In the latest “Tissue Talks” lecture hosted by Dr. Gordana Vunjak-Novakovic, Dr. Ron Weiss discussed his lab’s research on “programming” stem cells. Through this research, he hopes to unlock the secrets of organ development

On Wednesday, October 16, pioneering synthetic biologist Dr. Ron Weiss presented “Programmable Organoids: Guiding Cell Fate With Synthetic Biology and Neuromorphic Circuits,” as a part of the “Tissue Talks” series, a weekly webinar series hosted by Dr. Gordana Vunjak-Novakovic and the Laboratory for Stem Cells and Tissue Engineering at Columbia’s Department of Biomedical Engineering. 

In her introduction, Vunjak-Novakovic highlighted Weiss’s groundbreaking achievements at the intersection of experimental biology and computer science, a field he was inspired to explore while pursuing his PhD at MIT. In Weiss’s words, he became “fascinated with the idea that we could program cells the way we program computers.” He was one of the first biomedical engineers to recognize the potential for breakthroughs at the intersection of biological and computer engineering, which, at the time, were approached as entirely separate fields. As a doctoral student, he helped set up a wet lab in the Electrical Engineering and Computer Science department at MIT, a cutting-edge innovation. Upon graduation, Weiss was recruited to Princeton’s faculty but returned to MIT in 2009 to take a position as a tenured professor in the Department of Biological Engineering and Electrical Engineering and Computer Science. Now the Principal Investigator at MIT’s Weiss Laboratory for Synthetic Biology, Weiss has made major contributions to his field, earned numerous honors and awards, and his published papers have been cited over 25,000 times.

At the Weiss Lab, he oversees research into controlling cell behavior by constructing and modeling biochemical and cellular computing systems. Weiss and his laboratory can apply computer engineering principles to program cells, equipping them with sensors and actuators that can be controlled using analog and digital logic circuits. These researchers approach cells as biological computers. Cells run on “software” (DNA, RNA, and other biological signaling devices) that codes for desired behavior (usually sensing and responding to a certain stimulus). The lab’s research first models these algorithms in computer code, and then converts that high-level representation into a genetic regulatory network, embedding the corresponding RNA or DNA into cells to implement the desired behavior. 

Weiss’s group was the very first to construct systemic gene networks in biochemical logic circuits using E. Coli bacteria and discovered how to perform signal processing to detect specific chemical gradients in response to intercellular communication. His successes have been meteoric, but Weiss stressed that our current understanding of the complex mechanisms that regulate cell behavior remains limited. Generally, his research relies on encoding binary logic functions (or “booleans” in computer science) into DNA and RNA in the hopes that these operations will guide gene expression. However, this simple on-off logic can fail to address the complexity of the underlying systems that control cell behavior.

Weiss’s research also goes beyond the scale of single cells, applying coding techniques to program cell clusters. Much of this talk focused on his lab’s efforts to build genetic circuits that can guide the development of stem cells in forming three-dimensional structures with various specialized cell types, called “programmable organoids.” By encoding instructions into stem cell DNA to promote cell specialization and development, he and his colleagues have effectively produced vascularized liver organoids containing every type of liver cell. The next step is determining whether the techniques applied to generate liver cells are applicable to other organoids and their cell types. 

Weiss hopes to tackle this problem with neuromorphic computing in cells, a more advanced approach that doesn’t rely on the simple on-off logic of traditional binary circuits. His team has been working tirelessly to develop artificial neuronal networks, which allow for more inputs to produce more finely tuned responses, better mimicking the biological complexity that this research is trying to represent and control. Utilizing a machine learning technique, Weiss’s lab has been able to map experimental results for different inputs and outputs to see how they affect cell behavior. This, in turn, allows for encoding more complex, neuromorphic circuits to control cell development. With advanced techniques like these, synthetic biologists hope to coax stem cells into various specialized tissues and control their development with meticulous precision.

Weiss’s innovations have potential applications in areas like cancer biology, autoimmune treatments, drug testing, systems biology, neurobiology, and tissue engineering. MIT Technology Review named his synthetic biology research in its list of ten emerging technologies that will change the world. 

It’s clear that in the next decades, many people will have Dr. Weiss to thank for exploring this promising new frontier in biomedical engineering. But throughout his presentation, Weiss consistently expressed gratitude to others, thanking his students, colleagues, and the PhD advisor who inspired him to pursue synthetic biology. Interdisciplinary and interpersonal connections make groundbreaking science possible, and the visionary teachers and collaborators of the future will one day bring Weiss’ ideas from the petri dish to hospital shelves.

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