Positional Information

 

I’m reading The Master Builder by development biologist and professor Alfonso Martinez Arias. The first bit reminded me of In Search of Cell History, but then Arias moves on to discussing embryology, a topic I am not well-versed in. All, I can say is that I’m in awe. It’s a wonder that organisms develop the way they do. So many things can go wrong, and sometimes things do go awry. But evolution has honed a successful protocol to turn a single cell into a monster – the human being is made up of trillions of cells and over two hundred different cell types, sitting in the appropriate location to carry out their specific functions.

 

How does this happen? Arias tells the story of famed biologist Lewis Wolpert (who passed away two years ago) puzzling over why even though we humans have different sized hands, our finger sizes are always proportioned to the size of our own hands. Wolpert thought that “cells either receive or enact instructions about what they do based on their position within a group of cells. He called this positional information.” He imagined a chemical (calling it a morphogen) that “would leak from one side of [a] sheet, diffuse across it, generating a gradient. Then he posited that different concentrations of the morphogen would be read by the cells… the meaning of the message to a cell depends on how far away the cell is from the source”.

 

This made me think about my research projects on elucidating proto-metabolic cycles at the origin of life. While I’m taking into account the effects of concentration, I have not considered a spatial concentration gradient that might lead to differentiation of proto-cellular functions. It strikes me that I need to really think about analog signaling. As a quantum chemist who tends to focus on one or two or three molecules interacting with each other, my isolated digital point of view is simply too narrow. I’ve been starting to build in flux into my models, but in a steady state situation. I hadn’t been thinking about how different concentrations may trigger a proto-metabolic cycle to behave very differently.

 

And what did the biologists find when they hunted for the morphogen? A protein, which they named Sonic Hedgehog (after the video game). It’s quite the amazing protein. Arias writes that “different tissues interpret the same [Sonic] signal differently and that the function of the signal is not so much to instruct but to organize, to define the domains in which cells exercise their options. Whether Sonic comes from a mouse, fish, or bead, if it’s placed in a chicken limb bud, it will inspire cells to build extra digits, and if it’s placed in the mouth, it will inspire them to build teeth that the organism’s ancestors haven’t had for millions of years.” The upshot is that “cells in different locations are different because of who their neighbors are and the conversational partners they’re encountering”.

 

Another new thing I learned was somitogenesis – the process whereby the body extends in time. There exist particular “pairs of cysts of mesodermal cells called somites, which serve as a kind of yardstick for the growing body.” There’s a fixed clock for this “precisely timed pattern of activity”. In thinking about my research, not only do I have to think about how to include spatial concentration gradients in the model, I need to think about the timing. There’s the diffusion limit, but possibly all sorts of room for play depending on what else is in the proto-cellular environment. Hmmm… lots of food for thought since I don’t know how to do this yet for the systems I’m studying.

 

Two chapters later in Arias’ book, I’m reading about how immortal cancer cells break the Hayflick limit. That’s not news to me. I’d also known about the higher levels of the enzyme telomerase in such cells. What struck me is how to think about it. The perspective Arias provides is that in normally-behaving cells, genes are subject to the rule of the cell. Living is the cell’s business. But in HeLa and other such cells, “the genome, in hijacking the cell, puts itself first.” But this isn’t the immortality you want because it’s not eternal youth. The cells are aging and going uncontrollably haywire.

 

I’ve been focusing on autocatalytic cycles in my research. I think they’re crucial to how life started and they kill two birds with one stone by explaining both growth and selectivity simultaneously. But it’s a Goldilocks situation. Autocatalysis quickly vacuums up food and the cycle expands into hypercycles. Parasitic reactions begin to temper this, but too much parasitism on the cycles and the system collapses. I’m starting to think that the autocatalytic cycle run amok is analogous to what these cancers are doing. Can autocatalytic cycles be tamed? Maybe by introducing positional information and a concentration gradient. I don’t know how to do this either but I now have a glimmer of perhaps how to proceed.

 

And this is why I’m reminded of the value of reading outside my field!

 

P.S. In the same chapter, I’m learning about organoids that can be created from stem cells. Miniguts, minibrains, these seem like the prelude to a Tleilaxu business.