Humans face hundreds of decisions every day. But we’re not alone. Even the tiniest viruses also make decisions, and scientists are researching how they do so, to help lead to better treatments for some diseases. A team of scientists has discovered how the lambda phage decides what actions to take in its host, the E. coli bacterium.
The lambda phage prefers to destroy E. coli bacteria, which makes it a prime target for researchers. Dr. Lanying Zeng, left, and her graduate student Jimmy Trinh developed a four-color fluorescence reporter system to track it at the single-virus level. Credit: Texas A&M AgriLife Research photo by Kathleen Phillips
Humans face hundreds of decisions every day. But we’re not alone. Even the tiniest viruses also make decisions, and scientists are researching how they do so, to help lead to better treatments for some diseases.
In a study published Feb. 6 in the journal Nature Communications, Dr. Lanying Zeng and her team at Texas A&M AgriLife Research discovered how the lambda phage decides what actions to take in its host, the E. coli bacterium.
A phage is a virus that infects and replicates within a bacterium. Phages were first discovered about 100 years ago, but recently scientists have begun to study how they can be used to attack disease-causing bacteria, especially strains that have become more resistant to antibiotics.
So numerous and diverse are phages — numbering into the billions, according to various reports in the U.S. National Library of Medicine — that researchers are now hot on the trail of phages that have the potential for curing specific bacterial maladies.
The lambda phage, for example, prefers to destroy E. coli bacteria, which makes it a prime target for researchers. In tracking that target, Zeng’s graduate student Jimmy Trinh developed a four-color fluorescence reporter system to track it at the single-virus level. This was combined with computational models devised by Dr. Gábor Balázsi, a biomedical engineer and collaborator at Stony Brook University in Stony Brook, New York, “to unravel both the interactions between phages and how individual phages determine” the fate of a cell.
What they found was not unlike the decision-making process of humans. Sometimes the lambda phage cooperates with others. Sometimes it competes.
“Instead of just the cell making a decision, we found the phage DNAs themselves also make decisions,” Zeng said.
Through the process they developed, the scientists were able to determine that timing played a role in decision-making.
Zeng explained that some phages can have two cycles of reproduction: lytic and lysogenic.
In the lytic cycle, full copies of the virus are made inside of a cell, say an E. coli cell. When the phage-infected cell becomes full of the replicating viruses, it bursts open and is destroyed. In the lysogenic cycle, the phage’s DNA lives as part of the bacterium itself and both continue to reproduce as one. In short, lysis involves competition while lysogeny involves cooperation, she said.
So, a key to using phages to destroy bacteria, Zeng said, is to understand how and when a phage decides to “go lytic” on the pathogen.
“Say you have two lambda phages that infect one cell,” she said. “Each phage DNA within the cell is capable of making a decision. We want to know how they make a decision, whether one is more dominant than the other, whether they have any interactions and compete to see who will win, or whether they compromise.”
“They may even coexist for some time and then finally choose one decision,” she said. “But the phage is making a subcellular decision — and that is very important. There could be a lot of implications.”
The four-color fluorescence reporter system helped the researchers visualize that many factors contribute to the decision and that “from the evolutionary point of view, the phages want to optimize their own fitness or survival,” she said. “So that is why they choose either lytic or lysogenic to maximize or optimize their survival.”
The team identified some of the factors that led to competition and others that led to cooperation.
Zeng said because phage therapy is a growing field for seeking ways to treat bacteria, the results of this study will help other scientists advance their research.
“This is a paradigm for bacteriophages,” she said. “When we understand the mechanism of the decision more, that can lead to more applications and better characterization of other systems.”
Jimmy T. Trinh, Tamás Székely, Qiuyan Shao, Gábor Balázsi, Lanying Zeng. Cell fate decisions emerge as phages cooperate or compete inside their host. Nature Communications, 2017; 8: 14341 DOI: 10.1038/ncomms14341
Genetic material from ancient viral infections is critical to human development, according to researchers at the Stanford University School of Medicine.
They’ve identified several noncoding RNA molecules of viral origins that are necessary for a fertilized human egg to acquire the ability in early development to become all the cells and tissues of the body. Blocking the production of this RNA molecule stops development in its tracks, they found.
The discovery comes on the heels of a Stanford study earlier this year showing that early human embryos are packed full of what appear to be viral particles arising from similar left-behind genetic material.
“We’re starting to accumulate evidence that these viral sequences, which originally may have threatened the survival of our species, were co-opted by our genomes for their own benefit,” said Vittorio Sebastiano, PhD, an assistant professor of obstetrics and gynecology. “In this manner, they may even have contributed species-specific characteristics and fundamental cell processes, even in humans.”
Sebastiano is a co-lead and co-senior author of the study, which will be published online Nov. 23 in Nature Genetics. Postdoctoral scholar Jens Durruthy-Durruthy, PhD, is the other lead author. The other senior author of the paper is Renee Reijo Pera, PhD, a former professor of obstetrics and gynecology at Stanford who is now on the faculty of Montana State University.
Sebastiano and his colleagues were interested in learning how cells become pluripotent, or able to become any tissue in the body. A human egg becomes pluripotent after fertilization, for example. And scientists have learned how to induce other, fully developed human cells to become pluripotent by exposing them to proteins known to be present in the very early human embryo. But the nitty-gritty molecular details of this transformative process are not well understood in either case.
An ancient infection
The researchers knew that a type of RNA molecules called long-intergenic noncoding, or lincRNAs, have been implicated in many important biological processes, including the acquisition of pluripotency. These molecules are made from DNA in the genome, but they don’t go on to make proteins. Instead they function as RNA molecules to affect the expression of other genes.
Sebastiano and Durruthy-Durruthy used recently developed RNA sequencing techniques to examine which lincRNAs are highly expressed in human embryonic stem cells. Previously, this type of analysis was stymied by the fact that many of the molecules contain highly similar, very repetitive regions that are difficult to sequence accurately.
They identified more than 2,000 previously unknown RNA sequences, and found that 146 are specifically expressed in embryonic stem cells. They homed in on the 23 most highly expressed sequences, which they termed HPAT1-23, for further study. Thirteen of these, they found, were made up almost entirely of genetic material left behind after an eons-ago infection by a virus called HERV-H.
HERV-H is what’s known as a retrovirus. These viruses spread by inserting their genetic material into the genome of an infected cell. In this way, the virus can use the cell’s protein-making machinery to generate viral proteins for assembly into a new viral particle. That particle then goes on to infect other cells. If the infected cell is a sperm or an egg, the retroviral sequence can also be passed to future generations.
HIV is one common retrovirus that currently causes disease in humans. But our genomes are also littered with sequences left behind from long-ago retroviral infections. Unlike HIV, which can go on to infect new cells, these retroviral sequences are thought to be relatively inert; millions of years of evolution and accumulated mutations mean that few maintain the capacity to give instructions for functional proteins.
After identifying HPAT1-23 in embryonic stem cells, Sebastiano and his colleagues studied their expression in human blastocysts — the hollow clump of cells that arises from the egg in the first days after fertilization. They found that HPAT2, HPAT3 and HPAT5 were expressed only in the inner cell mass of the blastocyst, which becomes the developing fetus. Blocking their expression in one cell of a two-celled embryo stopped the affected cell from contributing to the embryo’s inner cell mass. Further studies showed that the expression of the three genes is also required for efficient reprogramming of adult cells into induced pluripotent stem cells.
Sequences found only in primates
“This is the first time that these virally derived RNA molecules have been shown to be directly involved with and necessary for vital steps of human development,” Sebastiano said. “What’s really interesting is that these sequences are found only in primates, raising the possibility that their function may have contributed to unique characteristics that distinguish humans from other animals.”
The researchers are continuing their studies of all the HPAT molecules. They’ve learned that HPAT-5 specifically affects pluripotency by interacting with and sequestering members of another family of RNAs involved in pluripotency called let-7.
“Previously retroviral elements were considered to be a class that all functioned in basically the same way,” said Durruthy-Durruthy. “Now we’re learning that they function as individual elements with very specific and important roles in our cells. It’s fascinating to imagine how, during the course of evolution, primates began to recycle these viral leftovers into something that’s beneficial and necessary to our development.”
Jens Durruthy-Durruthy, Vittorio Sebastiano, Mark Wossidlo, Diana Cepeda, Jun Cui, Edward J Grow, Jonathan Davila, Moritz Mall, Wing H Wong, Joanna Wysocka, Kin Fai Au, Renee A Reijo Pera. The primate-specific noncoding RNA HPAT5 regulates pluripotency during human preimplantation development and nuclear reprogramming. Nature Genetics, 2015; DOI: 10.1038/ng.3449
Summary: Inherited viruses that are millions of years old play an important role in building up the complex networks that characterize the human brain, researchers say. They have found that retroviruses seem to play a central role in the basic functions of the brain, more specifically in the regulation of which genes are to be expressed, and when.
A new study from Lund University in Sweden indicates that inherited viruses that are millions of years old play an important role in building up the complex networks that characterise the human brain.
Researchers have long been aware that endogenous retroviruses constitute around five per cent of our DNA. For many years, they were considered junk DNA of no real use, a side-effect of our evolutionary journey.
In the current study, Johan Jakobsson and his colleagues show that retroviruses seem to play a central role in the basic functions of the brain, more specifically in the regulation of which genes are to be expressed, and when. The findings indicate that, over the course of evolution, the viruses took an increasingly firm hold on the steering wheel in our cellular machinery. The reason the viruses are activated specifically in the brain is probably due to the fact that tumours cannot form in nerve cells, unlike in other tissues.
“We have been able to observe that these viruses are activated specifically in the brain cells and have an important regulatory role. We believe that the role of retroviruses can contribute to explaining why brain cells in particular are so dynamic and multifaceted in their function. It may also be the case that the viruses’ more or less complex functions in various species can help us to understand why we are so different,” says Johan Jakobsson, head of the research team for molecular neurogenetics at Lund University.
The article, based on studies of neural stem cells, shows that these cells use a particular molecular mechanism to control the activation processes of the retroviruses. The findings provide us with a complex insight into the innermost workings of the most basal functions of the nerve cells. At the same time, the results open up potential for new research paths concerning brain diseases linked to genetic factors.
“I believe that this can lead to new, exciting studies on the diseases of the brain. Currently, when we look for genetic factors linked to various diseases, we usually look for the genes we are familiar with, which make up a mere two per cent of the genome. Now we are opening up the possibility of looking at a much larger part of the genetic material which was previously considered unimportant. The image of the brain becomes more complex, but the area in which to search for errors linked to diseases with a genetic component, such as neurodegenerative diseases, psychiatric illness and brain tumours, also increases.”
Liana Fasching, Adamandia Kapopoulou, Rohit Sachdeva, Rebecca Petri, Marie E. Jönsson, Christian Männe, Priscilla Turelli, Patric Jern, Florence Cammas, Didier Trono, Johan Jakobsson. TRIM28 Represses Transcription of Endogenous Retroviruses in Neural Progenitor Cells. Cell Reports, 2015; 10 (1): 20 DOI: 10.1016/j.celrep.2014.12.004
Suspected Ebola patient Finda “Zanabo” prays over her sick family members before being admitted to the Doctors Without Borders Ebola treatment center on Aug. 21, 2014, near Monrovia, Liberia. Photo by John Moore/Getty Images
The gruesomeness with which it kills: by hijacking cells and migrating throughout the body to affect all organs, causing victims to bleed profusely.
The ease with which it is transmitted: through contact with bodily fluids, including sweat, tears, saliva, blood, urine, semen, etc., including objects that have come in contact with bodily fluids (such as bed sheets, clothing, and needles) and corpses.
Terrifying as these factors are, it is not clear to me that any of them capture what is truly, horribly tragic about this disease.
The most striking thing about the virus is the way in which it propagates. True, through bodily fluids, but to suggest as much is to ignore the conditions under which bodily contact occurs. Instead, the mechanism Ebola exploits is far more insidious. This virus preys on care and love, piggybacking on the deepest, most distinctively human virtues. Affected parties are almost all medical professionals and family members, snared by Ebola while in the business of caring for their fellow humans. More strikingly, 75 percent of Ebola victims are women, people who do much of the care work throughout Africa and the rest of the world. In short, Ebola parasitizes our humanity.
More than most other pandemic diseases (malaria, cholera, plague, etc.) and more than airborne diseases (influenza, swine flu, H5N1, etc.) that are transmitted indiscriminately through the air, this disease is passed through very minute amounts of bodily fluid. Just a slip of contact with the infected party and the caregiver herself can be stricken.
If Ebola is not stopped, this disease can destroy whole families within a month, relatives of those families shortly thereafter, friends of those relatives after that, and on and on. As it takes hold (and it is taking hold fast), it cuts out the heart of family and civilization. More than the profuse bleeding and high kill rate, this is why the disease is terrifying. Ebola sunders the bonds that make us human.
Such heroic efforts are the appropriate medical response to a virulent public health catastrophe. The public health community is doing an incredible job, facing unbelievable risks, relying on extremely limited resources. Yet these efforts can only do half of the work. Infected parties—not all, to be sure, but some (enough)—cannot abide by the rules of disease isolation. Some will act without donning protective clothing. Some will assist without taking proper measures. And still others will refuse to enter isolation units because doing so means leaving their families and their loved ones behind, abandoning their humanity, and subjecting themselves to the terror of dying a sterile, lonely death.
A man checks on a very sick Saah Exco, 10, in a back alley of the West Point slum on Aug. 19, 2014, in Monrovia, Liberia. Photo by John Moore/Getty Images
But imagine: You are a parent whose child has suddenly come ill with a fever. Do you cast your child away and refuse to touch him? Do you cover your face and your arms? Stay back! Unclean! Or do you comfort your child when he asks for you, arms outstretched, to make the pain go away?
Imagine: You live in a home with five other family members. Your sister falls ill, ostensibly from Ebola, but possibly from malaria, typhoid, yellow fever, or the flu. You are aware of the danger to yourself and your other family members, but you have no simple means to move her, and she is too weak to move herself. What do you do?
Imagine: You are a child of 5 years old. Your mother is sick. She implores you to back away. But you are scared. What you need, more than anything, is a hug and a cry.
Who can blame a person for this? It is a terrible, awful predicament. A moral predicament. To stay, comfort, and give love and care to those who are in desperate need, or to shuttle them off into an isolation ward, perhaps never to see them again? What an inhumane decision this is.
What makes the Ebola virus so terrifying is not its kill rate, its exponential growth, the gruesome way in which it kills, the ease of transmission, or the threat of mutation, but rather that people who care can do almost nothing but sit on the sidelines and watch.
* * *
Many have asked whether Ebola could come here, come West. (The implication, in its way, is crass—as if to suggest that we need not be concerned about a tragedy unless it poses a threat to us.) We have been reassured that it will never spread widely here, because our public health networks are too strong, our hospitals too well-stocked. The naysayers may be right about this. But they are not right that it does not pose a threat to us.
For starters, despite the pretense, the West is not immune from absurd, unscientific thinking. We have our fair share of scientific illiteracy, skepticism, ritualism, and foolishness. But beyond this, it is our similarities, not our differences, that make us vulnerable to this plague. We are human. Every mechanism we have for caring—touching, holding, feeding, playing, warming, comforting, caressing—every mechanism that we use to bind us to our families and our neighbors, is preyed upon by Ebola. We cannot seal each other into hyperbaric chambers and expect that once we emerge, the carnage will be over. We are humans, and we will care about our children and our families even if it means that we may die in doing so.
The lesson here is a vital one: People do not give up on humanity so very easily. Even if we persuade all of the population to forgo rituals like washing the dead, we will not easily persuade parents to keep from holding their sick children, children from clinging to their ailing parents, or children from playing and wrestling and slobbering all over one another. We tried to alter such behaviors with HIV/AIDS. A seemingly simple edict—“just lay off the sex with infected parties”—would seem all that is required to halt that disease. But we have learned over the decades that people do not give up sex so readily.
If you think curtailing sex is hard, love and compassion will be that much harder. Humans will never give this up—we cannot give this up, for it is fundamental to who we are. The more that medical personnel require this of people without also giving them methods to manifest care, the more care and compassion will manifest in pockets outside of quarantine. And the more humanity that manifests unchecked, the more space this virus has to grow. Unchecked humanity will seep through the cracks and barriers that we build to keep our families safe, and if left to find its own way, will carry a lethal payload.
The problem is double-edged. Ebola threatens humanity by preying on humanity. The seemingly simple solution is to destroy humanity ourselves—to seal everything off and let the disease burn out on its own. But doing so means destroying ourselves in order to save ourselves, which is no solution at all.
A medical worker in a protective suit works near Ebola patients in a Doctors Without Borders hospital on Sept. 7, 2014, in Monrovia, Liberia. Photo by Dominique Faget/AFP/Getty Images
We must find a method of caring without touching, of contacting without making contact. The physiological barriers are, for the time being, necessary. But we cannot stop people from caring about one another, so we must create, for the time being, mechanisms for caring. Since we will never be able to beat back humanity, we must coordinate humanity, at the family level, the local level, and the global level.
The only one way to battle a disease that affixes itself parasitically to our humanity is to overwhelm it with greater, stronger humanity. To immunize Africa and the rest of the world with a blast of humanity so powerful that the disease can no longer take root. What it will take to beat this virus is to turn its most powerful vehicle, our most powerful weapon, against it.
Here are some things we can do:
Donate to the great organizations that are working tirelessly to bring this disease under control. They need volunteers, medical supplies, facilities, transportation, food, etc. Share information about Ebola, so people will learn about it, know about it, and know how to address it when it comes. And inform and help others. It is natural at a time of crisis to call for sealing the borders, to build fences and walls that separate us further from outside threats. But a disease that infects humanity cannot easily be walled off in this way. Walling off just creates unprotected pockets of humanity, divisions between us and them: my family, your family; that village, this village; inside, outside.
* * *
One final thing.
When Prince Prospero, ill-fated protagonist of Edgar Allan Poe’s story “The Masque of the Red Death,” locked himself in his castle to avoid a contagion that was sweeping his country—a disease that caused “profuse bleeding at the pores”—he assumed mistakenly that the only reasonable solution to his problem was to remove himself from the scene. For months he lived lavishly, surrounded by courtiers, improvisatori, buffoons, musicians, and wine, removed from danger while the pestilence wrought havoc outside.
As with much of Poe’s writing, Prospero’s tale does not end well. For six months, all was calm. He and his courtiers enjoyed their lives, secure and isolated from the plague laying waste to the countryside. Then, one night during a masquerade ball, the Red Death snuck into the castle, hidden behind a mask and a cloak, to afflict Prospero and his revelers, dropping them one by one in the “blood-bedewed halls.” Prospero’s security was a façade, leaving darkness and decay to hold “illimitable dominion over all.” The eventual intrusion that would be his undoing foretells of a danger in believing that we can keep the world’s ills at bay by keeping our distance.
If we seek safety by shutting out the rest of the world, we are in for a brutally ugly awakening. Nature is a cruel mistress, but Ebola is her cruelest, most devious trick yet.