FindingsFALL 2017

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of General Medical Sciences features 1 Protein Paradox: Enrique De La Cruz Aims to Understand Actin

18 The Science of Size: Rebecca Heald Explores Size Control in Amphibians

articles 5 A World Without Pain 6 Demystifying General Anesthetics

10 There’s an “Ome” for That —TORSTEN WITTMANN, UNIVERSITY OF CALIFORNIA, SAN FRANCISCO

ON THE COVER This human skin cell was bathed 17 Lighting Up the Promise of Gene Therapy in a liquid containing a growth factor. The procedure for Glaucoma triggered the formation of specialized protein structures that enable the cell to move. We depend on our cells 24 NIGMS Is on Instagram! being able to move for basic functions such as the healing of wounds and the launch of immune responses. departments 3 Cool Tools: High-Resolution Microscopy— Editor In Living Color Chris Palmer 9 Spotlight on Videos: Scientists in Action Contributing Writers Carolyn Beans 14 S potlight on the Cell: The Extracellular Matrix, Kathryn Calkins Emily Carlson a Multitasking Marvel Alisa Zapp Machalek Chris Palmer Erin Ross Ruchi Shah activities Production Manager 22 Superstars of Science Quiz Susan Athey

Online Editor The Last Word (inside back cover) Susan Athey

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Produced by the Offce of Communications and Public Liaison https://www.instagram.com/nigms_nih National Institute of General Medical Sciences National Institutes of Health https://www.youtube.com/user/NIGMS U.S. Department of Health and Human Services More stories on our Biomedical Beat blog https://www.nigms.nih.gov/fndings https://biobeat.nigms.nih.gov Protein Paradox: Enrique De La Cruz Aims to Understand Actin

BY EMILY CARLSON

But De La Cruz isn’t a profes- sional performer. He’s a molecular biophysicist at Yale University. The show-and-tell performance was part of a scientifc lecture on a paradox De La Cruz has studied for more than 10 years—how a chain of molecules, called actin, that is strong enough to support a cell can break so easily. “I beneft from seeing and holding things as much as anyone else,” he says, explaining that the props help people—even scientists—under- stand his research. By his own account, De La Cruz is an unlikely scientist. A frst- generation Cuban-American, he grew up in and around Newark, New Jersey. Few of his friends earned more than a high school — XIAOWEI ZHUANG, HARVARD UNIVERSITY, AND NATURE PUBLISHING GROUP diploma. De La Cruz never thought Actin (blue) and other proteins support a cell’s structure similar to the way bones he’d end up running his own lab at support our bodies. an Ivy League research university. As a young adult, he recalls, Enrique De La Cruz stood off to the side in a packed room. “It wasn’t even on my radar as As he waited for his turn to speak, he stroked the beads of a necklace. a possibility.” Was he nervous? Quietly praying? When he took center stage, the purpose Although discovering new details about biology keeps his job of the strand became clear. exciting, he said sharing lessons Like a magician—and dressed all in black—De La Cruz held up the he’s learned with students and other aspiring scientists makes necklace with two hands so everyone, even those sitting in the back, could it truly rewarding. see it. It was made of snap-together beads. De La Cruz waved the strand. It wiggled in different directions. Then, with no sleight of hand, he popped Inner City to Ivy League off one of the beads. The necklace broke in two. De La Cruz’s frst taste of research For the next hour, De La Cruz pulled out one prop after another: a piece came during his senior year of high school, when he participated in of rope from his pocket, a pencil tucked behind his ear and even a fresh a work-study program at a nearby spear of asparagus stuffed in his backpack. At one point, De La Cruz pharmaceutical company. He tested assembled a conga line with people in the front row. chemical compounds for their

Findings | FALL 2017 1 Instead of feeling like effects on cholesterol in the blood- their shapes. The flaments also stream. Although the project was play a central role in muscle con- he didn’t belong, he unrelated to what he studies now, traction. Because of these tasks, De La Cruz said the experience the flaments must be strong. felt empowered to seek made science tangible, partly by Yet, the flaments can break. putting people and faces to In many cases, they must break the process. to carry out their functions. To out the knowledge and Because his parents—a welder assemble new chains, the flaments and a hospital pharmacist—instilled recycle their parts. Numerous guidance he needed in De La Cruz and his siblings the proteins facilitate this process in importance of education, he headed cells. Some of the proteins break to succeed. to college. But he stayed close to the flament chains to make more home. He applied only to Rutgers ends, which allows the chains to University. Interested in both shrink more rapidly and recycle medicine and teaching, De La Cruz parts faster. RESEARCHER ultimately decided to pursue a To investigate how actin flaments career doing research on basic life break, De La Cruz has relied heavily Enrique M. De La Cruz processes in an academic setting. on techniques, expertise and But his path to becoming a published papers from other felds. scientist almost hit a dead end “An hour in the library can save when De La Cruz started graduate a week in the lab,” De La Cruz says. school at Johns Hopkins University “There’s a lot of information already in Baltimore, Maryland. out there, and it’s always useful “On my frst exam—in a subject to look at others’ studies.” I wasn’t very familiar with—I scored Over the years, he and his team an 18.5,” he says. “The mean of the have pieced together many details class was an 88! I thought, ‘That’s on how actin flaments form it. I had my chance. This experiment and break. is over.’” “Curiosity is what gets you into His course instructor told him science and what keeps it fun,”

—JEFF FOLEY, AMER ICAN HEART ASSOCIATION not to stress about the score and he says. “You’re going to know

GRE W U P IN to work harder at the things he something in a few months that didn’t know. De La Cruz knew this you don’t know today.” Newark and Kearny, New Jersey was true: He had aced an exam Individual actin molecules, like

JOB SITE in biophysical chemistry, a subject the pop-beads of the necklace, Yale University he was interested in and already string together with the help of salt. knew a lot about. The salt helps “glue” the chain links FAVORITE FOOD Instead of feeling like he didn’t together, De La Cruz explains. His mom ’-s Spanish style polenta belong, he felt empowered to seek By integrating computer models (harina de maíz) out the knowledge and guidance with biochemical and biophysical he needed to succeed. experiments, the De La Cruz team IF I WASN ’T A SCIENTIST I WOULD BE learned where the salt connects Managing a vinyl record shop to actin molecules. Each salt-actin Actin Action joint is tight, making the chain stiff, FAVORITE SONG Much of De La Cruz’s career has like the pencil prop De La Cruz “Do Anything You Wanna Do ” focused on studying actin, one of showed the crowd. But a protein by Eddie & the Hot Rods the most prevalent proteins on the called coflin can push off the salt, planet. Actin molecules form long, weakening the joint so it becomes thin chains that grow and shrink wiggly—De La Cruz demonstrated from the ends. These chains, or this with the rope—and more likely flaments, allow cells to move and to come apart. contract, and they help cells keep

22 National Institute of General Medical Sciences cool tools cool High-Resolution Microscopy— Filament breaks occur in Living Color where different sections BY ALISA ZAPP MACHALEK meet, similar to the way

Cell biologists would love an asparagus spear to shrink themselves down and actually see, touch and hear cells’ snaps where the hard inner workings. Because that’s impossible, they have developed an ever-growing collection of part meets the soft, microscopes to study cellular innards from the outside. Using feshy part. these powerful tools, researchers can exhaustively inventory the molecular bits and pieces that make up cells, eavesdrop on cellular com- munication and spy on cells as they Because a flament has thousands The research team is now adapt to changing environments. of actin molecules and joints, some planning to use computer modeling In recent years, scientists have sections can be weak and wiggly, to better understand the specifc developed new cellular imaging while others are stiff. Filament roles of the wiggly and stiff techniques that allow them to breaks occur where different flament sections during the visualize cells’ contents in ways sections meet, similar to the way breaking process. They’ll test the and at levels of detail never before an asparagus spear snaps where modeling results with carefully possible. Many of these techniques the hard, woody part meets the designed lab experiments. soft, feshy part. “This explanation sounds like it was simple to fgure out, but it was Paying It Forward really diffcult,” says De La Cruz, De La Cruz credits his success adding that the team worked on as a scientist to the mentors he’s this study for several years. had since his very frst research experience in high school. “I’m an example of what can happen “I’m an example when good people take a genuine interest and care about you as —VERONICA FALCONIERI, SUBRAMANIAM LAB, a person.” NATIONAL CANCER INSTITUTE of what can For the students and aspiring This image, showing a single protein scientists working in his lab today, molecule, is a montage. It was created happen when De La Cruz tries to do the same. to demonstrate how dramatically cryo-EM He considers scientists’ most has improved in recent years. In the past, good people take cryo-EM was only able to obtain a blobby important job to be stimulating approximation of a molecule’s shape, such great minds to think independently as that shown on the far left. Now, the a genuine interest and continue to grow, even if it’s technique yields exquisitely detailed images in which individual atoms are nearly visible sometimes through failure. (far right). Color is artifcially applied. and care about He tells them, “The future is in your hands more than you know.” n you as a person.”

Findings | FALL 2017 3 build upon the power of electron patterns with which the rays bounce microscopy (EM) to see ever smaller off the object to indicate the exact aspects. location in space of every atom in Unlike traditional light micros- a molecule. copy, EM uses electrons, not light, Some scientists are using to create an image. To do so, EM cryo-EM to create 3-D models, accelerates electrons in a vacuum, or maps, of molecular complexes. shoots them out of an electron gun To make these models, scientists and focuses them with doughnut- record thousands of 2-D images shaped magnets onto a sample. of a single sample, or a set of When electrons bombard the identical samples, viewed from sample, some pass though without many angles. Then, they use being absorbed while others are specialized computer programs scattered. The transmitted electrons to combine these snapshots into land on a detector and produce an extremely detailed 3-D models. image, just as light strikes a detector This technique is yielding new (or flm) in a camera to create a information on biological molecule photograph. structures and on how these Transmission electron micro- molecules function and interact. scopes (TEM), the most powerful Historically, TEM images have EMs, can magnify objects more than only been in black and white. In late 10 million times, enabling scientists 2016, a group of researchers that to see the outline and some details included the late Roger Tsien—who cool tools of cells, viruses and even some large won a Nobel Prize for bringing color molecules. A relatively new form of to light microscopy using green transmission electron microscopy fuorescent protein—published the called cryo-EM enables scientists to frst ever color TEM images. The view specimens in their natural or technique uses rare earth metals near-natural state without the need called lanthanides to label different for dyes or stains. biomolecules. This multicolor TEM In cryo-EM—the prefx cry-, from is already providing scientists with the Greek cryos, means “cold” or previously unobtainable information “freezing”—scientists freeze a about cell structure, protein biological sample so rapidly that movements within and between water molecules do not have time cells, and views of cell components to form ice crystals, which could at a level of detail not possible with shove cellular materials out of their light microscopy. n normal place. Cold samples are —ADAMS ET AL./CELL CHEMICAL BIOLOGY 2016 more stable and can be imaged After decades of black-and-white electron many times over, allowing research- microscopy images, scientists now have a way to incorporate color. ers to refne the image, remove artifacts and produce even sharper images than ever before. Thanks to a new generation of detectors and improved image- processing software, cryo-EM enables extremely high magnifca- tion. The level of detail, or resolution, of cryo-EM imagery now rivals that obtained with x-ray crystallography, a technique in which scientists shoot x-rays at a structure and use the

4 National Institute of General Medical Sciences A World Without Pain

BY CHRIS PALMER

You glide across an icy canyon where you meet smiling snowmen, view waddling penguins and see a glistening river that winds forever. You toss snowballs, hear them smash against igloos, then watch them explode in vibrant colors. Back in the real world, a dentist digs around your mouth to remove an impacted tooth, a procedure that really, really hurts. Could experienc- ing a “virtual” world distract you from the pain? Scientists David Patterson and Hunter Hoffman show it’s a real possibility. Patterson, a psychologist at the University of Washington (UW) —ARI HOLLANDER AND HOWARD ROSE, COPYRIGHT HUNTER HOFFMAN, UNIVERSITY OF WASHINGTON in Seattle, and Hoffman, a UW In an immersive virtual reality environment called “Snow World,” people with burns cognitive psychologist, helped distract themselves from their pain by tossing snow balls, building snowmen and interacting with penguins. create the virtual reality program “Snow World” in an effort to reduce excessive pain experienced by a passive VR system that included In addition, the team recently people suffering from burns. glasses but no wireless mouse. This began testing augmented reality to However, the researchers expect group saw the snowy world as if prompt children with leg and foot “Snow World” to help alleviate all they were watching a movie, unable burns to move around. Movement kinds of pain, including the pain to go ice skating, make a snowball facilitates skin healing, prevents people experience during dental or pat a penguin. The researchers muscle atrophy and promotes procedures. Because our minds can exposed each group of students to mental health. Specifcally, the focus on just a few things at once, brief periods of painful, but tolerable, researchers are using the mobile the researchers say, if we’re busy heat both before and during their device game “Pokémon GO” to building igloos and making friends virtual reality experiences, and then motivate young people with burns with snowmen, we have less they measured students’ perception to walk around the hospital (with brainpower available to register of pain. close supervision) and capture the heat on our bodies or the The result? Even though all the Pokémon characters. The team twang in our tooth. students were exposed to an is pursuing formal clinical trials. To fnd out if life in “Snow World” identical amount of heat, the ones Although virtual environments really is painless, the scientists fully immersed in the interactive can have drawbacks—such as giving worked with healthy undergraduate virtual reality world reported users motion sickness—they offer student volunteers. One group of 75 percent less pain than those a promising new way to manage pain students received immersive virtual in the noninteractive world. during medical or dental procedures. reality (VR) glasses and a wireless Patterson and his team also have And, as recent research shows, mouse that they used to directly encouraging results using next- reducing pain can speed recovery. interact with the wintry environment. generation VR goggles to reduce Now that’s a relief! n A second group of students received pain in pediatric burn patients.

Findings | FALL 2017 5 Demystifying General Anesthetics

BY CA ROLY N B E A NS

Cell’s Energy Factories Play a Role When Sedensky set out to reveal how general anesthetics work on a molecular level, she didn’t want to focus on any single anesthetic target because she recognized that many targets could be important. She and Phil Morgan, also of Seattle Children’s Research Institute and Sedensky’s husband, decided to instead test anesthetics’ effects on a wide range of molecular targets by shutting down the genes that code for the targets one by one and

Anesthetics usually induce unconsciousness in about 2 minutes. in various combinations. Working with a tiny worm called C. elegans, which is an organism commonly When Margaret Sedensky, now of Seattle Children’s Research used to study health and disease, Institute, started as an anesthesiology resident, she wasn’t entirely clear they found that shutting down on how anesthetics—drugs given during surgery to prevent pain—worked. multiple genes affected the worm’s “I didn’t know, but I fgured someone did,” she says. “I asked the senior response to anesthetics. resident. I asked the attending. I asked the chair. Nobody knew.” For decades, doctors called general anesthetics a “modern mystery.” Even though they safely administered anesthetics to millions of Americans every year, they didn’t know exactly how the drugs produced the different states of general anesthesia. These states include unconsciousness, immobility, analgesia (lack of pain) and amnesia (lack of memory). Understanding anesthetics has been challenging for several reasons. Unlike many drugs that act on a limited number of proteins in the body, anesthetics interact with seemingly countless proteins and other molecules. The roundworm C. elegans is a widely studied research organism. Additionally, some anesthesiologists believe that anesthetics may work through many different molecular pathways. This means no single molecular target may be required for an anesthetic to work, or no single molecular target can do the job without the help of others. “It’s like a symphony,” says Roderic Eckenhoff of the University of Pennsylvania Perelman School of Medicine, who has studied anesthesia for decades. “Each molecular target is an instrument, and you need all of them to produce Beethoven’s 5th.” Another challenge is that general anesthetics function, in part, by halting —THOMAS DEERINCK, NATIONAL CENTER FOR MICROSCOPY AND IMAGING RESEARCH something else scientists don’t fully comprehend: consciousness. Anesthetics may work in part by limiting But in recent years, researchers have been making steady progress energy production in cellular structures toward understanding anesthetics. called mitochondria, shown here in pink.

6 National Institute of General Medical Sciences —WIKIMEDIA COMMONS, JYNTO

Ball and stick model of the chemical structure of the popular anesthetic Propofol. Black balls, carbon; silver balls, hydrogen; and red ball, oxygen.

Inactivating one of these genes mitochondria cause hypersensitivity made the worm hypersensitive to anesthetics at a molecular level. to every anesthetic the scientists “The molecular mechanisms are “It’s like a tested. It turns out that this gene, going to be not so simple to fgure called gas-1, codes for a protein out,” says Sedensky. symphony, … that controls a key component of mitochondria, the cell’s energy factories. Probing for Anesthetic Each molecular This fnding was interesting to Targets Sedensky and Morgan because Eckenhoff and his team work with target is an organs such as the brain and heart colleagues in the University of require a lot of energy—and anes- Pennsylvania’s chemistry depart- thetics have a major effect on them. ment to create chemical probes that instrument, and If anesthetics work by limiting energy identify the targets of anesthetic production in the mitochondria of drugs. These probes are molecules you need all of C. elegans, their impact could shaped like anesthetics. The probes produce a double whammy in include additional features that organisms (such as the gas-1 allow them to bind tightly to target them to produce mutants and people with a condition molecules whenever scientists called “mitochondrial disease”) shine light of a certain wavelength Beethoven’s 5th.” whose mitochondria are already on them. functioning at a lower capacity. The researchers place their Morgan thought the children probes in complex mixtures of he and Sedensky treat at Seattle brain, spinal cord and heart cells. Children’s Research Institute who The probes then show which sites that the anesthetics interact are hypersensitive to anesthetics molecules interact with anesthetics with. Understanding the structures might have alterations in their in these organs. The anesthetic and other features of the binding mitochondria as well. This proved Propofol, for example, interacts sites could help scientists design to be true: The children had with hundreds of different new anesthetics. decreased function in the key molecules. Eckenhoff has already used what mitochondrial component The researchers then use he’s learned about the structures involved in energy production. structural biology methods to get of anesthetic targets to identify Sedensky and her team are now a better look at the exact shapes what he hopes are the frst entirely using mice to study how altered of the target molecules’ binding new anesthetics developed since

Findings | FALL 2017 7 3-year-old patient 30-year-old patient 81-year-old patient

35 35

30 30 Frequency (Hertz) (Hertz) Frequency

25 25

20 20

15 15

Frequency (Hertz) 10 10

5 5

0 0 —EMERY BROWN, MASSACHUSETTS GENERAL HOSPITAL AND MASSACHUSETTS INSTITUTE OF TECHNOLOGY

The brain waves induced by a widely used anesthetic differ among age groups.

the 1970s. He and his team screened about half a million compounds and found that 1 percent of these drugs How does a change at the level targeted a molecule that was shaped similarly to the ones anesthetics of a single molecule affect typically target. Further testing is needed, but Eckenhoff hopes that at least one of these drugs will prove consciousness? to be an anesthetic with fewer side effects (e.g., nausea and vomiting) than those currently available. research suggests they occur Connecting the Pieces when the drugs bind to their “How do you connect an effect Brain Waves, molecular targets in the brain. at a single molecular target to an General Anesthesia Brown’s research also provides end point like consciousness?” and Unconsciousness insight into why the doses required asks Eckenhoff of the notion that Emery Brown of the Massachusetts to achieve an anesthetic state differ anesthetics generally change the General Hospital and Massachusetts among age groups. In one study, function of a single kind of molecule Institute of Technology is studying the anesthetic-induced brain waves on the surface of neurons. That how anesthetics act on the brain to of older adults were two to three question presents perhaps the create a state of unconsciousness. times smaller than those of younger biggest challenge facing anesthe- He uses an electroencephalogram adults. As we age, Brown explains, siology research today. Answering (EEG) to record the brain’s electrical brain cells function at a lower level, it, Eckenhoff, Sedensky and Brown activity while patients are under so weaker brain waves can disrupt all agree, will require collaborations anesthesia. their activity and cause uncon- across disciplines and research According to Brown, the anes- sciousness. spanning all levels of biological thetics generate electrical waves Now Brown is using animal organization—from the molecule that impair the brain’s ability to models to understand in greater to the whole being. And the answer transmit information. “If you do detail how anesthetics control could eventually mean safer use that in the circuits that are responsi- specifc brain circuits. His research of anesthetics. n ble for arousal and cognition,” he group is also developing strategies says, “then you’re going to cause for turning the brain back on after unconsciousness.” The anesthetic- general anesthesia as a way to induced brain waves are highly lessen the brain dysfunction that organized and larger than the can follow general anesthesia, brain’s natural waves. Brown’s particularly in elderly people.

8 National Institute of General Medical Sciences spotlight on videos videos on spotlight Scientists in Action

BY CHRIS PALMER AND ERIN ROSS

The world beneath our skin is full of movement. Hemoglobin in our blood grabs oxygen and delivers it throughout the body. Molecular motors in cells chug along tiny tubes, hauling cargo with them. Biological invaders such as viruses enter our bodies, hijack our cells and reproduce wildly before bursting out to infect other cells. To make sense of the subcutaneous world, Janet Iwasa, a molecular

— CHRIS PALMER AND ERIN ROSS animator at the University of Utah, creates “visual hypotheses”—detailed Janet Iwasa, Molecular Animator animations that convey the latest thinking of how biological molecules interact. “It’s really building the animated model that brings insights,” Iwasa says. “When you’re creating an animation, you’re really grappling with a lot of issues that don’t necessarily come up by any other means. In some cases, it might raise more questions and make people go back and do some more experiments when they realize there might be something missing.” As she discusses in a video interview, Iwasa collaborates with numerous scientists to develop animations of a range of biological processes and structures. Recently, she’s undertaken an ambitious, multiyear project to animate HIV reproduction.

— TOMAS KIRCHHAUSEN, HARVARD MEDICAL SCHOOL, AND JANET IWASA https://biobeat.nigms.nih.gov/2016/08/interview-with-a-scientist-janet- Cells form small intracellular bubbles, iwasa-molecular-animator called vesicles, to package extracellular materials that will be brought into the cell—a process called endocytosis.

The outside of every cell on Earth—from the cells in your body to single-celled microorganisms—is blanketed with a coat of carbohydrates, or sugar molecules, that extend from the cell surface, branching off and bending as they interface with the extra-cellular space. The specifc patterns in which these carbohydrates are arranged serve as an ID code that helps cells recognize each other. For example, human liver cells have one pattern, and human red blood cells have another. — CHRIS PALMER Certain diseases can even alter the pattern of surface carbohydrates, Laura Kiessling, Carbohydrate Scientist which is one way the body can recognize damaged cells. On foreign cells, including invading bacteria such as Streptococcus pneumoniae, the carbohydrate coat is even more distinct. In a video interview, Laura Kiessling, a professor of chemistry at the University of Wisconsin-Madison, discusses how carbohydrate coats are assembled and how cells use these coats to tell friend from foe. The implications of her research suggest strategies for targeting tumors, fghting diseases of infammation and developing new classes of antibiotics.

https://biobeat.nigms.nih.gov/2016/10/interview-with-a-scientist- laura-kiessling-carbohydrate-scientist

Streptococcus pneumoniae

Findings | FALL 2017 9 There’s an “Ome” for That

BY CHRIS PALMER

Have you ever collected coins, cards, toy trains, stuffed Genome animals? Did you feel the need to obtain every item in the set? If so, then The genome is the original ome. you may be a completist, someone who goes to great lengths to acquire In 1976, Belgium scientists iden- a complete set of something. tifed all 3,569 DNA bases—the Scientists can also be completists, inspired to identify and catalog A’s, C’s, G’s and T’s that make up every object in a particular feld to further our understanding of it. DNA’s code—in the genes of For example, a comprehensive parts list of the human body could aid bacteriophage MS2, immortalizing researchers in developing novel treatments for diseases in the same this bacteria-infecting virus as way that a parts list for a car enables auto mechanics to build or repair it. possessing the frst fully More than 15 years ago, scientists fgured out how to catalog every sequenced genome. gene in the human body. In the years since, rapid advances in technology Over the next two decades, and computational tools have allowed researchers to begin to categorize a small handful of additional numerous aspects of the biological world. There’s actually a special way genomes from other microorgan- to name these collections: Add “ome” to the end of the class of objects isms followed. The frst animal being compiled. So following this naming scheme, the complete set of genome was completed in 1998. genes in the body is called the “genome”; the complete set of proteins Just 5 years later, scientists is called the “proteome.” identifed all 3.2 billion DNA bases Here are three omes and descriptions of how they can be useful for in the human genome, representing understanding human health (see more examples, below). the work of more than 1,000 researchers from six countries over a period of 13 years. As more individuals’ genomes have been sequenced, scientists have found that humans share 99.5 percent of their genome with

Since the completion Allergenome of the human genome All of the proteins found in allergens, substances capable of more than 10 years ago, causing an allergic reaction, such as pollen, grass and dust mites. scientists continue to suggest new omes. Here’s a partial list (sorry, completists!).

Pollen grains, like the ones shown here, can cause seasonal allergies. 10 National Institute of General Medical Sciences Human

Zebrafsh each other. However, small differ- ences can be quite important. As the cost of sequencing genomes has plummeted from an initial $3 billion to the current $1,000, scientists are sequencing the genomes of people as well as those of other types of organisms used to investigate biological questions. And all the effort is paying off. Genomics—the study of genes Mouse and their function—is beginning to reveal many of the basic compo- Chimpanzee nents of cells and their interactions. Already, researchers are linking —MARTIN KRZYWINSKI, CANADA’S MICHEL SMITH GENOME SCIENCES CENTRE the presence of certain genes in Clockwise from top right, the genomes of a human, chimpanzee, the genome to specifc diseases. mouse and zebrafsh are arranged in a circle. Each colored square Furthering our understanding of at the outside of the circle corresponds to a pair of chromosomes, the the genome could have a profound threadlike packages of double helical DNA (inset) stored in the nucleus. Lines connect similar DNA sequences, visually emphasizing just how impact on the diagnosis and treatment much DNA humans share with other species. The density of the of disease. Also, comparing the connections indicates that humans have more in common with genomes of related and disparate chimpanzees than zebrafsh. species can shed light on how species evolve over time.

Epigenome The collection of chemical compounds that attach themselves to the genome as a way to regulate the activity, or expression, of all the genes within the genome.

Metabolome —THE HUMAN CONNECTOME PROJECT All of the small molecules, known Wiring diagram of the major connections within the human brain. as metabolites, produced by cells, tissues or whole organisms. Connectome All of the connections among neurons in the brain. The human brain has 86 billion neurons with an estimated 1 trillion total —EDNA, GIL AND AMIT CUKIERMAN, FOX CHASE CANCER CENTER connections among them.

Findings | FALL 2017 11 cellular membranes aren’t simply for protection. They’re also highly Proteins organized and dynamic work zones, seeded with proteins that help regulate the way cells attach to other cells, talk to each other, collect nutrients and grow. The lipid membranes inside the cell can similarly act as points of contact between cellular compart- ments, and they’re involved in nearly every aspect of cellular function. Recent experiments have revealed hundreds of distinct types of lipids produced by cells. The collection of lipids within cells has also been found to be remarkably fexible, capable of rapid, large- and small-scale rearrangements in response to different situations. For example, during early development, lipids

Lipids within the membrane reorganize Lipidome as a cell grows. Infectious viruses The lipidome is the collection can slam into and rupture the Composed of two layers of lipids (small red spheres) studded with proteins (elongated of all the lipids, or fat molecules, membrane of human cells, causing blue shapes), cell membranes form a barrier within a cell. Cells use lipids to localized lipid reshuffing. around cells. form a continuous membrane Disruptions of the lipid compo- around themselves and to separate nents of cellular membranes are their inner organelles (specialized associated with diverse diseases, cellular structures such as the including cardiovascular disease, nucleus) from each other. These autoimmunity, osteoporosis,

Microbiome

The complete set of genomes belonging to microbes— single-celled organisms that include bacteria and fungi—in a system such as the human gut. Current estimates suggest microbe genes in our bodies greatly outnumber our own genes.

—NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES

Streptococcus bacteria (yellow) on a human neutrophil, or white blood cell (blue).

12 National Institute of General Medical Sciences neurological disorders and cancer. Experiments investigating the lipidome of specifc cells with known roles in particular diseases could help researchers identify novel treatments.

Glycome The glycome is the complete set of glycans, also known as car- bohydrates or sugars, that cells produce. Many of these glycans are linked to proteins and lipids on cell —WIKIMEDIA COMMONS, ALLONWEINER surfaces, where they can interact Thousands of glycans protrude from the bacterium Bactillus with molecules on other cells. Single subtilis, forming a unique carbohydrate coat. sugars can also act as signaling molecules inside cells, altering gene editing, protein folding and other of a range of diseases, including recognize and bind to carbohydrate cellular functions. cancer, infammatory bowel disease coats. By analyzing the carbohy- A recent study of 650 different and cardiovascular disease. One drate binding properties of the fu species suggests that about 5 percent day, scientists may use imaging virus, for instance, researchers of an organism’s DNA codes for the techniques to rapidly identify a have been able to design antiviral proteins that synthesize, degrade cell’s glycome to diagnose specifc drugs that interfere with the virus’ and/or recognize and bind to kinds of cancer, for example. ability to infect our cells. n carbohydrates. Mutations in these Cells also use the glycans on genes can result in the dysfunction their outer surface, commonly of many organs, underscoring the referred to as carbohydrate coats, importance of carbohydrates to to recognize one another (see human health. In addition, changes “Spotlight on Videos,” page 9, to in the patterns of glycans in a learn more about carbohydrate person’s cells can be an indication coats). Likewise, viruses can

Proteome All of the proteins made by an organism.

Regulome

The entire set of transcription —MATT BERTONE, NORTH CAROLINA STATE UNIVERSITY factors—chemical compounds that The brown recluse makes one of the deadli- regulate gene expression—in an est toxins found in any spider’s venom. —SETH PINCUS, ELIZABETH FISCHER AND AUSTIN ATHMAN, organism. NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES Venome This human T cell (blue) is under attack by Transcriptome All of the toxins produced by each HIV (yellow), the virus that causes AIDS. The complete set of RNA molecules— species of venomous creature, including messenger RNA, ribosomal including scorpions, snakes, spiders Virome RNA and transfer RNA—in an and even mammals such as shrews The comprehensive list of viruses in organism. and moles. an environment.

Findings | FALL 2017 13 The Extracellular Matrix, a Multitasking Marvel

BY ALISA ZAPP MACHALEK, RUCHI SHAH AND KATHRYN CALKINS

When we think about how our bodies are made and what they do, we usually focus on organs, tissues and cells. These structures have well- known roles. But around, within and between them is a less understood material that also plays an essential part in making us what we are. This gelatinous fller material is known as the extracellular matrix (ECM). Once thought to be the biological equivalent of bubble wrap—serving only to provide protection—we now know that the ECM is a dynamic, physiologi- The extracellular matrix is essential for cally active component of all our tissues. It guides cell shape, orientation closing wounds. and function. The ECM is found in all of our body parts. In some tissues, it’s a thin layer separating cells, like mortar between bricks. In other tissues, it’s the major Sealing and Healing constituent. Wounds The ECM is most prevalent in connective tissue, the material that forms When we get injured, the frst thing our skeletons, cushions our internal organs and winds between blood our body does is to form a blood clot vessels and around nerves. In connective tissue, the ECM is more abundant to stop the bleeding. Skin cells then than the cells suspended within it. start migrating into the wound to What makes the ECM unique is its variability: Its texture, composition close the cut. The ECM is essential and functions vary by body part. That’s because the ECM’s deceptively for this step, creating a physical simple recipe of water, fbrous proteins and carbohydrates has virtually support structure—like a road or endless variations. train track—over which skin cells In general, the fbrous proteins give the ECM its texture and help cells travel to seal the injured spot. adhere properly. Carbohydrates in the ECM absorb water and swell to The ECM is made up of a host of form a gel that acts as an excellent shock absorber. proteins produced before and after injury. Some other proteins called matrix metalloproteinases (MMPs) also crowd into wounds. Because The extracellular matrix meets the needs of each body part. humans have so many different MMPs—24 of them—it’s been diffcult for scientists to fgure out what roles, if any, the proteins play in healing scrapes and cuts. To fnd out whether MMPs help close wounds, Andrea Page-McCaw and colleagues at the Vanderbilt University Medical Center turned to the fruit fy. This model organism has just two MMPs, only one of which (MMP1) can move about to do things such as helping repair damaged tissues. The scientists spotlight on the cell In teeth and bones, it’s In corneas, it’s a transparent In tendons, it forms used immature flies (larvae), rock-hard. gel that acts like a camera strong fbers that bind whose soft outer layer is easier to lens. muscle to bone. work with and, surprisingly, more similar to the epithelia—the outer covering—of our own skin than

14 National Institute of General Medical Sciences spotlight on the cell cell the on spotlight it is to the hard shell of adult fruit flies. Four types of proteins are closely associated The researchers examined with the Extracellular Matrix. wounds in the larvae of two special fruit fy strains: one that can’t make MMP1 and one that produces more Cadherin than the normal amount of MMP1. These protein molecules are like molecular pegs in the cells’ In the strain that lacked MMP1, membranes, providing tiny joints that attach the cells to each other. wounds failed to close. In the strain that had extra MMP1, wounds Collagen closed much more quickly than in This protein—the most abundant in the human body—provides normal fies. The researchers had strength and integrity to the ECM. their answer: Yes, MMP1 does help heal injuries because it’s necessary Elastin for wounds to close—at least in This fbrous protein in the ECM confers elasticity. fruit fies. As for how MMP1 works, Integrin Page-McGraw’s team has learned This collection of protein molecules bind cells to the ECM. that within hours of an injury, large amounts of MMP1 amass at the edges of the damaged tissue. The researchers know that collagen— a strong, fbrous protein—also it’s the nubby hardness of gravel their shape and to begin migrating accumulates at these edges. Now or the slickness of ice. away from the direction of the pull. they’re trying to tease out how It turns out that such fne-tuned Because similar forces yank and MMPs, collagen and other ECM movement also takes place during pull on cadherins when neighboring molecules work together to enable a baby’s frst few days in the womb. cells physically interact with each our bodies to heal themselves. Even when the embryo is still less another in a tissue, the researchers than an inch long, a whole lot of think that cadherins help relay these to-and-fro cell movement is going mechanical forces to coordinate the Cells on the Move in on, with many cells migrating en cells’ movements. This coordination Embryo Development masse to form tissues and organs. is essential so that the cells move with Help from the ECM If cells journey to the wrong place not in a slapdash fashion but in When we go for a run or stroll, we’re or fail to travel at all, birth defects a well-orchestrated march. usually unaware of how much coor- can result. So, scientists wondered, It turns out that the ECM helps dination it takes. To safely move us what role does the ECM play in cells coordinate these movements. forward, our feet must sense and these early mass cell migrations? Protein molecules called integrins quickly adjust to the friction of the This question was on the minds of fasten cells to the ECM. When surface beneath them—whether Douglas DeSimone and colleagues they do so, they activate cellular at the University of Virginia School machinery that primes cells to of Medicine. Using embryos of a move in response to tension—again type of clawed frog called Xenopus sensed via cadherins—and helps as stand-ins for human ones, roving groups of cells orient in one the researchers studied cadherins, direction. Assembling cells into protein molecules that are like tissues, organs and, eventually, a molecular pegs in the cells’ whole new person—just another membranes, providing tiny joints service the ECM provides. n that attach the cells to each other. When the researchers used sophisti- Sensing and responding to mechanical cated biophysical techniques to friction is important for all sorts of tug at the cadherins, they saw that movements, such as walking and even cell migration. this pull causes the cells to change

Findings | FALL 2017 15 Here’ s a collection of images featuring the Extracellular Matrix.

Photos are from the National Center for Microscopy and Imaging Research at the University of California, San Diego.

The main component of the ECM—and the most abundant protein in our bodies—is collagen. It accounts for about a quarter of our total protein mass. By assembling into a rope-like shape, it plays a variety of important roles, such as forming stretch-resistant fbers that give strength to our tendons, ligaments and bones and providing scaffolding for skin wounds to heal. There are about 20 different types of collagen in our bodies, each adapted to the needs of specifc tissues.

Elastin, another fbrous protein in the ECM, is abundant in artery walls like the broad, pastel-colored structure near the bottom of the photo (the smaller, curved, dark red structures near the top are red blood cells). As its name indicates, elastin confers elasticity. Fibers made of elastin are at least fve times more stretchy than rubber bands of the same size. Tissues that expand, such as blood vessels and lungs, need to be both strong and elastic, so they contain both collagen and elastin.

Scientists know less about the ECM in muscle than in other tissues, but studies are making it increasingly clear that ECM is critical to muscle function. Disruption of ECM is linked with many muscle disorders. Scientists have also found that the ECM in muscles can store and release substances called growth factors that stimulate , suggesting that the ECM might play a key role in cellular communication. This image shows the ECM on the surface of a soleus (lower calf) muscle. The winding, pink structures are blood vessels. At the bottom, a vessel has opened, revealing small clumps of red blood cells.

Although there is less ECM in nervous tissue than in connective tissue, it is found between the stems (axons) of nerve cells. In this image, nerve axons are blue. Surrounding the axons are Schwann cells (brown), which produce a fatty covering called myelin that acts as insulation. The open, somewhat colorless areas are ECM. Within the ECM, collagen fbers appear as tiny brown spots. spotlight on the cell

16 National Institute of General Medical Sciences Lighting Up the Promise of Gene Therapy for Glaucoma

BY A LISA Z A PP MACH A LEK

What looks like the gossamer wings of a butterfy is actually the retina of a mouse, delicately snipped to lay fat and sparkling with fuorescent molecules. Researchers captured this image while investigating the promise of gene therapy for glaucoma, a progressive eye disease. It all happened at the National Center for Microscopy and Imaging Research (NCMIR) at the University of California, San Diego. Glaucoma is the leading cause of irreversible blindness. It is character- ized by the slow, steady death of —KEUN-YOUNG KIM, WONKYU JU AND MARK ELLISMAN, NATIONAL CENTER FOR MICROSCOPY AND IMAGING RESEARCH, certain nerve cells in the retina. If UNIVERSITY OF CALIFORNIA, SAN DIEGO scientists can prevent the death of Retinal ganglion cells in the mouse retina that do (yellow) and do not (blue) contain a specifc these cells, called retinal ganglion gene that scientists introduced with a virus. cells, it might be possible to slow the progression of glaucoma. Some “It is amazing to see intricate and artistically researchers are examining the possibility of using gene therapy organized microscopic structures.… to do just that. A major challenge of gene therapy I encountered an entirely new world invisible is fnding a way to get therapeutic genes into the right cells without to the naked eye—a galaxy of infnite secrets damaging the cells in any way. Scientists have had success using and endless potential for discovery.” a nondisease-causing virus (adeno- associated serotype 2) for this task. —Keun-Young Kim, lead researcher Here’s how it works: Researchers insert the desired gene into the virus, Retinal ganglion cells that contain microscopy images of large samples, then let the virus do what it does a functional copy of the test gene such as an entire mouse retina. The best—enter cells. Once inside, the are yellow. Retinal ganglion cells that technique is similar to “Google Earth,” virus splits apart to release its genetic don’t are blue. These results bring in that it computationally stitches material, which gets incorporated the concept of gene therapy for together many small, high-resolution into the genome of the host (mice, glaucoma one step closer. images obtained with a powerful light in this case). Then the inserted genes The research was about more microscope. In essence, scientists function just like other genes normally than delivering genes or treating now have a vastly larger canvas on found in the host genome. eye diseases. It also showcases a which to reveal, in high defnition and This image shows that the process powerful technique pioneered by fuorescent colors, all the cellular worked—at least for some of the cells. NCMIR for obtaining high-resolution and molecular details of life. n

Findings | FALL 2017 17 The Science of Size: Rebecca Heald Explores Size Control in Amphibians

BY CHRIS PALMER

In amphibians, unlike in mammals, there are striking correlations among the size of the animals’ genomes (an organism’s complete set of genes; for more about genomes see “There’s an ‘Ome’ for That” on page 10) and several aspects of the animals’ size. For example, amphibians with large genomes tend to be bigger than those with smaller genomes. Larger genomes also correspond to larger cells and larger organelles (specialized cellular structures such as the nucleus). Heald has also demonstrated that these seemingly fxed parameters can be tweaked in the lab.

—NASSER RUSAN, NATIONAL HEART, LUNG, AND BLOOD INSTITUTE, International Woman NATIONAL INSTITUTES OF HEALTH of Science The spindle, composed of thousands of microtubules (green), grabs hold of chromosomes (purple), which replicate during . As the cell divides, the spindles will separate the Way before dreaming up ways paired chromosomes so that each daughter cell will contain a complete set of chromosomes. to design the frogs of people’s nightmares in her lab, Heald was fond of science. She remembers starting out with more mundane experiments in middle and high school, such as distilling gases A 50-pound frog isn’t some freak of nature or a creepy Halloween from burning wood, dissecting prank. It’s a thought experiment—an experiment carried out only in one’s fy embryo salivary glands and examining microorganisms under imagination—conceived by Rebecca Heald, a cell biologist at the University a microscope. of California, Berkeley, who is studying the factors that control size in animals. “I defnitely thought microscopy was just this whole new world, a Heald’s “50-pound frog project” speaks to the power of evolution and to whole new way of seeing things,” scientists’ ability to modify the physical characteristics of an organism by she recalls. Even earlier than these formative altering its genome. The project also incorporates many of Heald’s fascinating experiences, Heald found herself discoveries studying amphibian eggs and embryos. attracted to life as a scientist for other, more ethereal reasons. She would often accompany her

18 National Institute of General Medical Sciences chemistry professor father to his lab replicate, yielding two copies at Thiel College, a small liberal arts of each chromosome connected school in northwestern Pennsylvania, together. Spindle fbers attach to “Microscopy where she recalls enjoying the the chromosomes, pull them apart ambiance. She was even more and move the previously paired was a whole impressed by living with her parents chromosomes to opposite ends in Australia and New Zealand during of the cell. The goal of the whole new world, their sabbaticals. process is for each daughter cell “I think those experiences had a to contain a single copy of each big infuence on my interest in the chromosome—a complete genome. a whole new academic lifestyle, that you could Heald discovered that spindles go live other places and work with can form in the absence of chromo- way of seeing interesting people,” says Heald. somes. Instead of attaching onto After completing a Ph.D. at chromosomes, the spindles unite Harvard Medical School, Heald around DNA-coated beads through things.” arranged her own international a process of “self-organization.” excursion by working as a This fnding earned her a faculty researcher for 3 years in Germany. position at Berkeley, where she “It was exciting to see how set out to compile the minimum the critical factors that, when a different culture does science,” parts list necessary to make combined, would be suffcient she recalls. a functional spindle. to reconstitute the spindle. During her time in Germany, Because spindles are made When it came time for her frst Heald studied the football-shaped of microtubules along with about sabbatical a few years after landing cellular structure called the spindle, a thousand other proteins and her job at Berkeley, Heald again which is composed of thousands other various components, Heald looked abroad, spending a year of thin fbers called microtubules. estimates it could take more than doing research in Toulouse, France. During cell division, chromosomes a decade to tease out what are Her project focused on how

4 6 1 3 8 7 5

2 2 1. Grew up 4. Grad school 7. Faculty position 2. Parents’ sabbaticals 5. Postdoc 8. Sabbatical 3. College 6. Postdoc

Heald’s globetrotting adventures allowed her to experience how different cultures “do” science.

Findings | FALL 2017 19 microtubules organize during muscle The scientists then add chromo- development. An avid cyclist, she somes (usually from frog sperm) took advantage of down times in the to the extract, together with lab by racing through the Alps and fuorescent tags attached to various Pyrenees mountain ranges. spindle proteins, and use micro- “Mammals are actually At home in Berkeley, Heald enjoys scopes to observe the spindle form. cycling down by the San Francisco By manipulating the proteins in the quite boring,” says Heald. Bay and powering up the Berkeley egg extract mixture and substituting Hills to the east. For the past different kinds of DNA-coated beads 10 years or so, she has completed for the chromosomes, Heald learns what she calls “Triathlon Thursdays.” which factors are needed for spindle These early-morning blitzes begin assembly. She uses this information at 7:00. Instead of the traditional to support her long-term goal of RESEARCHER bike, swim and run, Heald meets building a spindle from a defned up with a friend or colleague for set of parts. Rebecca Heald a long bike ride. She then comes home and sinks into a bath. She wraps up by taking her dog, Louis, for a walk before heading to her lab.

Spindle Science Heald frst fell in love with frog eggs as a research system during her early studies of cell division. She was fascinated that spindle formation requires neither proper chromosomes nor intact cells. All it needs is isolated —the gel-like substance in which a cell’s organ- elles are embedded—and some DNA, either in the form of chromo- somes or DNA-coated beads. —MARK HANSON To fgure out which molecules GRE W UP IN are necessary for spindle assembly, Greenville, Pennsylvania Heald uses a cytoplasm extract, which contains all the components ST UDIED AT necessary to build a cell but lacks Hamilton College, Rice University, chromosomes. To obtain this Harvard Medical School extract, she and her colleagues collect thousands of eggs from the JO B SIT E African frog Xenopus laevis. They — STEVE HILL University of California, Berkeley then remove the eggs’ jelly-like Rebecca Heald rides through the Pyrenees outer coating and put them in a mountain range in southern France. FAVORI TE HOBBY centrifuge tube. Spinning the eggs Cycling in a centrifuge crushes them and separates the egg contents so that the cytoplasm can be isolated.

20 National Institute of General Medical Sciences —WIKIMEDIA COMMONS, H. KRISP

The (Xenopus laevis) is ideal for studying the connection between body size and spindle size.

Size Matters controlled in two ways: one that Cancer cells also tend to be While her research into spindles depends on the amount of certain unreliable when it comes to accu- was progressing, a colleague at proteins, and the other that rately divvying up chromosomes Berkeley introduced Heald to a depends on the specifc sequences during cell division, resulting in related frog, Xenopus tropicalis, of those proteins. For example, daughter cells that have too many that is smaller than the one she an enzyme that cuts microtubules, or too few chromosomes. Heald had been working with and also called Katanin, has a slightly plans to study this phenomenon has a smaller genome. X. tropicalis different amino acid sequence in using the frog Xenopus longipes, is the size of a kiwifruit, whereas the two different frog species. The whose genome of 108 chromo- X. laevis is the size of an orange. version of Katanin in X. tropicalis somes is signifcantly larger than Heald was enthralled with the fact is much more active at chopping that of the other frog species that X. tropicalis was smaller and its microtubules, which makes the (X. laevis has 18 chromosomes, and eggs, as well as the spindles formed spindles in that animal smaller. X. tropicalis has 10). An important in its egg extracts, were too. Even though, as Heald puts it, question for Heald is how these Realizing that body size seemed “mammals are actually quite boring; animals properly segregate such to correspond to spindle size was all of our genomes and cell-size a massive number of chromosomes exciting because it provided an relationships are pretty much the to two daughter cells. experimental system to investigate same,” her work with amphibians has Heald hopes her research can how spindle size is determined. important implications for humans. answer these questions and provide Heald and her colleagues learned Under certain circumstances, human leads on potential cancer therapies that they could mix together the cells, and the organelles within and diagnostics. cytoplasm from the eggs of the them, vary in size. For example, “One of the wonderful things two frogs and add in chromosomes. cancer cells are characterized by about is that you have The result was hybrid spindles of enlarged and misshapen nuclei. all these different animals…and intermediate size, suggesting that Researchers do not know whether you can fgure out what is a good there is something in the cytoplasm these abnormal cells are a cause, question and then fnd a great that is determining spindle size. or a result, of disease. system in which to answer that Heald’s group is now seeking Cancer messes up cells in several question,” says Heald. “I think to identify the factors—they call other ways. For example, many of amphibians are actually pretty them scaling factors—that work the thousands of factors that affect much the ideal system for my to regulate the size of the spindle. spindle assembly are altered in research questions.” n Subsequent experiments in her cancer cells, and it is not clear how lab revealed that spindle size is these changes impact the spindle.

Findings | FALL 2017 21 Superstars of Science Quiz

BY A LISA Z A PP M ACHALEK

Many different animals (and even plants, fungi and bacteria) play a starring role in biological and medical research. Research organisms typically reproduce quickly, are easy to raise in a laboratory, and have characteristics that make them a window into certain aspects of biology. Studying such organisms teaches researchers how life works normally, what happens when things go awry, and how we might fnd better ways to diagnose, treat or prevent diseases. See if you can match photos of each research organism (or parts of the organism) with the traits that make it useful to researchers. The photos were taken using microscopes. The colors, which help scientists study selected structures, come from chemical dyes or are created with graphic design programs.

A B C

—NIH —JESSICA PLAVICKI, UNIVERSITY OF WISCONSIN, MADISON —JÜRGEN BERGER, MAX PLANCK INSTITUTE FOR , AND MARIA LANGEGGER, FRIEDRICH MIESCHER Roundworm (Caenorhabditis elegans, Zebrafsh (Danio rerio) LABORATORY OF THE MAX PLANCK SOCIETY, GERMANY or C. elegans) Yeast (Saccharomyces cerevisiae)

Carefully observe the images above, then read the captions below and match each image to the appropriate caption.

Like other research Almost all human You’ve probably seen 1 organisms, this one 2 genes have a counter- 3 this insect buzzing grows and reproduces quickly. part in this common lab organism. around overripe bananas. Research It also has a genome that is easy The creature, a mammal like us, on it over the past century has to manipulate. Even though it’s even develops diseases that are taught scientists how genes affect a fowering plant, its cells work in similar or identical to ours. It is development, appearance, behavior much the same way that human frequently used to test experimen- and lifespan in living organisms. cells do. So researchers use it to tal therapies and has helped us Research using this organism has investigate basic biological process understand a range of conditions, also shed light on many aspects of such as how cells communicate, including autoimmune diseases, human biology, including biological how genes turn on and off, and obesity, diabetes, cancers and organ rhythms, learning, memory and how stem cells develop into rejection. Researchers can order by neurodegenerative diseases. The new tissues. mail specially bred or genetically image shows this creature’s ovary. engineered versions of this organism that have particular genetic profles, symptoms or diseases.

22 National Institute of General Medical Sciences D E F

—HOGAN TANG AND DENISE MONTELL, JOHNS HOPKINS UNIVERSITY —ARUN SAMPATHKUMAR AND ELLIOT MEYEROWITZ, —NATIONAL CENTER FOR MICROSCOPY AND IMAGING RESEARCH AND UNIVERSITY OF CALIFORNIA, SANTA BARBARA CALIFORNIA INSTITUTE OF TECHNOLOGY AT THE UNIVERSITY OF CALIFORNIA, SAN DIEGO

Fruit fy (Drosophila melanogaster) Mustard plant (Arabidopsis thaliana) Mouse (Mus musculus)

This fungal organism Native to shallow Normally, this tiny, 4 plays an important 5 ponds on the Indian 6 transparent creature role in making bread, beer and subcontinent, this creature is lives in dirt. But for the past wine. Research on it has yielded now a popular species for home 40 years, it has also lived in vast knowledge about basic cellular aquariums. Many researchers are research labs around the world. and molecular biology as well as drawn to it because its eggs and Scientists studying the organism about myriad human diseases, embryos are transparent, making teased out the role of all 959 of its including colon cancer and it possible to watch organs develop cells, learned that a large portion metabolic disorders. In this image, in real time. By studying this creature, of its genes are similar to those in an offspring is being released. scientists have learned about humans, and revealed many of the birth defects, the impact of early molecular underpinnings of organ exposure to environmental contam- development, aging and behavior. inants, and the proper development of organs that include the heart, bones, blood and the inner ear. Answers on inside back cover.

Findings | FALL 2017 23 NIGMS Is on Instagram!

BY A LISA Z A PP MACH ALEK

See gorgeous scientifc images and videos of #zinc #microscopy #researchorganism #heatmap #leaf brightly colored cells, molecular animations, pathogen innards and n We need zinc. more. It’s all on Instagram @nigms_nih. If you’ve never used Instagram, It’s an essen- just go to https://www.instagram.com, download and install the app tial nutrient for and search for #NIGMS. You can also see our offcial Instagram feed growth and devel- opment, fending using a web browser at https://www.instagram.com/nigms_nih. off invading Let us know what you think! microbes, healing If you have any stunning images or videos that relate to scientifc injuries and all sorts of cellular areas supported by NIGMS, please send them to us. They might processes. We end up on our Instagram feed or in our Image and Video Gallery —SUZANA CAR AND MARY LOU #botany #plant #arabidopsis GUERINOT, DARTMOUTH COLLEGE get the mineral (https://images.nigms.nih.gov). through our diet, To ensure our material shows up on relevant searches, we use but people in certain parts of the world don’t get enough. Researchers study how plants a collection of standard tags, such as: #science #scientifc #biology acquire and process zinc, hoping to fnd ways #bioscience #biomedical #research #scienceisbeautiful #scienceiscool to increase the nutrient in food crops. Using #sciart #nihfunded #nigms and #nih. synchrotron X-ray fuorescence technology, scientists created this heat map of zinc in a leaf We also use specialized tags to connect each image with its from a plant called Arabidopsis thaliana (zinc relevant topic area, as shown with the images here. levels from lowest to highest: blue, green,

#molecularbiology #imaging red, white). #DNA #celldivision #DNAreplication #cryoem #microscopy #cellbiology #microscopy #cells #brainimages #neuroanatomy n VIDEO Check out the kink in this chromosome. #cerebellum #neuroscience #brain #neurobiology Proteins (yellow and green) recognize a specifc spot on DNA (red and blue) known as the origin of replica- tion. Then, like a c-clamp on a copper pipe, they bend the DNA into a tight angle. Why? To ready the double helix to be unwound and copied as the cell prepares to divide. This research was done in yeast, but in many cases human cells behave similarly.

—HUILIN LI OF BROOKHAVEN NATIONAL LABORATORY, AND BRUCE STILLMAN OF COLD SPRING HARBOR LABORATORY

—TOM DEERINCK AND MARK ELLISMAN, NCMIR #mouse #researchorganism #animation #videos #electronmicroscopy n Beautiful brain! This image shows the cerebellum, which is the brain’s locomotion control center. Every time you shoot a basketball, tie your shoe or chop an onion, your cerebellum fres into action. Found at the base of your brain, the cerebellum is a single layer of tissue with deep folds like an accordion. People with damage to this region of the brain often have diffculty with —TORSTEN WITTMANN, UNIVERSITY OF balance, coordination and fne motor skills. CALIFORNIA, SAN FRANCISCO

n This picture shows developing

#marinebiology #marinescience #cells #pigmentcell #cellbiology #microscopy mouse nerve cells. The nucleus (yellow) is surrounded by a cell n Scientists can learn a lot by studying pigment body, with long extensions called cells, which give animals their colorful skins, axons and thin branching struc- eyes, hair and scales. We can even gain insight tures called dendrites. Electrical into skin cancers, such as melanoma, that origi- signals travel from the axon of one nate from pigment cells. Pigment cells can form cell to the dendrites of another. all sorts of patterns, such as these stripes on the

#researchorganism fn of a pearl danio, a type of tropical minnow.

#microscopy #nerves #nervecells #lifemagnif ed #nerves#microscopy #nervecells #lifemagnif #cellbiology #cells #zebrafish —DAVID PARICHY, UNIVERSITY OF WASHINGTON

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Accessibility Across Down This publication can be made available in formats that are more 6. Reduce, reuse… 1. Ouch! accessible to people with disabilities 7. A nerve’s long stem. 2. Scientists use fuorescent ones or in alternate languages for people 9. Makes our tissues gooey to color-code molecules. with limited English profciency. To or stiff. 3. Really cool microscopy technique. request this material in a different format or language, contact the 11. Preventing cell death in the 4. Forms flaments that allow cells NIGMS Offce of Communications ______might help treat eye to move, contract and keep and Public Liaison at 301-496-7301; diseases. their shape. send email to [email protected]; 13. Leading cause of blindness. 5. A whole new world. or write to the offce at the following 18. Enrique De La Cruz studies 8. Component of the cell. address: 45 Center Drive MSC 6200, how actin flaments ______. 10. Long chains of sugar molecules. Bethesda, MD 20892-6200. If you have questions or comments about 19. Cellular power plants. 12. Induce unconsciousness. this publication, you can use the 22. Most powerful type of 14. Microscope that uses light. same contact information to reach microscope. 15. Very small unit. the offce. 23. Study of proteins. 16. Most abundant protein in #marinebiology #marinescience #cells #pigmentcell #cellbiology #microscopy 24. Rebecca Heald’s favorite our bodies. research organism. 17. Inability to feel pain. Solve it online: An interactive 25. Sugary molecules. 20. Stuff inside a cell, minus version of the crossword puzzle 26. Complete collection of lipids. the organelles. and answers can be found at 27. Separates paired chromosomes 21. Really stretchy protein. https://www.nigms.nih.gov/fndings during cell division. 28. In amphibians, body size Superstars of Science Quiz (page 22) correlates with ______size. Answers: 1.E; 2.F; 3.D; 4.C; 5.B; 6.A U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH FIRST CLASS PRESORTED POSTAGE & FEES PAID NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES NIH/NIGMS 45 CENTER DR RM 3AN32 MSC 6200 PERMIT NO. G-813 BETHESDA MD 20892-6200

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