Using this type of model, sometimes called “organs-on-a-chip” or “physiome-on-a-chip,” the research team was able to explore the role of circulating immune cells in ulcerative colitis and other inflammatory diseases. They also discovered that a metabolic byproduct generated by bacteria living in the human gut plays an important role under these inflammatory conditions.

“We’ve shown that now you can start to attack some of these really thorny, chronic inflammatory diseases by designing experiments in these organs on chips,” says Linda Griffith, the School of Engineering Professor of Teaching Innovation, a professor of biological engineering and mechanical engineering, and the senior author of the study.

This approach, described today in the journal Cell Systems, could also lend itself to studying many other complex diseases, the researchers say.

“Now we have options to really decrease or increase the level of disease complexity, under controlled and systematic conditions,” says Martin Trapecar, an MIT postdoc and the lead author of the paper.

Complex models

Nearly 20 years ago, Griffith’s lab first began working on a model of the human liver known as the “liver chip.” This system, which consists of engineered human liver tissue grown on a specialized scaffold, can be used to test drug toxicity. More recently, she has been working on small-scale replicas of many interconnected organs, also known as microphysiological systems (MPS). In 2018, she reported the development of a platform that could be used to model interactions between up to 10 organs at a time.

These kinds of devices are well-suited for analyzing complex diseases, including those that involve multiple organs, are influenced by the immune system, or cannot be accounted for by a single gene or small number of genes.

“We wanted to build technologies that would let you connect several organ systems together, so that we could start to develop new tools to combat chronic inflammatory diseases,” Griffith says. “In drug development, the field really struggles with anything that’s not a single-gene disease.”

In the new Cell Systems study, she and Trapecar set out to model interactions between two organs, the colon and the liver. They also wanted to study how the immune system, especially T cells, influences those organs. It is already known that up to 80 percent of patients with a chronic liver autoimmune disease called primary sclerosing cholangitis also suffer from inflammatory bowel disease (IBD). And, patients with IBD have a much greater chance of developing autoimmune disorders of the liver.

The new system contains colon cells taken from patients with ulcerative colitis, along with healthy liver cells. The researchers found that when these tissues were connected, their physiological behavior completely changed as compared to when they are isolated. Inflammation in ulcerative colitis gut tissue decreased when the tissue was exposed to healthy liver cells. At the same time, genes and cellular pathways involved in metabolism and immune function became more active in both organs.

The researchers then added two types of T cells to the system: CD4+ T regulatory cells, which suppress other immune cells, and TH17 cells, which stimulate inflammation. Adding these T cells to the gut-liver interaction quickly increased inflammation and recreated certain features of both IBD and autoimmune liver diseases.

Lastly, the researchers decided to investigate the potential role of molecules called short-chain fatty acids (SCFAs) in inflammatory disease. These molecules are produced by microbes in the human gut as they feast on undigested fiber. SCFAs, which include butyrate, propionate, and acetate, are produced in large quantities and account for about 10 percent of our daily energy needs.

While these compounds have many beneficial effects in the human body, including reducing inflammation, a few studies in recent years have suggested that SCFAs can also cause harm by stimulating inflammation. The new MIT study found that adding SCFAs to the ulcerative colitis model greatly exacerbated inflammation throughout the liver and gut, but only if T cells were already present.

“The hypothesis we formed, based on these studies, is that the role of short chain fatty acids seems to depend on how much the adaptive immune system (which includes T cells) is involved,” Trapecar says.

That is, in early stages of inflammation, when T cells are not heavily involved, SCFAs can help reduce inflammation. But when many effector T cells are recruited, SCFAs stimulate them to be even more inflammatory. This could be useful in cases of infection, to help the body to fend off invaders, but it can also accelerate autoimmune disorders.

Modeling brain disorders

This study grew out of a related project in which the researchers planned to look at interactions between the gut, liver, and brain. A recent study from Sarkis Mazmanian, a professor of microbiology at Caltech, showed that in a mouse model of Parkinson’s, germ-free mice developed signs of the disease later than those housed under regular conditions. The study suggested that SCFAs produced by microbes might contribute to the observed phenomena and progression of the disease.

Griffith’s lab is now working to use the MPS system to shed light on the connection between SCFAs and Parkinson’s disease. The researchers also plan to study other complex diseases, in hopes that their results will help guide the development of new treatments for disorders that are currently difficult to treat.

“You really need very complex models,” Griffith says. “You can certainly get hypotheses from animal models, but to really go forward in drug development, you need better ways to identify targets that build on samples from human patients.”

The research was funded by the U.S. Defense Advanced Research Projects Agency, the National Institutes of Health, the National Institute of Biomedical Imaging and Bioengineering, the National Institute of Environmental Health Sciences, the Koch Institute Support (core) Grant from the National Cancer Institute, and the Pew-Stewart Trust Foundation.

“The image of a black hole actually contains a nested series of rings,” explains Michael Johnson of the Center for Astrophysics | Harvard and Smithsonian (CfA). “Each successive ring has about the same diameter but becomes increasingly sharper because its light orbited the black hole more times before reaching the observer. With the current EHT image, we’ve caught just a glimpse of the full complexity that should emerge in the image of any black hole.”

Because black holes trap any photons that cross their event horizon, they cast a shadow on their bright surrounding emission from hot infalling gas. A “photon ring” encircles this shadow, produced from light that is concentrated by the strong gravity near the black hole. This photon ring carries the fingerprint of the black hole — its size and shape encode the mass and rotation or “spin” of the black hole. With the EHT images, black hole researchers have a new tool to study these extraordinary objects.

“This is an extremely exciting time to be thinking about the physics of black holes,” says Daniel Kapec from the Institute for Advanced Study. “Einstein’s theory of general relativity makes a number of striking predictions for the types of observations that are finally coming within reach, and I think we can look forward to lots of advances in the coming years. As a theorist, I find the rapid convergence between theory and experiment especially rewarding, and I hope we can continue to isolate and observe more universal predictions of general relativity as these experiments become more sensitive.”

The research team included observational astronomers, theoretical physicists, and astrophysicists.

“Bringing together experts from different fields enabled us to really connect a theoretical understanding of the photon ring to what is possible with observation,” notes George Wong, a physics graduate student at the University of Illinois at Urbana-Champaign. Wong developed software to produce simulated black hole images at higher resolutions than had previously been computed and to decompose these into the predicted series of sub-images. “What started as classic pencil-and-paper calculations prompted us to push our simulations to new limits.”

The researchers also found that the black hole’s image substructure creates new possibilities to observe black holes. “What really surprised us was that while the nested subrings are almost imperceptible to the naked eye on images — even perfect images — they are strong and clear signals for arrays of telescopes called interferometers,” says Johnson. “While capturing black hole images normally requires many distributed telescopes, the subrings are perfect to study using only two telescopes that are very far apart. Adding one space telescope to the EHT would be enough.”

“Black hole physics has always been a beautiful subject with deep theoretical implications, but now it has also become an experimental science,” says Alex Lupsasca from the Harvard Society of Fellows. “As a theorist, I am delighted to finally glean real data about these objects that we’ve been abstractly thinking about for so long.”

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Babies born in big cities, on the other hand, typically are less fussy and not as bothered by limits set by their caregivers.

The study, led by Washington State University psychologist Maria Gartstein and WSU graduate student Alyssa Neumann, examines differences in infant temperament, parent-child interactions and parenting stress between families of similar socioeconomic and racial composition in the Inland Northwest and the San Francisco Bay Area.

The researchers found urban moms tend to be better at picking up on when their babies wanted or needed something, or were ready to be done with play, and responding accordingly. This in turn could have led to their infants generally being calmer and less easily upset.

Rural moms reported more frequent expressions of negative emotions from their infants, particularly when they were distressed due to limitations.

The results of Gartstein and Neumann’s work in many ways reflect the findings of previous research investigating differences in child-rearing practices between urban and rural families. However, unlike past studies, which have looked at the effects of living in an urban vs. rural environment on older children, Gartstein and Neumann’s analysis specifically focuses on infants.

“I was shocked, quite frankly, at how little there was in the literature on the effects of raising an infant in a rural vs. urban environment,” Gartstein said. “The fact that rural mothers in our study reported more frequent expressions of anger and frustration from their infants may be consequential as higher levels of frustration in infancy can increase risk for later attentional, emotional, social and behavioral problems.”

Gartstein said the next step in the research will be to try to pinpoint exactly what it is about living in a rural vs. urban context that causes the differences in temperament between the two groups.

“For example, access to mental and behavioral health services and child rearing resources tend to be limited in more rurally situated communities,” she said. “Figuring out what role, if any, these and other locational variables play in an infant’s social emotional development will be the next step in our research.”

For the study, Gartstein, Neumann, and colleagues at the University of Louisville School of Medicine and the Seattle Clinic analyzed and compared data from two previously conducted studies of mother-child interactions and infant temperament.

The first study consisted of 68 participants and their infants in the San Francisco Bay Area, and the second consisted of 120 rural mothers and their infants from Whitman and Latah counties in the Inland Northwest of the United States.

Mothers used a questionnaire to record the frequency of 191 different behaviors their child displayed at six and 12 months after birth. The researchers then analyzed babies along 14 different dimensions that ranged from cuddliness to vocal reactivity.

Parent-child interactions, where mothers were instructed to engage their infants in play in a typical fashion, were also video-recorded in the laboratory for analysis.

Gartstein said one of the more surprising findings from the study was that contrary to predictions, her team found no statistically significant differences in levels of parenting stress between urban and rural caregivers.

“This may be a result of different, but functionally equivalent, risk factors,” Gartstein said. “Whereas living in a big city generally brings more exposure or proximity to violent crime, isolation can also cause a great deal of stress for rural parents. This research opens up a lot of very interesting future avenues of investigation.”

Gartstein’s infant temperament research will also be featured in an episode of the Netflix documentary “Babies” this summer.

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Materials provided by Washington State University. Original written by Will Ferguson. Note: Content may be edited for style and length.

Laura van Holstein, a PhD student in Biological Anthropology at St John’s College, University of Cambridge, and lead author of the research published today (March 18) in Proceedings of the Royal Society, discovered mammal subspecies play a more important role in evolution than previously thought.

Her research could now be used to predict which species conservationists should focus on protecting to stop them becoming endangered or extinct.

A species is a group of animals that can interbreed freely amongst themselves. Some species contain subspecies — populations within a species that differ from each other by having different physical traits and their own breeding ranges. Northern giraffes have three subspecies that usually live in different locations to each other and red foxes have the most subspecies — 45 known varieties — spread all over the world. Humans have no subspecies.

van Holstein said: “We are standing on the shoulders of giants. In Chapter 3 of On the Origin of Species Darwin said animal lineages with more species should also contain more ‘varieties’. Subspecies is the modern definition. My research investigating the relationship between species and the variety of subspecies proves that sub-species play a critical role in long-term evolutionary dynamics and in future evolution of species. And they always have, which is what Darwin suspected when he was defining what a species actually was.”

The anthropologist confirmed Darwin’s hypothesis by looking at data gathered by naturalists over hundreds of years ¬- long before Darwin famously visited the Galapagos Islands on-board HMS Beagle. On the Origin of Species by Means of Natural Selection, was first published in 1859 after Darwin returned home from a five-year voyage of discovery. In the seminal book, Darwin argued that organisms gradually evolved through a process called ‘natural selection’ — often known as survival of the fittest. His pioneering work was considered highly controversial because it contradicted the Bible’s account of creation.

van Holstein’s research also proved that evolution happens differently in land mammals (terrestrial) and sea mammals and bats (non-terrestrial)¬ because of differences in their habitats and differences in their ability to roam freely.

van Holstein said: “We found the evolutionary relationship between mammalian species and subspecies differs depending on their habitat. Subspecies form, diversify and increase in number in a different way in non-terrestrial and terrestrial habitats, and this in turn affects how subspecies may eventually become species. For example, if a natural barrier like a mountain range gets in the way, it can separate animal groups and send them off on their own evolutionary journeys. Flying and marine mammals — such as bats and dolphins — have fewer physical barriers in their environment.”

The research explored whether subspecies could be considered an early stage of speciation — the formation of a new species. van Holstein said: “The answer was yes. But evolution isn’t determined by the same factors in all groups and for the first time we know why because we’ve looked at the strength of the relationship between species richness and subspecies richness.”

The research acts as another scientific warning that the human impact on the habitat of animals will not only affect them now, but will affect their evolution in the future. This information could be used by conservationists to help them determine where to focus their efforts.

van Holstein explained: “Evolutionary models could now use these findings to anticipate how human activity like logging and deforestation will affect evolution in the future by disrupting the habitat of species. The impact on animals will vary depending on how their ability to roam, or range, is affected. Animal subspecies tend to be ignored, but they play a pivotal role in longer term future evolution dynamics.”

van Holstein is now going to look at how her findings can be used to predict the rate of speciation from endangered species and non-endangered species.

Notes to editors: What Darwin said on page 55 in ‘On the Origin of Species’: “From looking at species as only strongly-marked and well-defined varieties, I was led to anticipate that the species of the larger genera in each country would oftener present varieties, than the species of the smaller genera; for wherever many closely related species (i.e species of the same genus) have been formed, many varieties or incipient species ought, as a general role, to be now forming. Where many large trees grow, we expect to find saplings.”

Datasets: Most of the data is from Wilson and Reeder’s Mammal Species Of The World, a global collated database of mammalian taxonomy. The database contains hundreds of years’ worth of work by taxonomists from all over the world. The current way of “doing” taxonomy goes all the way back to botanist Carl Linnaeus (1735), so the accumulation of knowledge is the combined work of all taxonomists since then.