Co-Innovating with Michigan Medicine

The Sexton (Jonathan Sexton) lab focuses on drug discovery and drug development for an interrelated set of disorders that emanate from type II diabetes and obesity. They specialize in phenotypic drug discovery and high-throughput drug screening.

Please tell us about your research.

My laboratory does drug discovery and drug development for an interrelated set of disorders that are emanating from type II diabetes and obesity. We use artificial intelligence enhanced methods to do drug discovery using human cells and tissues to help improve our translation from the bench side. Our lab specializes in phenotypic drug discovery and high-throughput drug screening. We create disease models from human cells and human tissue, then we develop bioassays that give us clinically meaningful responses to enable screening thousands of drugs. We will screen anywhere from tens of thousands to hundreds of thousands of potential drugs, then select the best ones and move those along our development pipeline. One of our big advantages is that we use human cellular systems, machine vision, and artificial intelligence to help us make good decisions early on for what compounds we want to advance towards clinical development. 
 

How has high-content imaging helped progress your research?

High-content imaging has helped immensely in progressing our research because, as they say, a picture is worth a thousand words. When we take pictures of human cells, they are worth tens of thousands of data points. Unlike conventional drug discovery methodology where we will survey a population of a few thousand cells and get a single number as a response, when we use high-content imaging we get reams of data that can tell us whether or not this drug had an effect. This allows us to detect nuanced effects to help us to make good decisions. 
 

Why did you choose the Yokogawa CellVoyager CV8000 High-Content Screening System and CellVoyager CQ1 Benchtop High-Content Analysis System for high-content imaging?

The Yokogawa systems are superior because of their speed and their resolution. When we are using our machine vision and artificial intelligence methods, the more you can see, the more you can know and the CV8000 is unparalleled in that respect. It is the highest resolution and fastest machine that currently exists that we have experienced, and that gives us a very strong advantage. We do a technique called cell morphologic profiling and the more you can see, the more data you can extract, and that helps us understand how a drug is affecting the cell not only in terms of efficacy, but also in terms of potential off-target effects or toxicity. We want to be aware of that as soon as possible to make good decisions for compound advancement because we do not want to select compounds that may ultimately fail because they generate adverse events that are not tolerable by patients. That is a big part of how the CV8000 helps our research. The CQ1, again a very impressive and very amazing instrument, is used heavily for imaging tissue and it is compatible with slides. We take histological sections from tissues and we can very quickly load sets of slides, image select regions where tissue is, and get high resolution images. That means we are not wasting time imaging open areas like other conventional slide scanners do. The CQ1 helps us to bridge the gap between studies that are done in individual cells to studies that are done in vivo systems and whole organisms, like laboratory animals or human beings. It is really the tissue imaging where the CQ1 is just phenomenal. 
 

What is the key to making full use of the Yokogawa CV8000’s and CQ1’s capabilities?

There is a lot of infrastructure that must accompany these instruments and that is what allows us to make full use of them; we must have a high throughput data infrastructure. Upfront, we must have laboratory automation and robots to help us prepare samples for the microscopes. We then run the experiments and do imaging on the microscopes, so we must have a very large data infrastructure to handle this large amount of image data. Without this setup, it is impossible to take full advantage of these machines’ capabilities because they are capable of this ultra-high throughput operation. While this is commonly found in Big Pharma, it is not commonly found in academic labs. That is what we have set up and that is what we are striving towards, a Big Pharma-style infrastructure that enables us to do the highest-quality drug discovery. 

 

Where do you want to see your research go in the next few years?

We have several new initiatives that are happening. One that is very important for us is we are learning about the connection between the gut and the microbiome to inflammatory diseases like non-alcoholic fatty liver disease, drug-induced liver injury, ulcerative colitis and Crohn's disease, and inflammatory bowel diseases. Because we have developed very sophisticated human tissue modeling systems, in the next three to five years we will investigate the role of the microbiome, so that we may be able to engineer it to affect disease states. I really think that engineering the microbiome to optimize gut health will have a large impact on many chronic diseases, help maintain optimal health, and have a big impact on medicine in the future. 

Outside the lab

Dr. Sexton loves spending time with his family. He has three boys under 13 years old and they keep him and his wife very busy. He loves to play a supportive role in his wife’s career. His wife is the Associate Vice President for the University of Michigan and he does everything he can to help enable her career and keep her happy. He also likes to play music with his family. He enjoys sourdough and loves baking sourdough bread. Although the lab keeps him busy, those are a few activities he likes to do in his spare time. 

 

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Jonathan Sexton Ph.D.
https://pharmacy.umich.edu/people/jzsexton
Assistant Professor of Internal Medicine, Medical School, and Assistant Professor of Medicinal Chemistry, College of Pharmacy 
 

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Interview date: 2022

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