Sunday, October 8, 2023, 5:00 -5:30 pm

Dr. Amy Moody, Pfizer, Senior Principal Scientist, Translational Modeling and Simulation Group

Talk Title: " Quantitative Model-Based Assessment of Multiple Sickel Cell Disease Therapeutic Approaches Alone and in Combination"

Bio: Amy Moody is a senior principal scientist in the Translational Modeling and Simulation group at Pfizer supporting small molecule programs during pre-clinical development. She uses a combination of modeling approaches, from simple empirical PK-PD to highly mechanistic quantitative systems pharmacology models, to predict the safe and effective drug dose for first in human clinical studies. Key to this process, she assesses the biologic pathway to determine the required extent and duration of target coverage and relates target modulation to biomarkers and clinical endpoints.

She began her scientific career as an experimentalist and completed her PhD studying the role of ion channels in cancer progression at Tufts University. She then transitioned to modeling during her post-doc advised by Bree Aldridge at Tufts University and Suzanne Gaudet at Dana Farber Cancer Institute with support from the Lab of Systems Pharmacology at Harvard Medical School. Her post-doc project involved investigating macrophage immune signaling dynamics using a combination of experimental and modeling approaches. Her post-doc provided a key opportunity to gain computational skills which enabled her to transition out of the lab and take a full-time modeler position at Pfizer.

Abstract: In sickle cell disease (SCD) red blood cell sickling is driven by concentration dependent polymerization of mutation-carrying deoxygenated hemoglobin (deoxHbS). Three strategies, inducing HbF, stabilizing oxygenated hemoglobin (oxyHbS), and lowering 2,3-BPG similarly aim to reduce deoxHbS. To predict the required level of target modulation, we extended the Monod-Wymann-Changeux (MWC) oxygen saturation model to include hemoglobin binding to 2,3-BPG and oxyHbS stabilizers and added an additional species to represent HbF. The model allows simulation of varying levels of oxyHbS stabilizer occupancy,  2,3-BPG lowering, or HbF intervention alone or in combination to calculate the deoxHbS concentration at oxygen tensions found in peripheral tissue and assess polymerization protection.

Sunday, October 8, 2023 5:30- 6:00 pm

Dr. Gevorg Grigoryan, Generate Biomedicines, Co-Founder and Chief Technology Officer

Talk Title: "Illuminating protein space with a programmable generative model"

Bio: Gevorg Grigoryan, PhD, is a co-founder and chief technical officer at Generate Biomedicines. He is also a research associate professor of computer science, biological sciences, and chemistry at Dartmouth College. He received two bachelor’s degrees, in computer science and biochemistry, and went on to obtain a PhD from the Massachusetts Institute of Technology, where he studied computational protein design and modeling of protein interactions. After completing his postdoctoral work at the University of Pennsylvania in 2011, Gevorg was appointed to the faculty at Dartmouth, where he obtained tenure in 2017.

Prior to co-founding Generate Biomedicines, Gevorg’s research at Dartmouth focused on understanding the relationship between amino-acid sequence and structure, seeking rigorous ways of inferring principles governing protein folding, interaction, and function from data. The powerful ideas that were discovered suggested a fundamentally new and promising paradigm for the design of macro-molecules that was based on general principles inferred from data. Armed with this new and powerful understanding, Gevorg envisioned the possibility of a company that uses the breakthrough of data-driven protein design, powered by Machine Learning, to transform therapeutic discovery towards a faster, more precise, and less expensive endeavor. Collaborating with colleagues at Flagship Pioneering brought this vision into reality, leading to the founding of Generate Biomedicines. The most enjoyable part of Gevorg’s role as the founding Chief Technology Officer at Generate has been to work with incredibly talented scientist on some of the world’s most challenging problems in molecular and therapeutic science.

Gevorg has authored over 50 peer-reviewed papers, including in Nature, Science, PNAS, and other top journals and conferences, and his work has received awards and recognition from the Alfred P. Sloan Foundation, the National Institutes of Health, the National Science Foundation, and the American Cancer Society.

Abstract: Three billion years of evolution have produced a tremendous diversity of protein molecules, and yet the full potential of this molecular class is likely far greater. Accessing this potential has been challenging for computation and experiments because the space of possible protein molecules is much larger than the space of those likely to host function. We recently introduced Chroma, a generative model for proteins and protein complexes that can directly sample novel protein structures and sequences and that can be conditioned to steer the generative process towards desired properties and functions. This talk will briefly discuss the technical underpinnings of the method and illustrate some of its applications, arguing that we are entering an age where design of functional proteins becomes increasingly routine. The question before the field now is what we will we do with this capability.