The study published in Cell Stem Cell therefore establishes senescence as a potentially targetable mechanism for future treatment of Down syndrome, said Hiruy Meharena, a new assistant professor at the University of California San Diego who led the work as a Senior Alana Fellow in the Alana Down Syndrome Center at MIT.

“There is a cell-type specific genome-wide disruption that is independent of the gene dosage response,” Meharena said. “It’s a very similar phenomenon to what’s observed in senescence. This suggests that excessive senescence in the developing brain induced by the third copy of chromosome 21 could be a key reason for the neurodevelopmental abnormalities seen in Down syndrome.”

The study’s finding that neural progenitor cells (NPCs), which develop into major cells in the brain including neurons, have a senescent character is remarkable and novel, said senior author Li-Huei Tsai, but it is substantiated by the team’s extensive work to elucidate the underlying mechanism of the effects of abnormal chromosome number, or aneupoloidy, within the nucleus of the cells.

“This study illustrates the importance of asking fundamental questions about the underlying mechanisms of neurological disorders,” said Tsai, Picower Professor of Neuroscience, director of the Alana Center, and of The Picower Institute for Learning and Memory at MIT. “We didn’t begin this work expecting to see senescence as a translationally relevant feature of Down syndrome, but the data emerged from asking how the presence of an extra chromosome affects the architecture of all of a cell’s chromosomes during development.”

Genomewide changes

Meharena and co-authors spent years measuring distinctions between human cell cultures that differed only by whether they had a third copy of chromosome 21. Stem cells derived from volunteers were cultured to turn into NPCs. In both the stem cells and the NPCs, the team examined 3D chromosome architecture, several metrics of DNA structure and interaction, gene accessibility and transcription, and gene expression. They also looked at the consequences of the gene expression differences on important functions of these developmental cells, such as how well they proliferated and migrated in 3D brain tissue cultures. Stem cells were not particularly different, but NPCs were substantially affected by the third copy of chromosome 21.

Overall, the picture that emerged in NPCs was that the presence of a third copy causes all the other chromosomes to squish inward, not unlike when people in a crowded elevator must narrow their stance when one more person squeezes in. The main effects of this “chromosomal introversion,” meticulously quantified in the study, are more genetic interactions within each chromosome and less interactions among them. These changes and differences in DNA conformation within the cell nucleus lead to changes in how genes are transcribed and therefore expressed, causing important differences in cell function that affect brain development.

Treated as senescence

For the first couple of years as these data emerged, Meharena said, the full significance of the genomic changes were not apparent, but then he read a paper showing very similar genomic rearrangement and transcriptional alterations in senescent cells.

After validating that the Down syndrome cells indeed bore such a similar signature of transcriptional differences, the team decided to test whether anti-senolytic drugs could undo the effects. They tested a combination of two: dasatinib and quercetin. The medications improved not only gene accessibility and transcription, but also the migration and proliferation of cells.

That said, the drugs have very significant side effects — dasatinib is only given to cancer patients when other treatments have not done enough — so they are not appropriate for attempting to intervene in brain development amid Down syndrome, Meharena said. Instead an outcome of the study could be to inspire a search for medications that could have anti-senolytic effects with a safer profile.

Senescence is a stress response of cells. At the same time, years of research by former MIT biology professor Angelika Amon, who co-directed the Alana Center with Tsai, has shown that aneuploidy is a source of considerable stress for cells. A question raised by the new findings, therefore, is whether the senescence-like character of Down syndrome NPCs is indeed the result of an aneuploidy induced stress and if so, exactly what that stress is.

Another implication of the findings is how excessive senescence among brain cells might affect people with Down syndrome later in life. The risk of Alzheimer’s disease is much higher at a substantially earlier age in the Down syndrome population than among people in general. In large part this is believed to be because a key Alzheimer’s risk gene, APP, is on chromosome 21, but the newly identified inclination for senescence may also accelerate Alzheimer’s development.

The Alana Foundation, the LuMind Foundation, Burroughs Wellcome Fund, UNCF-Merck and the National Institutes of Health funded the research.

“People may wonder why our team is working on fingerprints,” says Sijia Wang, a geneticist at the Shanghai Institute of Nutrition and Health, of Chinese Academy of Sciences, and co-senior author on the paper. “We started the work purely out of curiosity. But later it turns out fingerprint pattern is associated with genes for limb growth, which are critical for fetal development. This provides another classic example of pleiotropy, when multiple phenotypes are interrelated to each other and are affected by the same genes.”

While fingerprints are unique to individuals, they are generally categorized into three types: arch, loop, and whorl. These furrows and ridges begin to form on a fetus’ fingers and toes after the third month of pregnancy. Scientists have suspected that fingerprints have potentially evolved to help grab objects and sense their textures, but exactly how these patterns are formed remains unknown.

Wang and colleagues scanned the DNA of more than 23,000 people across ethnic groups and found that at least 43 regions on the genome are associated with fingerprint patterns. One of the most influential regions appeared to be regulating the expression of a gene called EVI1, which is known for its role in embryonic limb development.

To test their finding, the team modified the DNA of mice so their expression of EVI1 was turned down. They found that mice with downregulated EVI1 developed abnormal skin patterns on their digits compared with wild-type mice.

Analysis of human data revealed that fingerprint patterns are genetically correlated with finger length. For example, people with whorl-shaped fingerprints on both of their little fingers tend to have longer little fingers than those who do not, and this correlation is strongly linked to genes involved ini limb development.

“We don’t know exactly how the genes shape fingerprint patterns, but it could be determined by the amount of strength from growth that’s put on an embryonic tissue called volar pads that plays an important role in the formation of different patterns of fingerprint,” says Jinxi Li, a geneticist at the Human Phenome Institute at Fudan University in Shanghai, and a co-first author on the paper. She explains that as a fetus’ hands grow, the palms and fingers would stretch and elongate. These forces could turn a whorl into a loop, for example.

Notably, previous research has suggested that EVI1 is linked to risk of leukemia, and some studies have observed that people with more whorl patterns are more susceptible to the disease,” Wang says.

“Many congenital genetic disorders are related to different dermatoglyphic patterns, such as fingerprints,” he says. For example, children with Down’s syndrome are more likely to have a single crease running across the palm of their hands. “Our study suggests that dermatoglyphic patterns are affected by crucial development genes, which provides a strong theoretical basis for this kind of pleiotropy.”

The research is part of the International Human Phenome Project led by Fudan University in Shanghai that aims to map how the human phenotypical traits are correlated with each other. Next, the team plans to conduct more research on how dermatoglyphic patterns are related to diseases and the underlying pleiotropic mechanism.

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HGT is the movement of genetic material between disparate groups of organisms, rather than by the “vertical” transmission of DNA from parent to offspring. Previous studies have looked at HGT between bacteria and their viruses and have shown that it plays a major role in the movement of genes between bacterial species. However the new study, published in Nature Microbiology, looks at interactions between viruses and eukaryotes, which include animals, plants, fungi, protists and most algae.

“We knew from individual examples that viral genes have played a role in the evolution of eukaryotes. Even humans have viral genes, which are important for our development and brain function,” said the study’s lead author, Dr. Nicholas Irwin, a Junior Research Fellow at Merton College, University of Oxford, and former PhD student at the University of British Columbia (UBC). “We wanted to understand more broadly how HGT has affected viruses and eukaryotes from across the tree of life.”

To tackle this problem, the authors examined viral-eukaryotic gene transfer in the genomes of hundreds of eukaryotic species and thousands of viruses. They identified many genes that had been transferred and found that HGT from eukaryotes to viruses was twice as frequent as the reverse direction.

“We were interested to find that certain groups of viruses, especially those that infect single-celled eukaryotes, acquire a lot of genes from their hosts,” said the study’s senior author, Dr. Patrick Keeling, a professor in the Department of Botany at UBC. “By studying the function of these genes we were able to make predictions about how these viruses affect their hosts during infection.”

In contrast to viruses, eukaryotic organisms retained fewer viral genes, although the ones that were kept appear to have had a major impact on host biology over evolutionary time.

“Many of these viral-derived genes appear to have repeatedly affected the structure and form of different organisms, from the cell walls of algae to the tissues of animals,” said Dr. Irwin. “This suggests that host-virus interactions may have played an important role in driving the diversity of life we see today.”

“These transfers not only have evolutionary consequences for both virus and host, but could have important health implications,” Dr. Keeling said.

HGT allows genes to jump between species including viruses and their hosts. If the gene does something useful, it can sweep through the population and become a feature of that species. This can lead to a rapid emergence of new abilities, as opposed to the more incremental changes that result from smaller mutations.

Although viruses such as Zika and coronaviruses do not appear to participate in these gene transfers, they often manipulate similar genes in their hosts through complex mechanisms. Future research into these transferred genes may therefore provide a novel approach for understanding the infection processes of these and other viruses which could be important for drug discovery.

“The past two years have clearly demonstrated the destructive potential of viruses, but we think that this work serves as an interesting reminder that viruses have also contributed to the evolution of life on Earth,” said Dr. Irwin.

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“In the solar system, something happened to prevent the Earth from growing to become a much larger type of terrestrial planet called a super-Earth,” said Rice University astrophysicist André Izidoro, referring to the massive rocky planets seen around at least 30% of sun-like stars in our galaxy.

Izidoro and colleagues used a supercomputer to simulate the solar system’s formation hundreds of times. Their model, which is described in a study published online in Nature Astronomy, produced rings like those seen around many distant, young stars. It also faithfully reproduced several features of the solar system missed by many previous models, including:

• An asteroid belt between Mars and Jupiter containing objects from both the inner and outer solar system.
• The locations and stable, almost circular orbits of Earth, Mars, Venus and Mercury.
• The masses of the inner planets, including Mars, which many solar system models overestimate.
• The dichotomy between the chemical makeup of objects in the inner and outer solar system.
• A Kuiper belt region of comets, asteroids and small bodies beyond the orbit of Neptune.

The study by astronomers, astrophysicists and planetary scientists from Rice, the University of Bordeaux, Southwest Research Institute in Boulder, Colorado, and the Max Planck Institute for Astronomy in Heidelberg, Germany, draws on the latest astronomical research on infant star systems.

Their model assumes three bands of high pressure arose within the young sun’s disk of gas and dust. Such “pressure bumps” have been observed in ringed stellar disks around distant stars, and the study explains how pressure bumps and rings could account for the solar system’s architecture, said lead author Izidoro, a Rice postdoctoral researchers who received his Ph.D. training at Sao Paulo State University in Brazil.

“If super-Earths are super-common, why don’t we have one in the solar system?” Izidoro said. “We propose that pressure bumps produced disconnected reservoirs of disk material in the inner and outer solar system and regulated how much material was available to grow planets in the inner solar system.”

Pressure bumps

For decades, scientists believed gas and dust in protoplanetary disks gradually became less dense, dropping smoothly as a function of distance from the star. But computer simulations show planets are unlikely to form in smooth-disk scenarios.

“In a smooth disk, all solid particles — dust grains or boulders — should be drawn inward very quickly and lost in the star,” said astronomer and study co-author Andrea Isella, an associate professor of physics and astronomy at Rice. “One needs something to stop them in order to give them time to grow into planets.”

When particles move faster than the gas around them, they “feel a headwind and drift very quickly toward the star,” Izidoro explained. At pressure bumps, gas pressure increases, gas molecules move faster and solid particles stop feeling the headwind. “That’s what allows dust particles to accumulate at pressure bumps,” he said.

Isella said astronomers have observed pressure bumps and protoplanetary disk rings with the Atacama Large Millimeter/submillimeter Array, or ALMA, an enormous 66-dish radio telescope that came online in Chile in 2013.

“ALMA is capable of taking very sharp images of young planetary systems that are still forming, and we have discovered that a lot of the protoplanetary disks in these systems are characterized by rings,” Isella said. “The effect of the pressure bump is that it collects dust particles, and that’s why we see rings. These rings are regions where you have more dust particles than in the gaps between rings.”

Ring formation

The model by Izidoro and colleagues assumed pressure bumps formed in the early solar system at three places where sunward-falling particles would have released large amounts of vaporized gas.

“It’s just a function of distance from the star, because temperature is going up as you get closer to the star,” said geochemist and study co-author Rajdeep Dasgupta, the Maurice Ewing Professor of Earth Systems Science at Rice. “The point where the temperature is high enough for ice to be vaporized, for example, is a sublimation line we call the snow line.”

In the Rice simulations, pressure bumps at the sublimation lines of silicate, water and carbon monoxide produced three distinct rings. At the silicate line, the basic ingredient of sand and glass, silicon dioxide, became vapor. This produced the sun’s nearest ring, where Mercury, Venus, Earth and Mars would later form. The middle ring appeared at the snow line and the farthest ring at the carbon monoxide line.

Rings birth planetesimals and planets

Protoplanetary disks cool with age, so sublimation lines would have migrated toward the sun. The study showed this process could allow dust to accumulate into asteroid-sized objects called planetesimals, which could then come together to form planets. Izidoro said previous studies assumed planetesimals could form if dust were sufficiently concentrated, but no model offered a convincing theoretical explanation of how dust might accumulate.

“Our model shows pressure bumps can concentrate dust, and moving pressure bumps can act as planetesimal factories,” Izidoro said. “We simulate planet formation starting with grains of dust and covering many different stages, from small millimeter-sized grains to planetesimals and then planets.”

Accounting for cosmochemical signatures, Mars’ mass and the asteroid belt

Many previous solar system simulations produced versions of Mars as much as 10 times more massive than Earth. The model correctly predicts Mars having about 10% of Earth’s mass because “Mars was born in a low-mass region of the disk,” Izidoro said.

Dasgupta said the model also provides a compelling explanation for two of the solar system’s cosmochemical mysteries: the marked difference between the chemical compositions of inner- and outer-solar system objects, and the presence of each of those objects in the asteroid belt between Mars and Jupiter.

Izidoro’s simulations showed the middle ring could account for the chemical dichotomy by preventing outer-system material from entering the inner system. The simulations also produced the asteroid belt in its correct location, and showed it was fed objects from both the inner and outer regions.

“The most common type of meteorites we get from the asteroid belt are isotopically similar to Mars,” Dasgupta said. “Andre explains why Mars and these ordinary meteorites should have a similar composition. He’s provided a nuanced answer to this question.”

Pressure-bump timing and super-Earths

Izidoro said the delayed appearance of the sun’s middle ring in some simulations led to the formation of super-Earths, which points to the importance of pressure-bump timing.

“By the time the pressure bump formed in those cases, a lot of mass had already invaded the inner system and was available to make super-Earths,” he said. “So the time when this middle pressure bump formed might be a key aspect of the solar system.”

Izidoro is a postdoctoral research associate in Rice’s Department of Earth, Environment and Planetary Sciences. Additional co-authors include Sean Raymond of the University of Bordeaux, Rogerio Deienno of Southwest Research Institute and Bertram Bitsch of the Max Planck Institute for Astronomy. The research was supported by NASA (80NSSC18K0828, 80NSSC21K0387), the European Research Council (757448-PAMDORA), the Brazilian Federal Agency for Support and Evaluation of Graduate Education (88887.310463/2018-00), the Welch Foundation (C-2035) and the French National Centre for Scientific Research’s National Planetology Program.

“The impacts of climate change and extreme weather events on the grid, mostly in the form of drought and heat waves, are going to get worse under climate change,” said Jordan Kern, assistant professor of forestry and environment resources at NC State. “Even as the West Coast grid moves away from fossil fuels toward wind and solar, these extreme weather events will still impact system reliability and the price of power.”

Published in the journal Earth’s Future, the two studies project future power supply and demand under separate scenarios. In the first study, researchers used computer models to simulate the impacts of climate change on the current power grid in California and the Pacific Northwest. They evaluated the grid’s price and reliability under 11 different climate scenarios between 2030 and 2060, drawing on multiple scientific models for how the climate would change under a “worst-case scenario” of fossil fuel emissions, and another less severe scenario.

“The worst-case scenario is worth looking at even if there’s some evidence that the world is going to reduce fossil fuel emissions enough to avoid it,” Kern said.

The researchers found greater risk of power blackouts in summer and early fall, largely driven by extreme heat in California that causes high demand for power as people cool their homes. They projected there would be shortfall events in all but one scenario where climate change affected power generation in both regions simultaneously.

However, they noted these power shortfalls would remain relatively rare. The maximum under the worst case was 72 hours of West Coast-wide power supply shortages across 31 years.

“As it gets hotter and hotter and hotter, and demand for electricity gets higher, we expect the grid to fail,” Kern said. “Those extreme heat events are going to become much more severe.”

Extreme heat in California would also affect the price and supply of power in the Pacific Northwest. Historically, the regions have shared power.

“If, and that’s a big ‘if,’ historic exchanges of electricity continue, and California has a high demand for electricity because of heat, it could cause the Pacific Northwest to run out of electricity, as they won’t be able to meet their own demand,” Kern said.

They also found climate change could impact the Pacific Northwest directly by limiting supplies of hydropower, which is electricity powered by water. Snow serves as stored power, so reductions in snow or changes in the timing of snowmelt reduce power available in summer.

The biggest effects of climate change on the Pacific Northwest would also be in the late summer or early fall, when the grid is already stressed. Even small decreases in streamflow in September caused by climate change, along with increases in summer demand for power, would be enough to cause more shortfall events in the Pacific Northwest. However, they also projected West Coast-wide shortfall events due to climate impacts on the Pacific Northwest alone to be rare.

In addition to issues of reliability, the researchers also found climate change would increase the price of power. Under the worst case where climate change impacts power supply and demand in both California and in the Pacific Northwest, they expected more hours in which the wholesale price of electricity reaches the cap of $1,000 megawatts per hour in California, especially in late summer. Climate change in California would also have significant impact on prices in the Pacific Northwest.

“When prices go up to $1,000 per megawatt hour, that’s the grid ringing the alarm bell,” Kern said. “They’re making electricity so expensive partly in order to incentivize people to consume less.”

In a second study, researchers evaluated the price of power through 2050 with more renewable energy sources added to the grid, while assuming natural gas power plants would still be in place as back-up. They compared five scenarios for each market: two scenarios that varied the mix of solar and wind by cost; one scenario with more batteries added to store power; a scenario in which many people are adopting electric vehicles; and the status quo trend. They assessed the cost of electricity in these different systems under 100 representative years of both normal and extreme weather events that could occur under historic climate conditions — without additional climate warming.

“With the West Coast grid now, we know certain things about how it will perform because it relies so much on hydropower — that a dry year is a bad and a wet year is good,” Kern said. “What we wanted to know is: as you decarbonize the grid out West, adding electric vehicles, batteries, solar and wind, does that shift at all?”

Even with renewables, they found extreme drought and heat would still drive the extremes in price — with “good” years of the lowest prices driven by mild temperatures and high streamflow, and the highest prices driven by extreme heat or drought.

“When you think about the very worst years, those conditions will still be driven by what drives those events today: lack of water or a heat wave in the middle of the summer,” Kern said. “Adding renewable energy does not change the very worst or best year, but it kind of shifts things around in the middle.”

In California, the future scenario with increased wind energy led to the lowest prices, followed by solar. In the Pacific Northwest, the scenarios with the highest amount of both wind and solar had the lowest prices. Supply shortfalls would be most frequent under the pathway with the greatest demand for electric vehicles.

“As the grid uses more wind and solar, the price goes down because it’s less expensive, and it pushes out natural gas,” Kern said. “The exception is that when you have high demand for power from electric vehicles, demand gets so high, it breaks the system. It’s pretty rare in our models, but it happens when there isn’t much water and there’s a heat wave.”

Kern said the reductions that they projected in greenhouse gas emissions under the five scenarios were “conservative;” their models chart up to 50% de-carbonization through 2050, while most West Coast states have set goals to make more substantial shifts sooner.

“Our key finding was that as the grid decarbonizes, you are still going to be left with that vulnerability to water and heat,” Kern said. “This is a system that can’t run away from that.”

The study, “The Effects of Climate Change on Interregional Electricity Market Dynamics on the U.S. West Coast,” was published online in Earth’s Future on Dec. 7, 2021. In addition to Kern, the other authors were Joy Hill, David E. Rupp, Nathalie Voisin and Gregory Characklis. The study was supported by the National Science Foundation INFEWS program under awards 1639268 T2 and 170082 T1.

The second study, “Technology pathways could help drive the U.S. West Coast grid’s exposure to hydrometerological uncertainty,” was published online in Earth’s Future on Dec. 28, 2022. In addition to Kern, the other authors include Jacob Wessel, Nathalie Voisin, Konstantinos Oikonomou and Jannik Haas. The study was funded by the U.S. Department of Energy Office of Science as part of research in the MultiSector Dynamics, Earth and Environmental System Modeling Program as well as the National Science Foundation INFEWS program award 1639268.