Morphogenesis Seminar Cambridge – Dr. Alan Rodrigues

Our seminar at the Cambridge Morphogenesis Seminar Series is available online! Feel free to take a look if you are interested in attempts to transcend reductive machine thinking through an organic revival of morphogenesis. Listen to the seminar as presented by our Co-director at the Laboratory of Morphogenesis, Dr. Alan Rodrigues, as he presents to Cambridge students on the topic of morphogenesis.

Cambridge Morphogenesis Abstract

In recent decades, much progress has been made in understanding how genes within cells contribute to organ-specific fates or disease phenotypes. However, it is becoming more widely acknowledged that increasing understanding at the molecular scale has not been sufficient to fully grasp how tissues comprised of thousands of cells generate their structures. To address this gap, the Shyer/Rodrigues lab centers its studies on the behavior of cell collectives in vertebrate tissues. Using novel collective cell behavioral assays and the skin as a model, we find that emergent biophysical properties arise at the ‘supra’-cellular scale during organ development. Such emergent properties then serve to shape the skin. Our findings indicate that epigenetic processes beyond the cell scale can organize morphogenesis in vertebrate tissues. Finally, uncovering such epigenetic processes has allowed us to provide an account of morphogen function that re-envisions canonically accepted roles of these chemical cues.

Cambridge Morphogenesis Transcript

[Dr. Alan Rodrigues] Even though I can’t be there in person, it’s a really nice opportunity to get to speak to an audience at a place that I spent some very formative years. I think a lot of the ideas that have finally come to fruition in the lab that Amy and I run were really the seeds of those years for me at least conceptually. A lot of that was actually done at Cambridge.

It’s great to have a seminar series centered around morphogenesis. As you know, we chose to name of our laboratory at Rockefeller the Lab of Morphogenesis. We’re very interested in form and structure in the living world and we’re particularly interested in situations where you have to form structures where there are hundreds to thousands of cells sort of involved in making each unit.

You have to think about how many many cells have to somehow coordinate to make a structure and one has to wrestle with the idea of how molecules which are much smaller than the scale of an individual cell relate to these larger structures. What I hope to show you is that we in a sense have taken a perspective where we really try to organize our thinking around collective cell behavior. As we’ve been doing that, what’s happened for us is that we have been able to provide models or ways of thinking about questions that have gone unanswered in the field for a while. Also, along that way, I think what we’ve been forced to think about is the need to rethink some of the canonical models that tend to guide the field so I hope to share that and go through the journey.

I’m going to lead you through and I know in this audience I don’t have to argue for the significance of morphogenesis and form in a sense, form in animals is the feature that really differentiates organisms from each other. It’s not necessarily the fact that we have radically different types of genes. for instance, from species to species in the vertebrate kingdom. It really tends to be expressed in structure.

The Conception of Morphogenesis

You know if you think about morphogenesis and how people have conceived or approached morphogenesis from a conceptual perspective, I would say there’s a couple of things that have dominated that conception.

One is that when you think of life and living things as from the perspective of machines, you become interested in phenomena such as the encoding of information the processing and transmission of information such as input output relationships. You often assume that there are precision parts or precise calculations being made many times at the cell level and that order in a sense is the result of form and order is the result of some sort of external control. I think, broadly speaking, that control tends to come from outside of the system from in some form of molecular control so in a sense cells and collectives of cells are in a sense somehow ordered from codes or information that’s really generated at the molecular level and so one example of this is the type of conception was developed by people like Eric Davidson who spent a lot of his career at Cal Tech where he thought about curin embryo from the perspective of these gene regulatory networks almost these circuit diagrams and the idea here is that if you’re able to understand the wiring of these gene regulatory networks, you will be able to generate an explanation of how that animal develops so in contract to a machine way of thinking. What I hope to present and what guides how we approach questions in the lab is to present what we’re loosely calling an organic theory of form. In our view, it is any really meaningful theory that addresses the organic or living nature of morphogenesis, it really has to wrestle with a couple of key things that we think have been under studied.

In studies in developmental biology, the first is this notion of intrinsic information or order creation. Another way of saying that is self-organization. Self-organization is the idea that it’s actually the process that these collectives go through that in time that somehow generates the order that you see. It’s not something that’s being encoded prior to the process but there’s some sort of dynamics involving intrinsic organization that really needs to be understood. The second thing has to do with the causal structure in living systems and really focusing on this notion of reciprocal causality, or the idea that rather than focusing on linear chains of input output relationships, a gene affects Gene B which affects Gene B and so on and so forth. Especially in self-organizing systems, entites that reciprocally affect each other cannot separate their effect from each other in time which leads to certain issues in terms of how to go about studying these systems.

The Phenomena of Emergence

A third and key feature is the phenomena of emergence, which I think is becoming more and more appreciated. We think that emergent behavior is really central to the creation of organic form and it’s an issue that you have to take seriously when you’re focusing merely on reductionist approaches where you analytically break systems down into their individual components and then finally a key point about all of this is that these processes are fundamentally embedded in time and can’t really be extricated from a dynamic understanding. What that really requires is a study not merely of just parts, not merely just the identification of a master gene or a set of master genes or an initial stem cell or a primary cell state. Knowing what the system is trying to capture in a static way may not provide a very satisfying understanding of how these process occur.

Scales Beyond the Individual Cell

If you really want to understand morphogenesis, especially in systems where many cells are coming together to create structures, we have to think about scales beyond the individual cell. We’re very interested in using physics and physical concepts to recover the understanding of the system as a whole to come up with conceptual grammar to think about features and process beyond individual cells. What I call this is “post-molecular perspective” which is historically in the earlier 20th century where a lot of people focused on the development beyond the cell. In that era, there wasn’t as much known about the molecular lens scale. Now that we have a tremendous amount of information about the molecular lens scale and post-molecular perspective, we have this conceptual view of how we think about things. It’s obviously very important to make these questions tangible. We picked a concrete system to study these questions and that system is the vertebrate skin.

Patterning of Large Numbers of Cells

One of the nice things about the vertebrate skin is that is has these dual features of being a place where you can actually study patterning of large numbers of cells. You know, the skin is the largest organ of the body so you have the functional units which are these follicles that are forming and each are made up of many cells. At the same time, the pattern is quite simple right, so geometrically its basically an array of follicles here across the back in this image. I think a big advantage of the system for us has been the fact that the pattern and geometry is quite simple especially when we move into things like moding in theory. This system has been used in the vertebrate skin and has been one of the systems that people use as an example of molecular patterning mechanism. Basically, the idea here is that you have molecules that through some form of reaction diffusion patterning mechanism create molecular pattern across the field. Then, once that pattern has been generated, individual cells have to self-assemble into follicle non-follicle situations. I think that’s very compelling way of thinking about development but when Amy and I started working in this system around 2015, we were looking through the literature and seeing how people had characterized the avian skin. What we noticed was that in many of the reviews when you look deeply at those molecular networks, it was often the case that the most upstream trigger of this patterning process wasn’t really identified.

Thank you for reading the first 10 minutes of our Morphogenesis seminar. To listen or watch the rest of this presentation, please feel free to watch the video on this article or watch the Morphogenesis Seminar Cambridge on youtube.