Researchers at the Salk Institute compared stem cells created from individuals with ASD against stem cells created from those without ASD to uncover, for the first time, measurable differences in the patterns and speed of development in the ASD-derived cells.

The findings, published January 7, 2019, in the journal Nature Neuroscience, could lead to diagnostic methods to detect ASD at an early stage, when preventive interventions could potentially take place.

“Although our work only examined cells in cultures, it may help us understand how early changes in gene expression could lead to altered brain development in individuals with ASD,” says Salk Professor Rusty Gage, the study’s senior author and president of the Institute. “We hope that this work will open up new ways to study neuropsychiatric and neurodevelopmental disorders.”

For the study, the researchers took skin cells from eight people with ASD and five people without ASD and turned them into pluripotent stem cells — cells that have the ability to develop into any cell type. They then coaxed the stem cells to develop along the path of becoming neurons by exposing them to certain chemical factors.

By using molecular “snapshots” from different developmental stages in the stem cells, the team was able to track genetic programs that switched on in a certain order as the stem cells developed into neurons. This revealed key differences in the cells derived from people with ASD. For instance, the Salk team observed that the genetic program associated with the neural stem-cell stage turned on earlier in the ASD cells than it did in the cells from those without ASD. This genetic program includes many genes that have been associated with higher chances of ASD. In addition, the neurons that eventually developed from the people with ASD grew faster and had more complex branches than those from the control group.

“It’s currently hypothesized that abnormalities in early brain development lead to autism, but the transition from a normally developing brain to an ASD diagnosis is blurred,” says first author Simon Schafer, a postdoctoral fellow in the Gage lab. “A major challenge in the field has been to determine the critical developmental periods and their associated cellular states. This research could provide a basis for discovering the common pathological traits that emerge during ASD development.”

“This is a very exciting finding, and it encourages us to further refine our methodological framework to help advance our understanding of the early cell biological events that precede the onset of symptoms,” adds Gage, who holds the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease. “Studying system dynamics could maximize our chance of capturing relevant mechanistic disease states.”

The researchers say the experiments in this study will lead to more dynamic approaches for studying the mechanisms that are involved in ASD predisposition and progression.

They next plan to focus on the creation of brain organoids, three-dimensional models of brain development in a dish that enable scientists to study the interactions between different types of brain cells.

“The current diagnostic methods are mostly subjective and occur after the emergence of behavioral abnormalities in young children,” Schafer says. “We hope these studies will serve as a framework for developing novel approaches for diagnosis during an early period of child development — long before behavioral symptoms manifest — to have the maximum impact on treatment and intervention.”

Other researchers on the paper were Apua C. M. Paquola, Shani Stern, Monique Pena, Thomas J. M. Kuret, Marvin Liyanage, Abed AlFatah Mansour, Baptiste N. Jaeger, Maria C. Marchetto and Jerome Mertens of Salk; David Gosselin of Université Laval in Quebec City, Canada; Manching Ku of the University of Freiburg in Freiburg, Germany; and Christopher K. Glass of the University of California San Diego.

This work was funded by The James S. McDonnell Foundation, G. Harold & Leila Y. Mathers Charitable Foundation, JPB Foundation, the March of Dimes Foundation, National Institutes of Health (NIH) grants MH095741 and MH090258, The Engman Foundation, Annette C. Merle-Smith, The Paul G. Allen Family Foundation, and The Leona M. and Harry B. Helmsley Charitable Trust. It was also supported by NIH grant P30 014195, the German Research Foundation (DFG) and the Chapman Foundation.

The new planet, named HD 21749b, orbits a bright, nearby dwarf star about 53 light years away, in the constellation Reticulum, and appears to have the longest orbital period of the three planets so far identified by TESS. HD 21749b journeys around its star in a relatively leisurely 36 days, compared to the two other planets — Pi Mensae b, a “super-Earth” with a 6.3-day orbit, and LHS 3844b, a rocky world that speeds around its star in just 11 hours. All three planets were discovered in the first three months of TESS observations.

The surface of the new planet is likely around 300 degrees Fahrenheit — relatively cool, given its proximity to its star, which is almost as bright as the sun.

“It’s the coolest small planet that we know of around a star this bright,” says Diana Dragomir, a postdoc in MIT’s Kavli Institute for Astrophysics and Space Research, who led the new discovery. “We know a lot about atmospheres of hot planets, but because it’s very hard to find small planets that orbit farther from their stars, and are therefore cooler, we haven’t been able to learn much about these smaller, cooler planets. But here we were lucky, and caught this one, and can now study it in more detail.”

The planet is about three times the size of Earth, which puts it in the category of a “sub-Neptune.” Surprisingly, it is also a whopping 23 times as massive as Earth. But it is unlikely that the planet is rocky and therefore habitable; it’s more likely made of gas, of a kind that is much more dense than the atmospheres of either Neptune or Uranus.

“We think this planet wouldn’t be as gaseous as Neptune or Uranus, which are mostly hydrogen and really puffy,” Dragomir says. “The planet likely has a density of water, or a thick atmosphere.”

Serendipitously, the researchers have also detected evidence of a second planet, though not yet confirmed, in the same planetary system, with a shorter, 7.8-day orbit. If it is confirmed as a planet, it could be the first Earth-sized planet discovered by TESS.

In addition to presenting their results at the AAS meeting, the researchers have submitted a paper to Astrophysical Journal Letters.

“Something there”

Since it launched in April 2018, TESS, an MIT-led mission, has been monitoring the sky, sector by sector, for momentary dips in the light of about 200,000 nearby stars. Such dips likely represent a planet passing in front of that star.

The satellite trains its four onboard cameras on each sector for 27 days, taking in light from the stars in that particular segment before shifting to view the next one. Over its two-year mission, TESS will survey nearly the entire sky by monitoring and piecing together overlapping slices of the night sky. The satellite will spend the first year surveying the sky in the Southern Hemisphere, before swiveling around to take in the Northern Hemisphere sky.

The mission has released to the public all the data TESS has collected so far from the first three of the 13 sectors that it will monitor in the southern sky. For their new analysis, the researchers looked through this data, collected between July 25 and Oct. 14.

Within the sector 1 data, Dragomir identified a single transit, or dip, in the light from the star HD 21749. As the satellite only collects data from a sector for 27 days, it’s difficult to identify planets with orbits longer than that time period; by the time a planet passes around again, the satellite may have shifted to view another slice of the sky.

To complicate matters, the star itself is relatively active, and Dragomir wasn’t sure if the single transit she spotted was a result of a passing planet or a blip in stellar activity. So she consulted a second dataset, collected by the High Accuracy Radial velocity Planet Searcher, or HARPS, a high-precision spectrograph installed on a large ground-based telescope in Chile, which identifies exoplanets by their gravitational tug on their host stars.

“They had looked at this star system a decade ago and never announced anything because they weren’t sure if they were looking at a planet versus the activity of the star,” Dragomir says. “But we had this one transit, and knew something was there.”

Stellar detectives

When the researchers looked through the HARPS data, they discovered a repeating signal emanating from HD 21749 every 36 days. From this, they estimated that, if they indeed had seen a transit in the TESS data from sector 1, then another transit should appear 36 days later, in data from sector 3. When that data became publicly available, a momentary glitch created a gap in the data just at the time when Dragomir expected the second transit to occur.

“Because there was an interruption in data around that time, we initially didn’t see a second transit, and were pretty disappointed,” Dragomir recalls. “But we re-extracted the data and zoomed in to look more carefully, and found what looked like the end of a transit.”

She and her colleagues compared the pattern to the first full transit they had originally discovered, and found a near perfect match — an indication that the planet passed again in front of its star, in a 36-day orbit.

“There was quite some detective work involved, and the right people were there at the right time,” Dragomir says. “But we were lucky and we caught the signals, and they were really clear.”

They also used data from the Planet Finder Spectrograph, an instrument installed on the Magellan Telescope in Chile, to further validate their findings and constrain the planet’s mass and orbit.

Once TESS has completed its two-year monitoring of the entire sky, the science team has committed to delivering information on 50 small planets less than four times the size of Earth to the astronomy community for further follow-up, either with ground-based telescopes or the future James Webb Space Telescope.

“We’ve confirmed three planets so far, and there are so many more that are just waiting for telescope and people time to be confirmed,” Dragomir says. “So it’s going really well, and TESS is already helping us to learn about the diversity of these small planets.”

TESS is a NASA Astrophysics Explorer mission led and operated by MIT in Cambridge, Massachusetts, and managed by Goddard. Additional partners include Northrop Grumman, based in Falls Church, Virginia; NASA’s Ames Research Center in California’s Silicon Valley; the Harvard-Smithsonian Center for Astrophysics in Cambridge, Massachusetts; MIT Lincoln Laboratory; and the Space Telescope Science Institute in Baltimore. More than a dozen universities, research institutes, and observatories worldwide are participants in the mission.

“Our study spans 450 million years of evolution, which is how long ago all these species shared a common ancestor,” said Rebecca Young, research associate in UT Austin’s Department of Integrative Biology and first author of the study published today in the journal Proceedings of the National Academy of Sciences.

The authors define monogamy in animals as forming a pair bond with one mate for at least one mating season, sharing at least some of the work of raising offspring and defending young together from predators and other hazards. Researchers still consider animals monogamous if they occasionally mate with another.

The researchers studied five pairs of closely related species — four mammals, two birds, two frogs and two fish — each with one monogamous and one non-monogamous member. These five pairs represent five times in the evolution of vertebrates that monogamy independently arose, such as when the non-monogamous meadow voles and their close relatives the monogamous prairie voles diverged into two separate species.

The researchers compared gene expression in male brains of all 10 species to determine what changes occurred in each of the evolutionary transitions linked to the closely related animals. Despite the complexity of monogamy as a behavior, they found that the same changes in gene expression occurred each time. The finding suggests a level of order in how complex social behaviors come about through the way that genes are expressed in the brain.

This study covers a broader span of evolutionary time than had been explored previously. Other studies have looked at genetic differences related to evolutionary transitions to new traits, but they typically focus on animals separated by, at most, tens of millions of years of evolution, as opposed to the hundreds of millions of years examined with this study.

“Most people wouldn’t expect that across 450 million years, transitions to such complex behaviors would happen the same way every time,” Young said.

The paper’s other UT Austin authors are senior author professor Hans Hofmann and professor Steven Phelps. Researchers examined gene activity across the genomes of the 10 species, using RNA-sequencing technology and tissue samples from three individuals of each species. The scientists detected gene-activity patterns across species using bioinformatics software and the Texas Advanced Computing Center’s Wrangler data-intensive supercomputer. Arranging genes from distantly related species — such as a fish and a mammal — into groups based on sequence similarities, the team was able to identify the common evolutionary formula that led to pair bonds and co-parenting in the five species that behave monogamously.

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