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Creation of new brain cells plays underappreciated role in Alzheimer’s

Creation of new brain cells plays underappreciated role in Alzheimer’s

Much of the research on the underlying causes of Alzheimer’s disease focuses on amyloid beta (Aß), a protein that accumulates in the brain as the disease progresses. Excess Aß proteins form clumps or “plaques” that disrupt communication between brain cells and trigger inflammation, eventually leading to widespread loss of neurons and brain tissue.

Aß plaques will continue to be a major focus for Alzheimer’s researchers. However, innovative research by neuroscientists at the University of Chicago looks at another process that plays an underappreciated role in the progression of the disease.

In a new study published in the Journal of Neuroscience, Prof. Sangram Sisodia, a leading expert on the biology of Alzheimer’s disease, and his colleagues show how in genetic forms of Alzheimer’s, a process called neurogenesis—the creation of new brain cells—can be disrupted by the brain’s own immune cells.

Some types of early onset, hereditary Alzheimer’s are caused by mutations in two genes called presenilin 1 (PS1) and presenilin 2 (PS2). Previous research has shown that when healthy mice are placed into an “enriched” environment where they can exercise, play and interact, they have a huge increase in new brain cells being created in the hippocampus—the part of the brain that is important for memory. But when mice carrying mutations to PS1 and PS2 are placed in an enriched environment, they don’t show the same increase in new brain cells. They also start to show signs of anxiety, a symptom often reported by people with early onset Alzheimer’s.

This led Sisodia to think that something besides genetics had a role to play. He suspected that the process of neurogenesis in mice both with and without Alzheimer’s mutations also could be influenced by other cells that interact with the newly forming brain cells.

The researchers focused on microglia, a kind of immune cell in the brain that usually repairs synapses, destroys dying cells and clears out excess Aß proteins. When the researchers gave the mice a drug that causes microglial cells to die, neurogenesis returned to normal. The mice with presenilin mutations were then placed into an enriched environment and they were fine; they didn’t show any memory deficits or signs of anxiety, and they were creating the normal, expected number of new neurons.

“It’s the most astounding result to me,” said Sisodia, the Thomas Reynolds Sr. Family Professor of Neurosciences at UChicago. “Once you wipe out the microglia, all these deficits that you see in these mice with the mutations are completely restored. You get rid of one cell type, and everything is back to normal.”

“It’s the most astounding result to me … You get rid of one cell type, and everything is back to normal.”

—Prof. Sangram Sisodia

Sisodia thinks the microglia could be overplaying their immune system role in this case. Alzheimer’s disease normally causes inflammation in the microglia, so when they encounter newly formed brain cells with presenilin mutations they may overreact and kill them off prematurely. He feels that this discovery about the microglia’s role opens another important avenue toward understanding the biology of Alzheimer’s disease.

“I’ve been studying amyloid for 30 years, but there’s something else going on here, and the role of neurogenesis is really underappreciated,” he said. “This is another way to understand the biology of these genes that we know significantly affect the progression of disease and loss of memory.”

Additional authors include Sylvia Ortega-Martinez, Nisha Palla, Xiaoqiong Zhang and Erin Lipman from the University of Chicago.

Citation: “Deficits in Enrichment-Dependent Neurogenesis and Enhanced Anxiety Behaviors Mediated by Expression of Alzheimer’s Disease-Linked Ps1 Variants Are Rescued by Microglial Depletion.” Journal of Neuroscience, Aug. 21, 2019. DOI: 10.1523/JNEUROSCI.0884-19.2019

Materials provided by the University of Chicago

Why we’re so emotionally invested in the semicolon

Why we’re so emotionally invested in the semicolon

“The semicolon is a place where our anxieties and our aspirations about language, class and education are concentrated so that in this small mark big ideas are distilled down to a few winking drops of ink,” writes Cecelia Watson, AM’05, PhD’11.

Cecelia Watson

Cecelia Watson, AM’05, PhD’11

That’s a lot of baggage for a half-comma, half-colon, but Watson shows it’s more than up to the task in Semicolon: The Past, Present and Future of a Misunderstood Mark (Ecco, 2019)—a book that already has garnered the Bard College scholar critical acclaim from The New YorkerThe New York Times and National Public Radio.

Tracing the hybrid mark from its origins among 15th-century Italian humanists, her story describes early attempts to “scientize” language through grammar rules and raises questions about who made—and didn’t make—those rules. And with examples drawn from literature, legal history and her own life as a “reformed grammar fetishist,” Watson seeks to persuade readers to learn to love the semicolon. The following Q&A with The University of Chicago Magazine have been edited and condensed.

Why a book on the semicolon?

What really surprised me when I was working on this as an academic topic was the emotional investment people had in the semicolon. Usually when you’re giving an academic talk, everybody does the super professional, very objective, I’m-detached-from-this-topic type of performance. But when I would talk about the semicolon, people would tell me all of these personal stories, even about falling in love because of conversations about the semicolon—not the usual thing you hear when you’re an academic. That clued me in that maybe there was a way to reach out to a broader audience. When we pitched it to publishers, I think we ended up with seven houses in the auction.

Why do some people have such strong negative feelings about this punctuation mark?

Distaste for the semicolon comes from a lot of different angles. Some people have a sheer aesthetic distrust of it. They just like short sentences, for instance. They think that’s more direct or more pleasing in some way, or more clear. The semicolon, of course, can facilitate very long sentences. Other people think it’s elitist, and a reader is going to roll their eyes or feel alienated, and in some ways belittled, by the author’s advertisement of his or her own education level. Others have bad childhood memories associated with trying to use the semicolon and failing and being embarrassed.

Is there a way we could be using semicolons that we aren’t currently?

One use that has fallen out of practice is using the semicolon as a colon or sometimes a comma. You see this a lot in the late 19th or early 20th century. Nobody liked the colon at the time, and everybody loved the semicolon, so they wanted to stick it wherever they could. I think less about particular styles of semicolon usage and more about how easy it is to be lazy and use catch-all punctuation marks. I’ll just put dashes and ellipses for everything. Those are all points at which we could say, “Would a semicolon actually provide some interest here? Would it help create some new rhythms on the page? Would it make anything a little easier to read?”

Your book ranges into broader questions about who gets to dictate the rules of language. How did that happen?

Initially I was focused on where rules come from. A lot of the people who influenced me when I was at UChicago taught me to see that even things we wouldn’t think of as having a history have a history, like a set of punctuation rules. My discipline, history and philosophy of science, had a huge role in the history of the semicolon. A lot of the history of grammar rules is a direct function of this mid- to late-1800s obsession with being scientific and objective. Grammar was not excepted from that.

One thing that I hope the book’s readers notice is that every single person in the section about the founding of grammar is an elite white male. That’s no accident. It’s also no accident that when grammar rules were invented, women, and to some extent people of color and poor people, were gaining unprecedented access to education. Grammar is, and has always been, an incredibly effective way to enforce the status quo.

Materials provided by the University of Chicago

Pritzker School of Molecular Engineering research could lead to new technology

Scientists harness bacteria to create ‘living’ liquid crystals

Liquid crystals are widely used in technologies such as displays, which manipulate their orientation to display colors across the spectrum.

In traditional displays, liquid crystals are stationary and uniform, free of defects. But that stillness can be altered by adding bacteria to the crystals, creating what scientists and engineers call “living liquid crystals”: materials that can act autonomously. As bacteria swim around the liquid crystal, they generate “defects” that can be used for engineering purposes.

Juan de Pablo

Prof. Juan de Pablo

Researchers with the Pritzker School of Molecular Engineering at the University of Chicago, along with colleagues at UChicago-affiliated Argonne National Laboratory, have shown how this material becomes active and disordered through this process, creating floral patterns from the bending instabilities that eventually lead to creation of defects. But the results are not just aesthetic: They are an important step toward understanding how to ultimately control this material for emerging technologies that rely on defect formation.

“The genesis of these instabilities has been a topic of considerable debate, and now we truly understand how this process works, which will ultimately lead to controlling how this material behaves,” said Juan de Pablo, the Liew Family Professor in Molecular Engineering and co-author of the research, recently published in the journal Physical Review X.

Understanding pattern formation

Living liquid crystals are an example of materials that can act on their own. In nature, these materials are responsible for the motility of cells. Proteins within the cells “walk” along the surface of polymer molecules and exert a force that causes displacement and motion.

“There is a lot of interest in these materials because they are complex, beautiful and relevant,” said de Pablo, vice president for national laboratories. “But we want to understand just how motion and transport are generated within them.”

In the lab, one way to create an autonomous material like this is to combine a liquid crystal with bacteria, which then cause disorder among the liquid crystal when they move.

To study how the material becomes active, the researchers combined swimming bacteria with a liquid crystal in two formats: near the bottom surface of a drop suspended from a needle attached to a glass slide, and in a thin, freestanding film.

Though the bacteria and liquid crystal were initially aligned through a magnetic field, when the field was turned off, the bacteria began to move on their own, resulting in “bend instabilities.” These instabilities looked like petals on a flower or branches radiating out from a tree. The number of branches was controlled by the activity of the bacteria.

“Now we truly understand how this process works, which will ultimately lead to controlling how this material behaves.”

—Prof. Juan de Pablo

“The instabilities became more and more prominent as time proceeds, until the system eventually becomes completely disordered,” de Pablo said.

Through these experiments and computational simulations, the researchers discovered how these instabilities form through strain and geometry, and therefore developed a method to create and position the bend instabilities.

Controlling crystals for future technologies

The researchers hope to use this information to be able to fully control these living liquid crystals. That would allow them to eventually create a new kind of microfluidic device that transports fluids autonomously without pumps or pressure, or to create synthetic systems that resemble cells and that could move autonomously from one place to another.

“We have a real possibility to control these materials and use them for interesting new technologies,” de Pablo said.

Other authors include Alexey Snezhko, a physicist at Argonne; Andrey Sokolov, assistant scientist at Argonne; and postdoctoral researchers Ali Mozaffari and Rui Zhang.

Citation: Emergence of Radial Tree of Bend Stripes in Active Nematics. Sokolov et. al. Physical Review X, July 30, 2019. doi: 10.1103/PhysRevX.9.031014

Materials provided by the University of Chicago

Study questions expected link between farming and evolution of immune system

Study questions expected link between farming and evolution of immune system

Researchers have long theorized that cultural shifts thousands of years ago from hunting and gathering to agriculture and living in permanent settlements spurred an increase in diseases like smallpox and measles. Compared to hunter-gatherers, farmers stayed put, living close to one another and their animals.

It’s hypothesized this made it easier for viruses and bacteria to spread among humans or from animals to people. Consequently, it might be expected that the immune systems of people from these farming populations would show more signs of positive natural selection through adaptation to these pathogen conditions.

A new study published in Nature Ecology & Evolution by University of Chicago Medicine genetic researcher Luis Barreiro shows that the opposite is true when comparing farmers and hunter-gatherers in southwest Uganda. Instead, the immune systems of hunter-gatherers showed more signs of positive natural selection, in particular among genes involved in the response to viruses.

“It’s the complete opposite of what we expected, based on the longstanding hypothesis that the advent of agriculture increased selective pressures imposed by pathogens in human populations,” said Barreiro, the study’s senior author and an associate professor in the University’s section of genetic medicine.

Researchers studied the blood of the Batwa, a rainforest hunter-gatherer population from southwest Uganda, and compared it to the blood of their Bantu-speaking agriculturalist neighbors, the Bakiga.

“It’s the complete opposite of what we expected, based on the longstanding hypothesis that the advent of agriculture increased selective pressures imposed by pathogens.”

—Assoc. Prof. Luis Barreiro

White blood cells from the two groups were isolated and exposed to Gardiquimod, which mimics a viral infection, and lipopolysaccharide, which simulates a bacterial infection.

The authors observed increased divergence between hunter-gatherers and agriculturalists in their immune responses to viruses, compared to that for bacterial infections. A significant proportion of these differences were shown to be under genetic control and affected by recent positive natural selection.

“These findings suggest that differences in viral exposure may have been key contributors to the divergence in immune responses between the Batwa and the Bakiga populations, said co-author George Perry, an associate professor of anthropology and biology at Penn State University.

This study marks the first time the immune systems of hunter-gatherers and farmers have been compared to help researchers understand how agriculture may have impacted our immune system. The team spent three years establishing connections and discussing mutual research interests with the Batwa and Bakiga prior to collecting any blood samples. The Batwa have lived in settlements along the edges of the Bwindi Impenetrable Forest since 1991, after being displaced from the rainforest. As a result, the researchers limited their Batwa blood samples to individuals born before 1991 who had actually lived in the forest.

Since collecting the blood samples, the researchers have returned to Uganda multiple times to present the results of their research with these communities.

The researchers cautioned that the Batwa and Bakiga populations likely diverged more than 60,000 years ago, long before the origination and spread of agriculture in Africa. They hope to soon begin similar follow-up studies on additional pairs of hunter-gatherer and farming populations in other areas of the world.

Additional authors include Genelle Harrison and Erwin Schurr of McGill University, Joaquin Sanz and Jonathan Boulais of Université de Montréal, Lluis Quintana-Murci of Institut Pasteur, Jean-Christophe Grenier, Anne Dumaine and Vania Yotova of CHU Sainte-Justine Research Center, Yumei Leng, Stephen Elledge and Michael Mina of Harvard Medical School, Christina Bergey of Penn State and Samuel Nsobya of Makerere University.

Citation: Genelle F. Harrison et al. “Natural selection contributed to immunological differences between hunter-gatherers and agriculturalists.” Nature Ecology & Evolution July 29, 2019. DOI: 10.1038/s41559-019-0947-6

Materials provided by University of Chicago

CT Scan of Brain

Scientists studied the brains of more than 800 prisoners. Here’s what they found

The brains of murderers look different from those of people convicted of other crimes—differences that could be linked to how they process empathy and morality.

Examining brain scans of more than 800 incarcerated men, new research co-authored by a leading University of Chicago neuroscientist found that individuals who had committed or attempted homicide had reduced gray matter when compared to those involved in other offenses. Those reductions were especially apparent in regions of the brain associated with emotional processing, behavioral control and social cognition.

“More gray matter means more cells, neurons and glia,” said Jean Decety, the Irving B. Harris Distinguished Service Professor in Psychology and Psychiatry at UChicago, noting differences in the orbitofrontal cortex and anterior temporal lobes of the brain. “That’s what you need to make computations, to process information—whether it’s emotional information that you use to feel empathy for someone else, or information that you use to control your behavior, to suppress your tendencies to react.”

Aberrant gray matter

The colored sections in this figure highlight brain regions in murderers that exhibit reduced gray matter compared to other violent offenders. The data comes from a study of more than 800 incarcerated men. Image courtesy of Sajous-Turner et al.

A pioneering scholar in the cognitive neuroscience of moral reasoning and social decision-making, Decety’s research has focused both on psychopathy and on childhood moral development. The innovative study is a result of his longtime collaboration with University of New Mexico neuroscientist Kent Kiehl, who helps direct the nonprofit Mind Research Network.

“This work represents more than 10 years of data collection across eight prisons in two states,” Kiehl said. “We are fortunate to present the world’s largest sample of its kind and the results are quite remarkable.”

Published in the journal Brain Imaging and Behavior, the new study relied on structural MRI scans of the brains of men incarcerated in New Mexico and Wisconsin, which the researchers had obtained through previous studies.

Participants were divided into three groups: 203 individuals who were convicted of or self-reported a homicide or homicide attempt; 475 individuals who had committed aggravated battery/assault, armed robbery or other violent crimes; and 130 individuals involved in non-violent or minimally violent crimes.

Researchers excluded from the homicide group those who had been convicted as accomplices, as well as those whose criminal files or court records indicated a strong possibility of accidental death.

Although previous neuroimaging studies also have examined brains of murderers, this is the first research that uses such a large sample and that controls for factors like psychosis—excluding individuals who suffered brain injuries or psychiatric disorders such as schizophrenia.

“More gray matter means more cells, neurons and glia…that’s what you need to make computations, to process information.”

—Prof. Jean Decety

In addition to Decety and Kiehl, other researchers on the study include first author Ashly Sajous-Turner, a University of New Mexico post-baccalaureate scholar; and Michael Koenigs of the University of Wisconsin.

However, the scholars note that they do not have enough evidence to draw a causal relationship between reduced gray matter and homicide. Ongoing research by Kiehl and Decety is following up a large sample of ultra high-risk boys—now in their mid-20s—to determine if the brain regions identified in this sample are predictive of future homicidal behavior. This work, the scholars feel, would help determine whether or not the results are causal.

Citation: “Aberrant brain gray matter in murderers,” Sajous-Turner et al., Brain Imaging and Behavior, July 5, 2019. DOI: 10.1007/s11682-019-00155-y

Materials provided by the University of Chicago

Scientists combine light and matter to make particles with new behaviors

Scientists combine light and matter to make particles with new behaviors

Every type of atom in the universe has a unique fingerprint: It only absorbs or emits light at the particular energies that match the allowed orbits of its electrons. That fingerprint enables scientists to identify an atom wherever it is found. A hydrogen atom in outer space absorbs light at the same energies as one on Earth.

While physicists have learned how electric and magnetic fields can manipulate this fingerprint, the number of features that make it up usually remains constant. In work published July 3 in the journal Nature, the University of Chicago researchers challenged this paradigm by shaking electrons with lasers to create “doppelganger” features at new energies—a breakthrough that lets scientists create hybrid particles which are part-atom and part-light, with a wide variety of new behaviors.

The research is part of a greater effort in Assoc. Prof. Jonathan Simon’s lab to break down the walls between matter and light, in order to investigate their fundamental properties. In addition to learning about how materials behave at the quantum level, this work could one day help create more powerful computers or virtually “unhackable” quantum communications.

One step along the way to making matter out of light is to make individual packets of light, called photons, interact with each other like matter does. (Normally photons zip along at the speed of light and don’t react to each other at all.)

“In order to make photons collide with one another, we use atoms as a go-between,” said postdoctoral researcher Logan Clark, who led the research. “But we were running into a problem because the photons only interact with atoms whose electronic orbitals are at very particular energies. So we asked: What if we could make copies of the orbitals at whatever energies we wanted?”

Clark had already developed techniques to manipulate quantum matter by shaking it —called Floquet engineering—as part of his PhD project. The right sort of shaking naturally produces copies of quantum states at multiple energies along the way. “We had always viewed the copies as a side effect rather than the goal,” he said, “but this time, we shook our electrons with the specific intent of making the copies.”

“We asked: What if we could make copies of the orbitals at whatever energies we wanted?”

—Postdoctoral researcher Logan Clark

By varying the intensity of a laser field tuned precisely to an atomic resonance, the team was able to shift the orbitals of an electron. Shaking the orbitals by periodically varying this intensity produced the desired copies.

But these doppelgangers come with an important catch: “While the atomic orbital does appear at multiple distinct energies, it is important to note that these copies are actually bound to the original like puppets,” explained postdoctoral researcher Nathan Schine, a co-author on the study. “When any of the copies shifts, the original and all of the other copies shift with it.”

By allowing photons to interact with these shaken atoms, the team has created what they call “Floquet polaritons”—quasi-particles which are part-light and part-atom, and unlike regular photons, interact with each other quite strongly. These interactions are essential for making matter from light. Making polaritons with shaken atoms can give the polaritons much more flexibility to move around and collide with each other in new ways.

“Floquet polaritons are full of surprises; we’re still continuing to understand them better,” Clark said. “Our next order of business, though, will be to use these colliding photons to make topological ‘fluids’ of light. It is a tremendously exciting time.”

Having copies of an atomic state at multiple energies also offers exciting possibilities for optical frequency conversion—a key tool in creating secure quantum communication methods.

“It turns out shaking things is not only a lot of fun, but can lead to some really fascinating science,” Clark said.

Citation: “Interacting Floquet polaritons.” Clark et al, Nature, July 3, 2019. DOI: 10.1038/s41586-019-1354-5

Materials provided by the University of Chicago

Researchers pioneer method to purify water using solar energy

Researchers pioneer method to purify water using solar energy

As the global population grows, fresh water supplies are more precious than ever. While scientists and engineers know how to purify water, making those methods sustainable and energy efficient is another question.

One promising approach is solar-driven distillation, or solar steam generation, which can help us get fresh water from wastewater or seawater. Researchers have used this method to successfully distill small batches of purified water, but they are still searching for a way to do this on a large scale.

Researchers at the University of Chicago’s Pritzker School of Molecular Engineering and UChicago-affiliated Argonne National Laboratory were part of a team that developed a pioneering new method of solar steam generation that could help bring this technology into the real world. The materials can be grown on top of wood, fabric or sponges in an easy, one-step process, and show promise for large-scale manufacturing.

“Solar steam generation techniques are still mostly focused on lab use now,” said Zijing Xia, a graduate student at Pritzker Molecular Engineering and lead author of the research. “We want to find an easy way to fabricate solar steam generators at relatively low cost.”

The results of their innovative work were recently published in the journal Advanced Materials Interfaces.

“We want to find an easy way to fabricate solar steam generators at relatively low cost.”

—Graduate student and study lead author Zijing Xia

In the search for solar steam systems, researchers have already tried various materials which convert light to heat, such as carbon materials, plasmonic metals and semiconductors. But many of these options have relatively low efficiency, among other challenges, and so the search continues for a truly transformative method.

A high-performance solar steam generator will ideally combine several characteristics. It should be buoyant on water, be able to absorb a broad spectrum of light, convert light to heat efficiently and be able to transfer that heat to water. Unfortunately, many previously studied methods lack the porous structure needed to facilitate the heat transfer to water.

“Most existing methods cannot be easily engineered to produce steam-generating devices with both arbitrary control over the shape and high photothermal efficiency,” Xia said.

What sets Xia’s method apart is the use of a porphyrin covalent organic framework, or POF. A newly discovered class of materials, POFs can grow uniformly on the surface of a variety of materials with different levels of porosity, and they show high performance for water evaporation. POFs also have unique light-harvesting characteristics beneficial for new applications.

In the lab, POFs successfully grew on the inner and outer surfaces of every tested material. And every template showed favorable photothermal properties, indicating that POF-based materials are promising candidates for solar steam generation. The POF membrane was able to capture more than 95% of light across the majority of the spectrum of sunlight.

The most promising result of the research, Xia said, was the POFs’ ability to grow at the surface of many different kinds of materials, including membranes, fabrics, sponges and wood. The wood showed particularly strong performance, with researchers measuring roughly 80% light-to-steam conversion efficiency.

Solar Steam Illustration

An illustration of water evaporation through the POF‐based materials. (Credit: Zijing Xia et al)

The ability of POFs to grow on many types of materials makes them easily adaptable for use with locally available materials. This versatility, coupled with the easy, one-step fabrication process, could make the method practical for large-scale production.

The POF-based approach proved highly effective in a lab setting, and the research team plans to conduct further experiments outside the lab to observe the practical performance of POFs.

So far, the research suggests POFs could help drive the sustainable water purification systems of the future.

“POF-based interface engineering design shows promise for large-scale purification methods, and it could also be used for desalination, wastewater treatment and beyond,” Xia said.

Other authors of the paper include PME graduate students Ruben Z. Waldman and Chao Zhang, PME professor and Argonne scientist Shrayesh Patel, and Argonne scientist and PME fellow Seth Darling. Additional authors include Zhaowei Chen of Argonne, Hao-Cheng Yang of Sun Yat-sen University and Yusen Zhao of UCLA.

Citation: “Porphyrin Covalent Organic Framework (POF)-Based Interface Engineering for Solar Steam Generation.” Zijing Xia et al. Advanced Materials Interfaces. Doi: 10.1002/admi.201900254

Funding: The Advanced Materials for Energy-Water Systems (AMEWS) Center

Materials provided by the University of Chicago

CRISPR Cas9

Using human genome, scientists build CRISPR for RNA to open pathways for medicine

Less than a decade ago, biology underwent one of those once-in-a-generation events that shakes up a scientific field, when the discovery of gene editing technology called CRISPR/Cas-9 made it possible to precisely alter the sequence of DNA in a living being.

But while DNA may be the raw blueprints for life, RNA is the architect—translating those ideas into reality for the cell through proteins and regulation. While CRISPR systems that target RNA have recently been discovered, none offers a single clear solution.

A group of scientists from the University of Chicago has announced a breakthrough method to alter RNA—and instead of using a protein from bacteria, like CRISPR, the new system is built out of parts from the human genome. Announced June 20 in Cell, the discovery could open new pathways for treating diseases or injuries by temporarily altering how the genetic template is carried out in the cell.

“People had delayed targeting RNA for a long time because it’s so complex in how it works,” said study author Bryan Dickinson, an associate professor of chemistry at UChicago. “But I think now we’re realizing that complexity is an opportunity to figure out how to exploit and change those pathways. In principle, you could make even more dramatic changes to the cell than with DNA, and now we finally have the tools to do so.”

Even as DNA-targeting CRISPR methods begin their initial clinical trials in humans, scientists have become increasingly interested in equivalent systems for RNA. An RNA-targeting method that can safely be applied to humans would be a valuable complement to CRISPR, Dickinson said.

“If you imagine the universe of diseases that CRISPR is going to correct, it’ll be really important ones, but only those that are based off of one single mutation in your DNA,” said Dickinson, whose work tries to create functional molecules that lead to biological breakthroughs. “There are many more diseases out there with multiple causes in the cell, which may be much more difficult to understand—and there will also be those where the risks associated with changing someone’s DNA permanently are just too high.”

Because the effects of RNA alteration are temporary rather than permanent, an RNA-CRISPR is inherently less risky, because doctors can simply stop the treatment if there are intolerable side effects. It could also be used for things like briefly boosting a person’s system to accelerate wound healing: “We know what to do for that—you would encourage processes for cell growth and proliferation,” Dickinson said. “But those are the same things that cause cancer, so you could never do that at the DNA level.”

But translating these microbial systems into therapeutics is going to be challenging, he said. “RNA-targeting drugs need to be continually administered, so the foreign nature of CRISPR/Cas systems it going to create an immune backlash when applied to humans.”

This presents key roadblocks for natural CRISPR systems, which Dickinson’s team realized it had an opportunity to correct by reengineering the whole system from scratch.

“In principle, you could make even more dramatic changes to the cell than with DNA, and now we finally have the tools to do so.”

—Assoc. Prof. Bryan Dickinson on targeting RNA

Because it’s a very large protein, CRISPR is generally too big to use the most common delivery system to insert genetic material into cells—“phages,” which originate from tiny viruses. This is a problem, especially if you need to deliver them continually. More critically, because CRISPR comes from a microbe, there are significant concerns about the human immune system reacting to it.

Instead, the team broke down CRISPR into its components based on what each part does, and looked for human versions of those proteins that did equivalent tasks. Then they cobbled those together into a cohesive whole—which is smaller than CRISPR, and made out of human material.

“Although there’s still a lot of work to do, the crazy thing is it actually works,” Dickinson said.

Their system succeeded in altering RNA in tests in the lab. The scientists plan to improve the system at a few points where the performance is not as good as CRISPR, they said, but they’re encouraged by the early results.

“As we learn more, you could imagine targeting multiple RNAs in different ways, and doing more complex reprogramming of the cell at the RNA level,” Dickinson said. “It’s a really exciting field right now.”

The first author was graduate student Simone Rauch; other co-authors were visiting scholar Michael Srienc, postdoctoral fellow Huiqing Zhou, high school student Emily He and graduate student Zijie Zhang.

The scientists are working with the Polsky Center for Entrepreneurship and Innovation at the University of Chicago to advance this discovery.

Materials provided by University of Chicago

galactic clusters plasma

Scientists use X-rays from faraway galaxy cluster to reveal secrets of plasma

Most visible matter in the universe doesn’t look like our textbook picture of a nucleus surrounded by tethered electrons. Out beyond our borders, inside massive clusters, galaxies swim in a sea of plasma—a form of matter in which electrons and nuclei wander unmoored.

Though it makes up the majority of the visible matter in the universe, this plasma remains poorly understood; scientists do not have a theory that fully describes its behavior, especially at small scales.

However, a University of Chicago astrophysicist led a study that provides a brand-new glimpse of the small-scale physics of such plasma. Using NASA’s Chandra X-ray Observatory, scientists took a detailed look at the plasma in a distant galaxy cluster and discovered the flow of plasma is much less viscous than expected and, therefore, turbulence occurs on relatively small scales—an important finding for our numerical models of the largest objects in the universe.

“High-resolution X-ray observations allowed us to learn some surprising truths about the viscosity of these plasmas,” said Irina Zhuravleva, an assistant professor of astrophysics and first author of the study, published June 17 in Nature Astronomy. “One might expect that variations in density that arise in the plasma are quickly erased by viscosity; however, we saw the opposite—the plasma finds ways to maintain them.”

Scattered around the universe are massive clusters of galaxies, some of them millions of light-years across containing thousands of galaxies. They sit in a type of plasma that we cannot recreate on Earth. It is extremely sparse—on the order of a sextillion times less dense than air on Earth—and has very weak magnetic fields, tens of thousands of times weaker than we experience on the Earth’s surface. To study this plasma, therefore, scientists must rely on cosmic laboratories such as clusters of galaxies.

Scientists used NASA’s Chandra X-ray Observatory to take a detailed look at the plasma in a distant galaxy cluster. (Courtesy of NASA/CXC/SAO)

Zhuravleva and the team chose a relatively nearby galaxy cluster called the Coma Cluster, a gigantic, bright cluster made up of more than 1,000 galaxies. They chose a less dense region away from the cluster center, where they hoped to be able to capture the average distance that particles travel between interactions with NASA’s Chandra X-ray Observatory. In order to build a high-quality map of the plasma, they observed the Coma cluster for almost 12 days—much longer than a typical observing run.

One thing that jumped out was how viscous the plasma was—how easily it’s stirred. “One could expect to see the viscosity resisting chaotic motions of plasma as we zoom in to smaller and smaller scales,” Zhuravleva said. But that didn’t happen; the plasma was clearly turbulent even on such small scales.

“It turned out that plasma behavior is more similar to the swirling motions of milk stirred in a coffee mug than the smoother ones that honey makes,” she said.

Such low viscosity means that microscopic processes in plasma cause small irregularities in the magnetic field, causing particles to collide more frequently and making the plasma less viscous. Alternately, Zhuravleva said, viscosity could be different along and perpendicular to magnetic field lines.

Understanding the physics of such plasmas is essential for improving our models of how galaxies and galaxy clusters form and evolve with time.

“Plasma behavior is more similar to the swirling motions of milk stirred in a coffee mug than the smoother ones that honey makes.”—Asst. Prof. Irina Zhuravleva Click To Tweet

“It is exciting that we were able to use observations of clusters of galaxies to understand fundamental properties of intergalactic plasmas,” said Zhuravleva. “Our observations confirm that clusters are great laboratories that can sharpen theoretical views on plasmas.”

Materials provided by the University of Chicago

A heart muscle cell shows bundles of actin filaments and bands of myosin.

For the first time, scientists recreate cell division—outside a cell

Every living thing moves—prey from predators, ants to crumbs, leaves toward sunlight. But at the most fundamental level, scientists are still struggling to grasp the physics behind how our own cells build, move, transport and divide.

“The mechanisms that allow organisms to move and change shape are inherent to life, and they are all underlaid by physics,” said Margaret Gardel, professor of physics at the University of Chicago. “But despite how central they are for our understanding of biology, a great deal of these remain poorly understood.”

Gardel led an innovative new study, which for the first time recreates the mechanism of cell division—outside a cell. The experiment, led by postdoctoral fellow Kim Weirich and published May 21 in the Proceedings of the National Academy of Sciences, helps scientists understand the physics by which cells carry out their everyday activities, and could one day lead to medical breakthroughs, ideas for new kinds of materials or even artificial cells.

“How cells divide is one of the most basic aspects of trying to create life, and it’s something we’ve been trying to understand for hundreds of years,” said study senior author Gardel, who combines physics and biology to study the ways by which cells transform themselves.

Cells move through the body, but some of the most complex motion takes place inside the cell, as it ships ingredients and supplies from place to place, flattens or expands, and divides to recreate itself. One of the key players in this dance is actin, a protein that assembles itself into rods and structures.

IT’S SOMETHING WE’VE BEEN TRYING TO UNDERSTAND FOR HUNDREDS OF YEARS.”—Prof. Margaret Gardel on cell division Click To Tweet

Gardel’s team wanted to understand the physics behind the actions of actin. So Weirich turned to one of the main ways that scientists have for this question: take the ingredients and try to build with them outside the cell.

Weirich separated out actin proteins, and watched as they formed droplets that took on an almond shape. When Weirich added myosin (“motor” proteins common in muscles), they spontaneously found the center between the two ends of the droplet and pinched off the droplet into two.

They were totally shocked to see the process, Gardel said. “There’s no precedent for this. It looks exactly like the spindles that drive cell division.”

Working with fellow UChicago physicist Thomas Witten and chemist Suriyanarayanan Vaikuntanathan, postdoctoral fellow Kinjal Disbaswas modeled the physics at play.

When in a droplet, the rod-like actin molecules like to align themselves in parallel to minimize conflict, forming the almond shape. The longer myosin molecules prefer to gather in the center so that they can still stay parallel to the actin. But as more myosins gather, they begin to stick together, forming clusters that favor tilting rather than staying parallel—so it pinches off into two. It’s the first such detailed look at how a cell might accomplish this task.

           

Myosin molecules (white) gather in the center of the rod-like actin molecules (red). (Courtesy of Weinrich et al)

Watching this process—how living things exploit the structure of a droplet to form more life—is not only fascinating but useful, Gardel said. Though the types of proteins are different in cell division, the underlying principles are likely similar. “This is the kind of thing you need to know to imagine building things like artificial tissue for a wound,” she said.

“Ultimately, a great deal of problems in biology are about how ensembles of molecules work together,” she said, “and because these are often materials with chemical reactions going on inside, they’re very hard to model. These kinds of studies allow us the opportunity to explore the basic principles of the forces at play.”

Materials provided by University of Chicago