Can you change a chicken into a frog, a fish or a chameleon?

Gastrulation is one of the most important phases in early embryonic development. Before gastrulation, vertebrate embryos are simple two-dimensional sheets of cells. By the end of gastrulation, an embryo will have begun to differentiate distinct cell types, set up the basic axes of the body and internalize some of the precursors for organs in a three-dimensional structure. Amniotes, like chickens and humans, will have developed a primitive streak, the precursor to the brain and skin, while fish and amphibians will have developed a spherical-shaped blastopore.

Gastrulation is a feat of self-organization, requiring the ballet-like coordinated movements of hundreds to tens of thousands of cells.

But, despite its importance in development, scientists only partially understand the underlying mechanisms that coordinate this large-scale movement of cells.

Now a team of researchers from the Harvard, the University of California San Diego and the University of Dundee in the U.K., have developed a theoretical framework that can reproduce and predict the patterns associated with gastrulation in a chicken embryo.

Building on their experimental findings published earlier this year in Science Advances, and using a combination of theory and experiment, the researchers demonstrated that small changes in cell parameters and behavior can have a dramatic impact on the resulting gastrulation patterns.

The new research was also published in Science Advances.

"Linking the developmental processes underlying morphogenesis in an organism to the variations of these same processes across evolution is an old question in biology," said L. Mahadevan, the Lola England de Valpine Professor of Applied Mathematics at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), and Professor of Organismic and Evolutionary Biology, and of Physics in the Faculty of Arts and Sciences (FAS) and senior author of the paper.

"Moving away from the gene-centric molecular focus on this question, we asked if there are emergent biophysical principles that operate on the multi-cellular level and can help explain the self-organized gastrulation patterns from both a developmental and an evolutionary perspective."

Working closely with experimentalists, the researchers developed a theoretical and computational model that could recreate the movement of the epithelial layer of cells in chick embryos during gastrulation.

The team then identified two parameters -- one related to the initial distribution of cells in an embryo and the other related to cell behavior -- to tweak during gastrulation.

"When we changed these two parameters in the model, which was only informed by the mechanisms of chick development, it remarkably showed gastrulation patterns naturally seen in other species," said Mattia Serra, first author of the paper and former Schmidt Science fellow in the Mahadevan group.

Serra is an Assistant Professor in Physics at UC San Diego.

Consistent with the computational results, experiments show that perturbing the same parameters in vivo in a chick embryo caused the chick to form a disk-like blastopore, seen in frogs, a ring-like circular primitive streak, like those seen in fish, or an elongated elliptical canal-like streak seen in chameleon.

"Our work suggests that the general biophysical principles underlying active self-organized flows and forces during embryogenesis have the power to explain developmental processes and their evolutionary variations across different species of vertebrates," said Mahadevan.

"We were surprised to see how simple mechanochemical rules could predict highly distinct coherent flows of thousands of cells measured in a living chick embryo," said Serra.

This research not only sheds light on the principles for self- organization in early development but could also help researchers understand the evolutionary history of developmental processes and suggest ways to control the development of synthetic organoids.

This research looked at the early stages of development, when the embryo is just transforming from two-dimensions into three.

Next, Mahadevan wants to understand what happens when the embryo starts to fold and buckle to create the more complex shapes of organs and eventually whole organisms.

"Using our knowledge of developmental processes at the molecular and cellular level, we eventually hope to provide an integrated framework for how cells form into tissues and tissues into organs, towards a better understanding of morphogenesis," said Mahadevan.

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New research explores future limits of survival and livability in extreme heat conditions

Commonly associated with longer days and slower paces, this summer's record-smashing heat in Arizona demonstrated a concerning future for the planet's warmest season. From power outages endangering entire neighborhoods and heat-related deaths rising among some of the state's most vulnerable populations, the city of Phoenix found itself in national headlines. As national attention grew, one question became clear: How does anyone live there?

The consequences of extreme heat do not affect Arizona residents alone.

Extreme heat made worldwide news this year, including in November when a 23-year-old woman died of cardiorespiratory arrest at a Taylor Swift concert in Brazil where heat indexes that day exceeded 120 degrees.

Jennifer Vanos, associate professor in the School of Sustainability at Arizona State University, studies extreme heat and its health impacts.

She is the lead author of a new paper published Nov. 29 in Nature Communications. Titled "A physiological approach for assessing human survivability and liveability to heat in a changing climate," the paper explores temperatures at which humans can survive.

The research demonstrates that the current estimated upper temperature and humidity limits used for human survivability may not paint an accurate picture of the impacts of a warming planet on human health.

"For the past decade or so we have been using what we call a 'wet bulb temperature' of 35 degrees Celsius, or 95 degrees Fahrenheit, as the limit for human survivability," said Vanos, also a Senior Global Futures Scientist in the Julie Ann Wrigley Global Futures Laboratory.

The wet-bulb temperature limit for human survival indicates the maximum combinations of temperature and humidity that humans can tolerate without suffering inevitable heat stroke over a fixed duration of exposure.

"The idea is that you could survive for up to six hours at that level of heat exposure," Vanos said.

"That number really oversimplifies what happens physiologically in the body when your body is exposed to that temperature, and it doesn't account for important variables like age or other vulnerability factors."

Vanos said the commonly-used wet-bulb temperature for human survivability assumes the person is indoors or shaded, unclothed, completely sedentary, fully heat acclimatized and of an "average size." These assumptions do not align, in most cases, with how humanity navigates the summer season.

The paper models scenarios that adjust for factors such as humidity, age, activity level and sun exposure, and provides a range of safe temperatures based on a series of characteristics.

"We didn't only want to better understand the conditions that people could survive in," Vanos said.

"We wanted to understand the conditions that allowed people to live their lives. If the only safe way to live in an area is to be completely sedentary, people won't want to live there. Being able to spend time outdoors and live your life without seeing a sustained rise in core temperature is a really important metric to understand today and as we move into the future."

Vanos said Gisel Guzman Echavarria, an ASU student, was instrumental in creating the figures used throughout the paper to demonstrate the research findings.

The research, funded by the National Science Foundation, was conducted by a combination of climate scientists and physiologists, a collaboration that Vanos said was crucial in understanding the intertwined nature of heat and human health.

Ollie Jay, professor and director of the Heat and Health Research Incubator at the University of Sydney, said the combined perspectives allow for a cohesive understanding of exactly how climate outcomes can impact people on the physiological and biophysical level.

"The existing wet-bulb temperature estimate of 35 degrees Celsius is used very commonly, with one example being the Intergovernmental Panel on Climate Change report," said Jay, senior author of the paper.

"These kinds of reports can shape policy efforts, but they are using a model for heat that is a very conservative estimate of what the impacts are going to be on humans. If we start using a more realistic, human-based model, the impacts are going to be more severe. They're going to be more widespread and they're going to happen sooner than we are projecting."

Vanos and Jay agree that the survivability ranges provided in the paper can give an important glimpse into the future: one that includes an increased need for cooling infrastructure, a personalized approach to heat protection and possible heat-driven migration.

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Biophysicists use machine learning to understand, predict dynamics of worm behavior

Caenorhabditis elegans.

Biophysicists have used an automated method to model a living system -- the dynamics of a worm perceiving and escaping pain. The Proceedings of the National Academy of Sciences (PNAS) published the results, which worked with data from experiments on the C. elegans roundworm.

"Our method is one of the first to use machine-learning tools on experimental data to derive simple, interpretable equations of motion for a living system," says Ilya Nemenman, senior author of the paper and a professor of physics and biology at Emory University. "We now have proof of principle that it can be done. The next step is to see if we can apply our method to a more complicated system."

The model makes accurate predictions about the dynamics of the worm behavior, and these predictions are biologically interpretable and have been experimentally verified.

Collaborators on the paper include first author Bryan Daniels, a theorist from Arizona State University, and co-author William Ryu, an experimentalist from the University of Toronto.

The researchers used an algorithm, developed in 2015 by Daniels and Nemenman, that teaches a computer how to efficiently search for the laws that underlie natural dynamical systems, including complex biological ones. They dubbed the algorithm "Sir Isaac," after one of the most famous scientists of all time -- Sir Isaac Newton. Their long-term goal is to develop the algorithm into a "robot scientist," to automate and speed up the scientific method of forming quantitative hypotheses, then testing them by looking at data and experiments.

While Newton's Three Laws of Motion can be used to predict dynamics for mechanical systems, the biophysicists want to develop similar predictive dynamical approaches that can be applied to living systems.

For the PNAS paper, they focused on the decision-making involved when C. elegans responds to a sensory stimulus. The data on C. elegans had been previously gathered by the Ryu lab, which develops methods to measure and analyze behavioral responses of the roundworm at the holistic level, from basic motor gestures to long-term behavioral programs.

C. elegans is a well-established laboratory animal model system. Most C. elegans have only 302 neurons, few muscles and a limited repertoire of motion. A sequence of experiments involved interrupting the forward movement of individual C. elegans with a laser strike to the head. When the laser strikes a worm, it withdraws, briefly accelerating backwards and eventually returning to forward motion, usually in a different direction. Individual worms respond differently. Some, for instance, immediately reverse direction upon laser stimulus, while others pause briefly before responding. Another variable in the experiments is the intensity of the laser: Worms respond faster to hotter and more rapidly rising temperatures.

The researchers fed the Sir Isaac platform the motion data from the first few seconds of the experiments -- before and shortly after the laser strikes a worm and it initially reacts. From this limited data, the algorithm was able to capture the average responses that matched the experimental results and also to predict the motion of the worm well beyond these initial few seconds, generalizing from the limited knowledge. The prediction left only 10 percent of the variability in the worm motion that can be attributed to the laser stimulus unexplained. This was twice as good as the best prior models, which were not aided by automated inference.

"Predicting a worm's decision about when and how to move in response to a stimulus is a lot more complicated than just calculating how a ball will move when you kick it," Nemenman says. "Our algorithm had to account for the complexities of sensory processing in the worms, the neural activity in response to the stimuli, followed by the activation of muscles and the forces that the activated muscles generate. It summed all this up into a simple and elegant mathematical description."

The model derived by Sir Isaac was well-matched to the biology of C. elegans, providing interpretable results for both the sensory processing and the motor response, hinting at the potential of artificial intelligence to aid in discovery of accurate and interpretable models of more complex systems.

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Light used to measure the 'big stretch' in spider silk proteins

While working to improve a tool that measures the pushes and pulls sensed by proteins in living cells, biophysicists at Johns Hopkins say they've discovered one reason spiders' silk is so elastic: Pieces of the silk's protein threads act like supersprings, stretching to five times their initial length. The investigators say the tool will shed light on many biological events, including the shifting forces between cells during cancer metastasis.

"All other known springs, biological and nonbiological, lengthen in a way that is directly proportional to the force applied to them only until they have been stretched to about 20 percent of their original length," notes Taekjip Ha, Ph.D., the study's lead researcher. "At that point, you have to apply more and more force to stretch them the same distance as before. But the piece of the spider silk protein we focused on continues to stretch in direct proportion to the force applied until it reaches its maximal stretch of 500 percent."

Details of the research were published online in the journal Nano Letters on Feb. 5.

Ha, a Bloomberg Distinguished Professor of biophysics and biophysical chemistry at the Johns Hopkins University School of Medicine, says the new discovery came during follow-up to research he and his team, then at the University of Illinois at Urbana-Champaign, described in the journal Nature in 2010, work done in collaboration with cell biologists led by Martin Schwartz, then at the University of Virginia.

The Virginia team set up those experiments by inserting a repeating amino acid sequence -- taken from the spider silk protein known as flagelliform -- into a human protein called vinculin. Vinculin is responsible for internalizing forces outside a cell by bridging the cellular membrane and the actin network within the cell, making it an important mechanical communicator within the cell.

The scientists also flanked the flagelliform insert in vinculin with two fluorescent proteins to light up and "report" what was going on through fluorescence resonance energy transfer, or FRET. FRET occurs when one fluorescent molecule is close enough to another that it activates the second. So, when vinculin was relaxed within a cell, it "glowed" yellow, the color of the second fluorescent protein being activated by the first. As vinculin stretched, it began to glow blue -- the color of the first fluorescent protein -- because the lengthening distance between the two made FRET activation of the yellow protein impossible.

Using regular fluorescence microscopy, the scientists were able to watch the forces acting on vinculin in live cells in real time. But an issue remained: how to translate the changing colors into measurements of force "sensed" by vinculin.

That's where his team came in, says Ha. The researchers attached one end of modified vinculin to a glass plate and the other to a tether made of DNA with a small plastic bead at the end. They then pulled on the bead with what Ha describes as "chopsticks made of light," focusing a beam of light on a tiny spot nearby and generating an attractive force that pulled the bead toward the light source. That way, Ha says, his investigators could link the amount of FRET with the amount of force on vinculin, allowing them to measure the dynamic forces acting on proteins in live cells just by imaging them.

In that earlier study, the team inserted 40 flagelliform amino acids into vinculin, composed of eight repeats of the amino acid sequence GPGGA. In this new study, the scientists wanted to learn more about the flagelliform tool by varying its length, so they created inserts of five and 10 repeats to test alongside the original insert of eight. What they found is that the shortest insert was the most responsive to the widest range of forces, responding with linear increases in length to forces from 1 to 10 piconewtons. (Ha says that 1 piconewton is approximately the weight of a bacterium.)

The team wasn't expecting the spider silk inserts to show such linear behavior because, according to Ha, they don't form well-defined, three-dimensional structures. "Usually, unstructured proteins show disorderly, nonlinear behavior when we pull on them," says Ha. "The fact that these don't act that way means that they will be really useful tools for studying protein mechanics because their behavior is easy to understand and predict."

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