical experience.
RELATED: Stanford researchers link lupus to common virus in ‘breakthrough’ study
From the days of Aristotle in ancient Greece, many philosophers and scientists have held the belief that the human brain is formed devoid of activity or structure before the sights, smells, sounds, tastes and textures of experience begin to give it shape — an idea known as “tabula rasa,” Latin for “blank slate.”
However, by using innovative methods to measure the electrical impulses of lab-grown brain tissue, Sharf and the study’s authors discovered compelling evidence that the brain is already encoded with instructions for making sense of the world even before it receives any sensory input, which he said is more akin to the philosopher Immanuel Kant’s idea of a priori cognition, and which Sharf calls a “primordial operating system.”
“It’s been hard for the neuroscience community to take a step back from this old school interpretation that the brain is this blank slate,” said Sharf. “Our work suggests that an intrinsic physiologic scaffold forms early in brain development and provides the foundational structure for encoding information.”
Published in Nature Neuroscience and titled “Preconfigured neuronal firing sequences in human brain organoids,” the study examined the activity of developing human and rodent brain tissue and found that “temporal sequences do not arise in an experience-dependent manner, but are rather constrained by an innate preconfigured architecture established during neurogenesis.” Sharf served as the senior author of the study, which also included a global team of researchers from UC Santa Barbara, Washington University in St. Louis, Johns Hopkins University, the University Medical Center Hamburg-Eppendorf and ETH Zurich.
Sharf leads the eponymous Sharf Lab at UCSC and is an applied physicist by training. He told the Sentinel that he became fascinated by the interaction of electrically charged molecules in living systems while earning his Ph.D. in 2014. It was then that he committed himself to understanding the dynamics of electricity and biology.
“I decided that I needed to work in a neurobiology lab so I could navigate this space and understand more about the biology,” said Sharf. “I went to Ken Kosik’s lab, who is the director of the Neuroscience Research Institute at UC Santa Barbara and then I took to learning more about modeling the brain with stem cells. Coming from a physics background, I was really interested in working with materials and building something to understand this. So we started working with these stem cells to construct a model of the developing central nervous system.”
Because of the sourcing difficulty and obvious ethical concerns associated with experimenting on a developing human brain, scientists use three-dimensional models of brain tissue grown from stem cells, known as organoids, to conduct their research.
“It’s so hard to access the early developing central nervous system without destroying it,” said Sharf. “And you’re definitely not going to access the developing brain of a human fetus. It’s impossible. Most of what we know comes from post-mortem tissue and that’s a tragic scenario, and also from surface recordings from surgeries.”
While conducting research at UCSB, Sharf said there was a boom in the use of organoid models. After receiving an Arnold O. Beckman Postdoctoral Fellowship in 2016, he gained the freedom to use the lab-grown brain tissue to pursue his own research ideas.
“After several years of learning neuroscience and developing computational skills and working with devices, I was able to interface organoids with super high-resolution microelectrode arrays containing 26,400 recording sites,” said Sharf. “This meant bridging solid-state electronics with developing brain models to capture electrical activity as it emerges. This approach allowed me to generate the first map of these circuits as they assembled from human-induced pluripotent stem cells. From there, we could observe networks that are truly self-organized and spontaneously active, showing strong similarities to early developing rodent cortex and more mature human patient tissue.”
Following his fellowship, Sharf landed a job in the Biomolecular Engineering Department at UCSC, where he has continued his work, combining physics, engineering and neuroscience and is now a member of the interdisciplinary coalition of researchers called the Braingeneers. The coalition is led by UCSC distinguished professor of biomolecular engineering and scientific director of the Genomics Institute, David Haussler, who is acknowledged in the study.
“I was folded into this big consortium and it’s been great,” said Sharf. “We are finding ways in which we can make an ethical, scalable model (of the brain) to study the complex properties of what neurons do when they self-organize, and find a way to model early brain development so that we can make transformative tools for biomedical research.”
For the study, researchers used microelectrode arrays created by MaxWell Biosystems, which feature roughly 26,000 recording sites to detect neuronal activity in the organoids specifically grown for the study. Sharf said that using the array, they can record about 20,000 data points on the organoids every second or one every 50 microseconds. While the organoids were developing, they displayed electrical signals as if they were translating sensory input, despite the complete absence of external stimuli.
“They (the organoids) look like these blobs that are a few millimeters,” said Sharf. “With some of them, we section them into little slices that are a few hundred microns thick and we use these high-resolution arrays to map them. Other times we placed whole organoids directly onto the arrays and we’ve also inserted ultrathin needles with cross-sections smaller than a human hair, and containing thousands of recording electrodes, directly into the organoid.”
Now that the study has shown that the neurons in the organoids spontaneously fire in a structured manner without external input, Sharf intends to improve the methods and continue the research. He believes that improved brain modeling as a result of his research could lead to a better understanding of neurodevelopmental and neurological disorders such as Parkinson’s and autism spectrum disorder — alongside the impact that environmental toxins, or insults, as Sharf refers to them, such as microplastics and pesticides, have on the developing brain.
“We need to understand how these environmental insults are impacting developing organs and a very important organ is the brain,” said Sharf. “Ideally, we wouldn’t have a large-scale mechanized agricultural system, and more of a European model, but that’s not the world we live in. Parkinson’s disease, for instance, is a disease of the 21st century and it’s highly linked to regions with exposure to pesticides.”
Sharf also believes that working with organoids will lead to breakthroughs in biocomputing and recently received $1.9 million in funding from the National Science Foundation to create an interactive system that tests the ability of lab-grown brain tissue to learn from experience, respond to feedback and solve tasks.
“We’re trying to see to what extent these systems can self-organize and actually solve meaningful problems,” said Sharf. “And also to understand what makes the brain so efficient. The brain computes on 20 watts and most of that energy isn’t going to computation but maintaining the voltages in the cells, so it computes very efficiently.”
Sharf said that although research on brain models is still in its early stages, it is advancing rapidly, and he and the interdisciplinary Braingeneers team are on its cutting edge.
“Bioengineering, basic stem cell biology and neuroscience all need to meet,” said Sharf. “And the group that we have here is filling that niche.”
To read the study, visit nature.com.