Waiting in the Wings: Computer Model Accurately Predicts Cellular Adaptation

A fruit fly larva developing. Fruit Fly eggs Credit: University of Manchester and Cell (Martin Baron et. al.), used with permission

A fruit fly larva developing in a fruit fly egg.
Credit: University of Manchester and Cell (Shimizu et. al). Used with permission.

On Earth, and likely elsewhere in the Universe, life develops in response to the environment. When the temperature changes or the food source shifts, life reshapes itself in an attempt to survive. This effect is especially well illustrated by a species here on our planet: the fruit fly, whose eggs have an extensive capacity for endurance over a wide range of temperatures.

In a recent attempt to uncover the secret to the fly’s success, our species developed a computer model that predicted the presence of a previously unseen adaptation. The predicted adaptation not only exists, but also elucidates a mechanism that confers robustness to temperature to the fly and possibly, much further down the road, a new way to approach tumors in humans. The secret lies in the activity of a protein-Notch-that exists in flies, in human beings and in every other animal species on the planet.

Member of the genus Drosophila adapt quite literally on the fly. Fruit fly eggs lack the capacity to regulate their own temperature. This leaves them at the mercy of the external environment. Nonetheless, whether the external temperature is 30° C (86°F) or 14° C (57° F), the Drosophila eggs successfully develop into larvae, then into full-fledged flies. How they accomplish this is an intriguing mystery recently addressed by researchers at The Universities of Manchester and Sheffield in England, who focused on signaling—in cells and between cells—as the key to survival.

Here’s why they chose signaling as their focus: every complex species begins with a single cell. We develop every specialized tissue in our bodies from there: eyes and heads on which to place them, legs and torsos, hearts and lungs and, in some cases, wings. How a single cell knows that it needs to become a wing—and how it knows where to go to do so—is through developmental signaling.

The Notch signalling protein, which functions within and between cells to affect how they can adapt to environmental changes. Credit: Wikimedia Commons, By National Institute of Health. U.S. [1] Upload: JWSchmidt. [Public domain], via Wikimedia Commons

The Notch signaling protein, which functions within and between cells to affect how they can adapt to environmental changes. Credit: Wikimedia Commons, By National Institute of Health. U.S. [1] Upload: JWSchmidt. [Public domain], via Wikimedia Commons

“Developmental signaling happens between the cells, that tells them where they are in the organism and what type of cell them need to be,” said Dr. Martin Baron, senior lecturer at the University of Manchester in England, a researcher in the field and senior author on a paper in Cell describing how environmental adaptation in Drosophila eggs.

A fully developed, functioning organism with organs and tissues in the right places is only possible if developmental signaling is working. It turns out that in spite of the remarkable diversity within a species and between species, developmental signaling in all animals boils down to only a handful of different signals.

“Developmental signals turn out to be highly conserved in evolution. You tend to get the same seven or eight basic signals used again and again to control different tissue development,” said Baron, “Flies have the same types of signals that we also use to develop. One of the those signals is a protein called Notch.”

The Notch protein earned its name from the wings of a fruit fly. When one copy of Notch lost the fly’s wings becomes notched, as if little bites have been taken out of them.

The effects of the Notch protein were first noted 100 years ago. The alleles—the genes responsible—were identified shortly thereafter, in 1917, but not sequenced until the 1980’s. We now know that all animal species have the Notch protein—including flies—and that if both copies are missing it’s completely lethal to the fly. When present and functional, the Notch protein works over a wide range of temperatures to help the fly develop wings and other important things.

“Temperature is quite a perturbing environmental variable because it changes the rates of things which ought to affect the strengths of the signals that control development and prevent it developing normally,” said Baron, “[over a wide temperature range] But in fact we know the signals are stable over a wide temperature range which makes development robust to a varying environment.”

Baron and colleagues found some mutant flies whose phenotype—or physical appearance—changed as the temperature changed. When they looked more closely at these mutant flies, it became clear that in these flies as the temperature changed Notch’s behavior was changing, too.

Instead of being insensitive to temperature changes, the strength of the Notch signals were increasing and decreasing due to pressure from the environment.  The flies’ wings were changing in time to the process.

Other things were probably changing as well. As one of the major developmental signals, Notch affects many organs and tissues. Wing development is one of the more easily observed markers for Notch’s activity because Notch controls the boundaries of wing veins-the dark lines that cut across the wings’ surface. Too much Notch signal and the veins go missing. Too little and they became thick.

How Notch controls wing development—and presumably other organ development—is by attaching to cells from the outside.  Part of Notch is then brought into the cell. That part can head into the nucleus—the heart of the cell’s machinery—where it takes control of the cell’s fate, dictating the type of tissue or organ that cell will become.

A model of the portion of the Notch signalling protein that acts as a signal between cells (ligand portion) Credit: Cell, M. Baron et al. Used with Permission.

A model of the portion of the Notch signaling protein that acts as a signal between cells (ligand portion) Credit: Cell, Shimizu et al. Used with Permission.

This is how Notch drives the fate of an animal from the cellular level to the tips of its wings and grants it adaptability at the same time. Baron and colleagues found by studying this pathway in isolated cells that Notch’s signal increased with temperature. At higher temperatures, say 29 °C, Notch was more active as a ligand-a signal between cells- but less active inside the cells themselves. As the temperature dropped, the between-cell activity of Notch dropped, but the inside-cell activity increased. So the overall effect was Notch was to act as a sort of balance to temperature–like a seesaw. When one part of Notch’s activity rose, and the other fell, allowing, in some as-yet unknown way-the developing animal to survive in a wide range of temperatures.

The whole signaling pathway seemed to function a little like a network whose goal was to improve survivability, or robustness, in the face of a changing environment. Baron and his colleagues decided to program some aspects Notch’s networking-for-robustness style into computer model. When they did, something very interesting happened.

The model not only simulated what was happening to the flies at high temperatures, but also predicted that Notch signaling in the mutant flies would become unstable at low temperature.  Based on the model’s predictions, Baron and colleagues went looking for those low-temperature phenotypes in the mutant flies.

They found them. Low-temperature incubated flies took weeks to hatch instead of days, but when they did, it was with the same thick wing veins that occurred at high temperatures. The same robustness proteins were acting to stabilize Notch signaling at both high and low temperature extremes.

The repercussions of a model that predicts Notch function are far-reaching, with potentially significant benefits for our own species. For the purposes of modeling development and disease in humans, fruit flies are a surprisingly decent stand-in.  In their DNA Drosophila harbor analogs to 75% of all known human disease genes. In humans Notch is both an oncogene as well as a tumor suppressor gene. In other words, it prevents or promotes cancer depending, like so many things, on the circumstances.  If we can predict Notch’s behavior inside cells and between them, we might be able to develop approaches to cancer that involve shutting Notch down and revving it up, as needed.

“We just need to keep Notch within the right thresholds,” said Baron.

For Baron and colleagues, the next logical step is to model a multi-cellular system so we can predict better the patterning of the tissues. While we wait in the wings to see what the next models predict, we may find ourselves marveling over the fact that a computer program can make accurate predictions about an animal will look like based on the activities going on in only a single simulated cell.

In and between cells, fundamental functions of Notch and other developmental signals are not yet fully understood. How life itself arises is not yet understood, but how life persists in the face of a changing environment is beginning to be understood: it seems to be a combination of resistance to change and openness to change, by turns.

Notch’s effect on the veins of a fly’s wing as the temperature changes. Credit: Cell, Shimizu et al. Used with Permission.

“In some cases, life has to be robust to environmental change,” said Baron. “But in other cases it has to respond to the environmental change.”

The type of robustness conferred by Notch’s behavior across a range of temperatures is ultimately balanced out by responsiveness in other areas: for example, the availability of food. Fruit flies will change their egg-laying behavior depending upon how many nutrients are available in the environment. This prevents them from attempting to lay eggs in nutrient-poor circumstances. This is Baron’s next area of inquiry: to discover how the food supply affects the Notch signal in cells that regulate egg production.

Overall, the more we know about how the fruit fly adapts, the more we’ll appreciate about life’s capacity to find its way through the ever-changing world, or maybe, by then, worlds.

“It’s a largely under-exploited area of research, and it’s really interesting,” said Baron.

One model, one signal, one Notch at a time, we’re making headway toward understanding the multi-fold mechanisms of life’s adaptation to ever changing circumstances.