Spike proteins on the surface of a coronavirus. Credit: David Veesler, University of Washington.
Since the start of the COVID-19 pandemic, researchers from many areas of biomedical science have worked together to learn how this new disease affects the human body, how to prevent its spread, and how to treat it. Severe cases of COVID-19 and cases of sepsis share many symptoms. Sepsis is the body’s overactive and extreme response to an infection. It’s unpredictable and can progress rapidly. Without prompt treatment, it can lead to tissue damage, organ failure, and death.
Sepsis has similarities with some cases of COVID-19, most likely because the two conditions trigger the same reactions at the cellular level. Researchers have studied these reactions in sepsis for many years.
“When we look back on 2020 and the speed with which progress was made against COVID-19, two features will stand out,” says John Younger, M.D., a member of the NIGMS Advisory Council who recently co-chaired a working group on advancing sepsis research. “The first is how quickly the biotechnology community came together to develop vaccine candidates. The second, and arguably the most immediately impactful, is how caregivers and clinical researchers were able to rapidly refine the care of COVID-19 patients based on decades of experience with sepsis.”
This post highlights a few of the many sepsis researchers supported by NIGMS who are applying their expertise to COVID-19.
When someone mentions aging, you may think of visible changes, like graying hair. Scientists can see signs of aging in cells, too. Understanding how basic cell processes are involved in aging is a first step to help people lead longer, healthier lives. NIGMS-funded researchers are discovering how aging cells change and applying this knowledge to health care.
Discovering the Wisdom of Worms
C. elegans with a ribosomal protein glowing red and muscle fibers glowing green. Credit: Hannah Somers, Mount Desert Island Biological Laboratory.
Aric Rogers, Ph.D., and Jarod Rollins, Ph.D., assistant professors of regenerative biology and medicine at Mount Desert Island (MDI) Biological Laboratory in Bar Harbor, Maine, are investigating aging by studying a tiny roundworm, Caenorhabditis elegans. Researchers often study C. elegans because, though it may seem drastically different from humans, it shares many genes and molecular pathways with us. Plus, its 2- to 3-week lifespan enables researchers to quickly see the effects of genetic or environmental factors on aging.
Drs. Rogers and Rollins investigate how C. elegans expresses genes differently under dietary restriction, enabling it to live longer. Understanding how genes are expressed when organisms live an extended life sheds light on the genetics underlying aging. This information could help researchers develop drugs or behavior modification programs that prolong life and delay the onset of age-related diseases such as heart disease, diabetes, cancer, and dementia.
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
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.
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 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 further increased the number of available human genomes by adding 300 individuals representing 142 populations around the globe.
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.
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. Continue reading “Our Complicated Relationship With Viruses”
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, 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”
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”
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 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. Continue reading “Field Focus: Progress in RNA Interference Research”
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.
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.
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”