Tag: Research Roundup

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Freezing a Moment in Time: Snapshots of Cryo-EM Research

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To get a look at cell components that are too small to see with a normal light microscope, scientists often use cryo-electron microscopy (cryo-EM). As the prefix cryo- means “cold” or “freezing,” cryo-EM involves rapidly freezing a cell, virus, molecular complex, or other structure to prevent water molecules from forming crystals. This preserves the sample in its natural state and keeps it still so that it can be imaged with an electron microscope, which uses beams of electrons instead of light. Some electrons are scattered by the sample, while others pass through it and through magnetic lenses to land on a detector and form an image.

Typically, samples contain many copies of the object a scientist wants to study, frozen in a range of orientations. Researchers take images of these various positions and combine them into a detailed 3D model of the structure. Electron microscopes allow us to see much smaller structures than light microscopes do because the wavelengths of electrons are much shorter than the wavelength of light. NIGMS-funded researchers are using cryo-EM to investigate a range of scientific questions.

Caught in Translation

One cluster that is yellow, purple, and orange and another that is beige, purple, and green. 3D reconstructions of two stages in the assembly of the bacterial ribosome created from time-resolved cryo-EM images. Credit: Joachim Frank, Columbia University.

Joachim Frank, Ph.D., a professor of biochemistry and molecular biophysics and of biological sciences at Columbia University in New York, New York, along with two other researchers, won the 2017 Nobel Prize in Chemistry for developing cryo.

Dr. Frank’s lab focuses on the process of translation, where structures called ribosomes turn genetic instructions into proteins, which are needed for many chemical reactions that support life. Recently, Dr. Frank has adopted and further developed a technique called time-resolved cryo-EM. This method captures images of short-lived states in translation that disappear too quickly (after less than a second) for standard cryo-EM to capture. The ability to fully visualize translation could help researchers identify errors in the process that lead to disease and also to develop treatments.

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Field Focus: High-Quality Genome Sequences Inform the Study of Human Evolution

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Leafing through my favorite biology textbook from a handful of years ago, I was struck by the relative brevity of the chapter on human evolution. While other fields of biological research have enjoyed a steady gallop of productivity over the last few decades due in part to advances in computing power, imaging technology and experimental methods, the study of human evolution can be seen as having lagged behind until recently due to an almost complete dependence on fossil evidence.

Fortunately, contemporary biology textbook chapters on human evolution are being primed for a serious upgrade thanks to the recent availability of high-quality genome sequences from diverse modern human populations as well as from ancient humans and other non-human hominids, including the Neanderthals and Denisovans (but, for purposes of this story, not the Great Apes).

Modern human skull (left) and Neanderthal skull (right), shown to scale. There are not enough Denisovan bone fragments to reconstruct its skull. Credit: Wikimedia Commons, hairymuseummatt.

What are the new resources for studying human evolution?

The cost of DNA sequencing has dropped precipitously in the last decade. As a result, more complete human genome sequences become available for analysis with each passing year.

For example, the 1000 Genomes Project Exit icon includes more than 1,000 full human genome sequences of individuals from European, Asian, American and Sub-Saharan African populations. Earlier this year, the Simons Genome Diversity Project Exit icon further increased the number of available human genomes by adding 300 individuals representing 142 populations around the globe.

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Our Complicated Relationship With Viruses

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Illustration of Influenza Virus H1N1. Swine Flu.
Nearly 10 percent of the human genome is derived from the genes of viruses. Credit: Stock image.

When viruses infect us, they can embed small chunks of their genetic material in our DNA. Although infrequent, the incorporation of this material into the human genome has been occurring for millions of years. As a result of this ongoing process, viral genetic material comprises nearly 10 percent of the modern human genome. Over time, the vast majority of viral invaders populating our genome have mutated to the point that they no longer lead to active infections. But they are not entirely dormant.

Sometimes, these stowaway sequences of viral genes, called “endogenous retroviruses” (ERVs), can contribute to the onset of diseases such as cancer. They can also make their hosts susceptible to infections from other viruses. However, scientists have identified numerous cases of viral hitchhikers bestowing crucial benefits to their human hosts—from protection against disease to shaping important aspects of human evolution, such as the ability to digest starch.

Protecting Against Disease

Geneticists Cedric Feschotte, Edward Chuong and Nels Elde Exit icon at the University of Utah have discovered that ERVs lodged in the human genome can jump start the immune system.

For a virus to successfully make copies of itself inside a host cell, it needs molecular tools similar to the ones its host normally uses to translate genes into proteins. As a result, viruses have tools meticulously shaped by evolution to commandeer the protein-producing machinery of human cells.

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New Views on What the Cell’s Parts Can Do

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Studying some of the most well-tread territory in science can turn up surprising new findings. Take, for example, the cell. You may have read in textbooks how the cell’s parts look and function during important biological processes like cellular movement and division. You may have even built models of the cell out of gelatin or clay. But scientists continue to learn new facts that require those textbooks to be updated, and those models to be reshaped. Here are a few examples.

Nuclear Envelope: More Than a Protective Barrier

Damaged heterochromatin represented by nucleotides GCAT
Damaged heterochromatin, a tightly packed form of DNA, travels to the inner wall of the nuclear envelope for repair. Credit: Irene Chiolo and Taehyun Ryu, University of Southern California.

Like a security guard checking IDs at the door, the nuclear envelope forms a protective barrier around the cell’s nucleus, only letting specific proteins and chemical signals pass through. Scientists recently found that this envelope may also act as a repair center for broken strands of heterochromatin, a tightly packed form of DNA.

Irene Chiolo of the University of Southern California and Gary Karpen of the University of California, Berkeley, and the Lawrence Berkeley National Laboratory were part of a team that learned that healthy fruit fly cells mend breaks in heterochromatin by moving the damaged DNA strands to the inner wall of the nuclear envelope. There, proteins embedded in the envelope make the necessary repairs in a safe place where the broken DNA can’t accidentally get fused to the wrong chromosome. Continue reading “New Views on What the Cell’s Parts Can Do”

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The Simple Rules Bacteria Follow to Survive

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Left: Football stadium. Right: Colored contoured lines showing the periodic stops in the growth of a bacterial colony
Football image credit: Stock image. The colored contoured lines show the periodic stops in the growth of a bacterial colony. Credit: Süel Lab, UCSD.

What do these images of football fans and bacterial cells have in common? By following simple rules, each individual allows the group to accomplish tasks none of them could do alone—a stadium wave that ripples through the crowd or a cell colony that rebounds after antibiotic treatment.

These collective behaviors are just a few examples of what scientists call emergent phenomena. While the reasons for the emergence of such behavior in groups of birds, fish, ants and other creatures is well understood, they’ve been less clear in bacteria. Two independent research teams have now identified some of the rules bacterial cells follow to enable the colony to persist. Continue reading “The Simple Rules Bacteria Follow to Survive”

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Field Focus: Progress in RNA Interference Research

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Scientists first noticed what would later prove to be RNA interference when puzzling over an unexpected loss of color in petunia petals. Subsequent studies in roundworms revealed that double-stranded RNA can inactivate specific genes. Credit: Alisa Z. Machalek.

In less than two decades, RNA interference (RNAi)—a natural process cells use to inactivate, or silence, specific genes—has progressed from a fundamental finding to a powerful research tool and a potential therapeutic approach. To check in on this fast-moving field, I spoke to geneticists Craig Mello of the University of Massachusetts Medical School and Michael Bender of NIGMS. Mello shared the 2006 Nobel Prize in physiology or medicine with Andrew Fire Exit icon of Stanford University School of Medicine for the discovery of RNAi. Bender manages NIGMS grants in areas that include RNAi research.

How have researchers built on the initial discovery of RNAi?

A scientific floodgate opened after the 1998 discovery that it was possible to switch off specific genes by feeding microscopic worms called C. elegans double-stranded RNA that had the same sequence of genetic building blocks as a target gene. (Double-stranded RNA is a type of RNA molecule often found in, or produced by, viruses.) Scientists investigating gene function quickly began to test RNAi as a gene-silencing technique in other organisms and found that they could use it to manipulate gene activity in many different model systems. Additional studies led the way toward getting the technique to work in cells from mammals, which scientists first demonstrated in 2001. Soon, researchers were exploring the potential of RNAi to treat human disease.

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Nature’s Medicine Cabinet

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More than 70 percent of new drugs approved within the past 30 years originated from trees, sea creatures and other organisms that produce substances they need to survive. Since ancient times, people have been searching the Earth for natural products to use—from poison dart frog venom for hunting to herbs for healing wounds. Today, scientists are modifying them in the laboratory for our medicinal use. Here’s a peek at some of the products in nature’s medicine cabinet.

Vampire bat

A protein called draculin found in the saliva of vampire bats is in the last phases of clinical testing as a clot-buster for stroke patients. Vampire bats are able to drink blood from their victims because draculin keeps blood from clotting. The first phases of clinical trials have shown that the protein’s anti-coagulative properties could give doctors more time to treat stroke patients and lower the risk of bleeding in the brain.

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Structural Studies Demystify Membrane Protein

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Animated structural model of TSPO.
Animated structural model of TSPO. Credit: Michigan State University.

Mitochondria have proteins that span their membranes to control the flow of messages and materials moving into and out of the organelle. One way scientists can learn more about how membrane proteins function—and how medicines might interact with them—is to determine their structures. But for a variety of reasons, obtaining the structures has been notoriously difficult.

Two structural studies have now shed light on the mysterious mitochondrial membrane protein TSPO. This protein plays a key role in transporting cholesterol and drugs into the cell’s mitochondria. While here, the cholesterol is converted to steroid hormones that are essential for numerous bodily functions. Although many researchers have been studying TSPO since the 1990s, they’ve remained uncertain about its mechanisms and how it truly functions. Continue reading “Structural Studies Demystify Membrane Protein”

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Field Focus: Making Chemistry Greener

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Bob Lees
NIGMS’ Bob Lees answers questions about green chemistry. Credit: National Institute of General Medical Sciences.

Chemists funded by NIGMS are working to develop “greener” processes for discovering, developing and manufacturing medicines and other molecules with therapeutic potential, as well as compounds used in biomedical research. One of our scientific experts, organic chemist Bob Lees, recently spoke to me about some of these efforts.

What is green chemistry?

Green chemistry is the design of chemical processes and products that are more environmentally friendly. Among the 12 guiding principles of green chemistry Exit icon are producing less waste, including fewer toxic byproducts; using more sustainable (renewable) or biodegradable materials; and saving energy. Continue reading “Field Focus: Making Chemistry Greener”

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Cellular ‘Cruise Control’ Systems Let Cells Sense and Adapt to Changing Demands

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Cells are the ultimate smart material. They can sense the demands being placed on them during critical life processes and then respond by strengthening, remodeling or self-repairing, for instance. To do this, cells use “mechanosensory” systems similar to the cruise control that lets a car’s engine adjust its power output when going up or down hills.

Researchers are uncovering new details on cells’ molecular cruise control systems. By learning more about the inner workings of these systems, scientists hope ultimately to devise ways to tinker with them for therapeutic purposes.

Cell Fusion

To examine how cells fine-tune their architecture and force output during the merging or fusion of cells, Elizabeth Chen and Douglas Robinson of Johns Hopkins University teamed up with Daniel Fletcher of the University of California, Berkeley. Cell fusion is critical to many developmental and physiological processes, including fertilization, placenta formation, immune response, and skeletal muscle development and regeneration.

Illustration of cell fusion

Fingerlike protrusions of one cell (pink) invade another cell prior to cell fusion. Credit: Shuo Li. Used with permission from Developmental Cell.

Using the fruit fly Drosophila melanogaster as a model system, Chen’s research group Exit icon previously found that when two muscle cells merge during muscle development, fingerlike protrusions of one cell invade the territory of the other cell to promote fusion. In the new study, led by Chen, the researchers showed that cell fusion depends on the ability of the “receiving” cell to put up resistance against the invading cell Exit icon.

In fusing fruit fly cells, the scientists saw that in areas where the invading cells drilled in, the receiving cells quickly stiffened their cell skeletons, effectively pushing back. This mechanosensory response allows the outer membranes of the two cells to be pushed together and later fuse, Chen explains.

The team then explored the mechanisms underlying the stiffening response. They found that a protein called myosin II, which is part of the cell skeleton, senses the pushing force from the invading cell. Myosin II swarms to the fusion site and binds with fibers just beneath the cell membrane to put up the necessary resistance. Continue reading “Cellular ‘Cruise Control’ Systems Let Cells Sense and Adapt to Changing Demands”