Discovery on Target: A Deeper Look at 3D Cellular Models

August 26, 2021 | “This field is developing so rapidly. If it has been six months…, you're behind.”

That’s how Christopher Austin describes the 3D cellular models research landscape. As the past director for NCATS, the National Center for Advancing Translational Sciences, Chris knows the pace of this research area well. He recently left NCATS to serve as one of Flagship Pioneering’s CEO-Partners.

Austin will be chairing a session on 3D Cellular Models during the Discovery on Target event held both online and in person at the Sheraton Hotel Boston, September 28-29. Mary Ann Brown, conference director for the event, recently spoke with Austin about what he’s bringing from NCATS into the private sector, and what he’s hoping to learn from the event.

Mary Ann Brown: Chris, can you share what's been taking place over the past year and what initiated the move from Washington, D.C. to Boston?

Chris Austin: Sure. I was at the NIH for 20 years—an unexpectedly long period of time. And it was a wonderful run. What I was able to do with my great colleagues at NIH and our extramural colleagues was far on beyond what I expected when I went there 20 years ago. The move to Boston was really initiated by two things. First, I felt that I had done what I went to NIH to do. NCATS, this organization that I helped found, is in wonderful shape; I felt like I could leave it in good hands. And second, I wanted to take everything that I had learned and done at the NIH and bring it to the place where the rubber really hits the road for therapeutic development and deployment: the private sector. I had an opportunity to join this really remarkable organization, Flagship Pioneering, as a partner and as a CEO to do many of the things that we're going to talk about today, as part of my new mission here in Boston.

As mentioned, Chris, you are chairing the Best of Boston plenary keynote session during the 3D Cellular Models meeting this September. What presentations are you looking forward to?

Well, I'm looking forward to all of them. Part of that is because I'm such a 3D models junkie. I was lucky at the NIH to help lead the microphysiological systems program. That was really started out of NCATS and DARPA initially. And many of the people on the dais here for the meeting in September were grantees of my organization when I was at NIH. So I know most all of them quite well. And I think anyone who can join us is really in for a treat.

I will make no secret of this: I think this technology, which continues to rapidly evolve and mature, has one of the greatest potentials to really transform our understanding of disease and our efficiency and effectiveness in translating that understanding into effective therapies.

Look at some of the people who were talking; it will give you a good example of how broad the applications are here. Just taking a few examples, Linda Griffith, who is a longtime friend and colleague has been interested in this really fascinating question of the interplay between the microbial world and the human world and the epithelia, which mediate that interaction in a variety of tissues. Linda's really been a leader both in that arena and in the integration of various organs-on-chips or tissue chips or microphysiological systems. They're all different words for the same thing: integration of different organ systems together. It's always a treat for me to listen to Linda, and I'm sure this will be no exception.

Roger Kamm, who's speaking after Linda, is addressing one of the critical issues in therapeutic development: the blood-brain barrier. I'm a neuroscientist by training and by interest and this has been our Achilles' heel in neuroscience and neurological therapeutic development. Understanding the blood-brain barrier and being able to test compounds in a more effective way is really going to transform neuroscience therapeutic development. The current models for predicting and testing a blood-brain barrier penetration are really quite limited. This has enormous potential.

Look at Chris Chen studying vascular physiology, which of course, has the potential to apply to every organ system because the blood vessels exist in every system. Look at John Garlick's presentation. He is focusing on an often-forgotten part of the system—which we're finding in all microphysiological systems—which is the extracellular matrix: very critical in normal physiology, but of course, in the kind of cell culture that I have done during most of my career before I got into this business of 3D models, really ignored most of the time.

Senthil Muthuswamy is talking about one organ-specific problem that is in pancreas, but he's going to address a very practical problem, which we've run into in putting organs together. We're all familiar with the different cell types of different organs that all like different media. If you're going to create a little human in a dish, a little homunculus in a dish if you will, you have to find media which are relatively universal or a way to have a blood substitute, which will keep all the cells happy at the same time. It’s a non-trivial problem.

Then Mehmet Toner, a really distinguished professor of surgery at the Mass General, is focusing on integration of these kinds of systems and application to engineering and medicine.

If you look at these, you might say, "Well, gosh, these are all over the place." But they all have common themes: modeling human disease in a more effective way, and integration, whether they use the word integration or not. That's really the coin of the realm here. We've gotten a lot in the last 30 years out of the reductionist paradigm and going back to all the way down to DNA and or individual nucleotides. But of course, we're finding that what we observe in those very simple systems may not translate back to the human again. And that's what you're going to see: really exciting integrative biology.

Where is this technology headed? Where is going to be the grand path of translational research?

The most immediate applications in many cases are to understand physiology of disease. I've spent a lot of my career doing simple cell culture models and mouse models. And those still have enormous value and potential, but 3D models are new tools in our toolbox to understand normal physiology like the blood-brain barrier.

When things go wrong in disease, why do they go wrong? I think that's going to continue to be the most immediate application for these in science and medicine. At the same time, when we started this project on tissue chips at the NIH now over 10 years ago now, the effort was actually focused on the regulatory space. Could we begin to supplant some of the obligatory animal testing that is the gold standard now, but we know is incompletely predictive of the human condition?

It's turning out, perhaps not surprisingly, that that's just a higher hurdle. The FDA really puts appropriate focus on being sure that they have the data to say that, "Yes, these microphysiological systems really are better than the current animal models that we rely on." And so though FDA has been very involved, as have our European colleagues and industry in using these for regulatory applications, I think that's going to come a little bit later just given the very high bar appropriately for regulatory utilization.