Impact of Alan Turing's approach to morphogenesis

Question

Shortly before his untimely passing, the computing pioneer Alan Turing published his most cited paper The Chemical Basis of Morphogenesis (1952).

The central question for Turing was: how does a spherically symmetric embryo develop into a non-spherically symmetric organism under the action of symmetry-preserving chemical diffusion of morphogens (as Turing calls them, an abstract term for arbitrary molecules relevant to development)? The insight that Turing made is that very small stochastic fluctuations in the chemical distribution can be amplified by diffusion to produce stable (i.e. not time varying except slow increases in intensity; although also potentially time-varying with 3 or more morphogens) patterns that break the spherical symmetry.

The theory is beautifully simple and abstract, and produces very important qualitative results (and also quantitative results through computer simulation, which unfortunately Turing did not get to fully explore). However, even in the definition Turing discusses some potential limitations such as ignoring mechanical factors, and the inability to explain preferences in handedness. The particular models he considers -- a cycle of discrete cells and a circular tissue -- do not seem particularly relevant. As far as I understand, the key feature is his observation of symmetry breaking through small stochastic noise and instability.

What was the most important contribution of Turing's paper to developmental biology? Is his approach still used, or has the field moved on to other models? If his approach is used, how was the handedness problem resolved?

Answer 1

This is a very interesting question. Many people have researched this topic, and many still are. But regardless, I had never heard of Alan Turing's contributions, so thank you!

First of all, I cannot actually find who first coined the term morphogen. Though people had hypothesized that chemicals could play a critical role in development through much of the 20th century, I cannot actually find the first person to use morphogen. But the most important paper really came from a guy named Lewis Wolpert, who came up with the model of a gradient of morphogens leading to differential cell fates. The idea being that if some area of an embryo produces a morphogen at a very high concentration, then as you move away from that area, the concentration goes down. So if this morphogen is required at or above a certain threshold for activity, then only those cells with that concentration will have a certain cell fate, while at lower concentrations, the cells can become something different.

But this does not really answer your question. You are asking how a single cell, which is spherically symmetrical, can determine a particular axis. Though most organisms do this is in slightly different ways, the most common feature is that sperm entry point breaks the symmetry. The best way to explain this is to show you a diagram of Xenopus (frog) eggs.

Image from: http://studentreader.com/nieuwkoop-center/

The Xenopus egg, first of all, is inherently not spherically symmetrical. There is a black animal pole, and a white vegetal pole. The sperm can only enter a marrow region of the egg about 30˚ north of the animal/vegetal line. Upon fertilization, an event occurs where the pigmented areas turn toward the sperm entry point, leaving a gray crescent. Nearby the gray crescent, in the vegetal pole, a structure called the organiser develops. This organiser creates many of the morphogens that then pattern the rest of the embryo.

Researchers have studied this a lot in many different organisms, but a few things really remain constant: eggs are not exactly spherically symmetrical, and the sperm entry point provides asymmetry.

Answer 2

I would think this is very much still "used." 60 years later, we finally have the first experimental support for it:

In this blog article about this journal piece the authors studied the ridges that form on the roof of mouse mouths. They manipulated the signaling molecules that induce their formation and observed changes in line with Turing's theory. Of course, this doesn't preclude other mechanisms from occurring, but supports that of Turing.

Answer 3

While Turing did not include mechanical effects on the differentiaton/patterning in his seminal work, other researchers have expanded on that idea. These do not necessarily change the premises that led Turing to his conclusions, nor make his contribution less relevant today. Adding a dynamic component or mechanics to the substrate in which the diffusion-driven instabilities happen can simply yield more complicated solutions.

Clear examples of this interaction between the reaction-diffusion mechanism and the mechanics or boundary conditions can be found in several places: the formation of palatal ridges in the roof of the mouth in animals, teeth formation across species, bacterial colonies both natural and synthetic and even the issue of boundary conditions has been explored in animal coating patterns.

In the case of handedness, I think this also a question of symmetry breaking, such as with Turing patterns, but happening at different scale. Skeletal primordia are thought to be formed through a Turing-type mechanism. The "issue" with handedness would be that in Turing's formulation all fingers would be equal, but superimposing the patterning already created by the Spemman organizer which polarizes the hand, makes the fingers distinct. So, in essence, a prior symmetry breaking event (which could be caused by a different lateral inhibition process or diffusion-driven instability acting a larger scale) can modulate a downstream developmental process.

Answer 4

Turing patterning has had a large impact in systems biology understandings of morphogenesis. The general idea is that Turing mechanisms can be coupled with other mechanisms to build robust patterning methods.

So while not too many people would say that an entire mechanism is ONLY due to Turing patterning, a lot of regulatory networks can be understand as having the components allow for a Turing patterning mechanism (under certain parameter constraints), and thus they can understand "why" certain interactions exist and predict the behavior of perturbations. Usually there are multiple mechanisms involved in a patterning system so doing some knockouts will not get rid of patterning, but by disturbing the Turing mechanism you will many times see a decrease in the robustness of the patterning.

A lot of systems biology has focused on robustness: what kinds of network motifs allow for robust switch-like behavior? etc. The Turing mechanism is a network motif which allows for robust spatial behaviors.