Bacterial cells transmit memories to offspring

Bacterial cells can "remember" brief, temporary changes to their bodies and immediate surroundings, a new Northwestern University and University of Texas-Southwestern study has found.

And, although these changes are not encoded in the cell's genetics, the cell still passes memories of them to its offspring -- for multiple generations.

Not only does this discovery challenge long-held assumptions of how the simplest organisms transmit and inherit physical traits, it also could be leveraged for new medical applications. For example, researchers could circumvent antibiotic resistance by subtly tweaking a pathogenic bacterium to render its offspring more sensitive to treatment for generations.

The study will be published Wednesday (Aug. 28) in the journal Science Advances.

"A central assumption in bacterial biology is that heritable physical characteristics are determined primarily by DNA," said Northwestern's Adilson Motter, the study's senior author. "But, from the perspective of complex systems, we know that information also can be stored at the level of the network of regulatory relationships among genes. We wanted to explore whether there are characteristics transmitted from parents to offspring that are not encoded in DNA, but rather in the regulatory network itself. We found that temporary changes to gene regulation imprint lasting changes within the network that are passed on to the offspring. In other words, the echoes of changes affecting their parents persist in the regulatory network while the DNA remains unchanged."

Motter is the Charles E. and Emma H. Morrison Professor of Physics at Northwestern's Weinberg College of Arts and Sciences and director of the Center for Network Dynamics. The study's co-first authors are postdoctoral fellow Thomas Wytock and graduate student Yi Zhao, who are both members of Motter's laboratory. The study also involves a collaboration with Kimberly Reynolds, a systems biologist at the University of Texas Southwestern Medical Center.

Learning from a model organism

Since researchers first identified the molecular underpinnings of genetic code in the 1950s, they have assumed traits are primarily -- if not exclusively -- transmitted through DNA. However, after the completion of the Human Genome Project in 2001, researchers have revisited this assumption.

Wytock cites the World War II Dutch famine as a famous example pointing to the possibility of heritable, non-genetic traits in humans. A recent study showed that the children of men, who were exposed to the famine in utero, exhibited an increased tendency to become overweight as adults. But isolating the ultimate causes for this type of non-genetic inheritance in humans has proved challenging.

"In the case of complex organisms, the challenge lies in disentangling confounding factors such as survivor bias," Motter said. "But perhaps we can isolate the causes for the simplest single-cell organisms, since we can control their environment and interrogate their genetics. If we observe something in this case, we can attribute the origin of non-genetic inheritance to a limited number of possibilities -- in particular, changes in gene regulation."

The regulatory network is analogous to a communication network that genes use to influence each other. The research team hypothesized that this network alone could hold the key to transmitting traits to offspring. To explore this hypothesis, Motter and his team turned to Escherichia coli (E. coli), a common bacterium and well-studied model organism.

"In the case of E. coli, the entire organism is a single cell," Wytock said. "It has many fewer genes than a human cell, some 4,000 genes as opposed to 20,000. It also lacks the intracellular structures known to underlie the persistence of DNA organization in yeast and the multiplicity of cell types in higher organisms.Because E. coli is a well-studied model organism, we know the organization of the gene regulatory network in some detail."

Reversible stress, irreversible change

The research team used a mathematical model of the regulatory network to simulate the temporary deactivation (and subsequent reactivation) of individual genes in E. coli. They discovered these transient perturbations can generate lasting changes, which are projected to be inherited for multiple generations. The team currently is working to validate their simulations in laboratory experiments using a variation of CRISPR that deactivates genes temporarily rather than permanently.

But if the changes are encoded in the regulatory network rather than the DNA, the research team questioned how a cell can transmit them across generations. They propose that the reversible perturbation sparks an irreversible chain reaction within the regulatory network. As one gene deactivates, it affects the gene next to it in the network. By the time the first gene is reactivated, the cascade is already in full swing because the genes can form self-sustaining circuits that become impervious to outside influences once activated.

"It's a network phenomenon," said Motter, who is an expert in the dynamic behaviors of complex systems. "Genes interact with each other. If you perturb one gene, it affects others."

Although his team is deactivating genes to test the hypothesis, Motter is clear that different types of perturbations could cause a similar effect. "We also could have changed the cell's environment," he said. "It could be the temperature, the availability of nutrients or the pH."

The study also suggests that other organisms have the necessary elements to exhibit non-genetic heritability. "In biology, it's dangerous to assume anything is universal," Motter contends. "But, intuitively, I do expect the effect to be common because E. coli'sregulatory network is similar or simpler than those found in other organisms."

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Chimp moms play with their offspring through good times and bad

When it comes to nurturing their young, mother chimpanzees go the extra mile, according to a new study. Using 10 years of observational data on wild chimpanzees, researchers found that while adults often play, and young chimps play a lot, when food gets scarce, the adults put mutual play aside and focus on survival.

But in the meantime, mother chimps continue to be their offspring's primary playmate, tickling, chasing, playing 'airplane'. That suggests the mother chimps take on an indispensable role fostering their young's physical and social development even when they are under food stress.

The study observations took place in Kibale National Park in Uganda, and the study analysis, published in Current Biology, was led by Zarin Machanda, an assistant professor of anthropology and biology, and her former postdoctoral associate Kris Sabbi, who is currently a college fellow in human evolutionary biology at Harvard University.

Kibale is the most primate-dense forest in the world, with thirteen species living there including over 1,000 chimpanzees. Researchers started habituating the chimps to the presence of humans in 1987. Over the decades, teams of researchers took detailed field notes of almost every observable behavior -- including climbing, feeding, grooming, calling, aggression, and play.

Through their previous work, Machanda and Sabbi were familiar with the playfulness of chimpanzees and decided to look deeper into the patterns of play behavior. They expected seasonal variations in food availability would affect adult chimps' time spent playing.

For example, when supplies of quality fruits were low, the chimps focused on finding and gathering figs and leaves, and put play time aside. Surprisingly, although chimp mothers had the same challenge in finding food, they continued devoting a lot of their time to nurturing their offspring's development through play.

Learning Lessons from Play

"The research on play ties into an effort to understand the evolution of leadership among chimps," said Machanda. "We were trying to see whether chimps have only one pathway to leadership, which has always been assumed to be aggressiveness, or whether play and other behaviors build multiple dimensions of character that might make them more or less successful."

Play is not very common in the wild, at least among adult animals. Young mammals do play often, but mostly with each other, or at the expense of an exasperated and passive adult. Exceptions include dolphins, monkeys, and apes. Natural selection tends to suppress the costly exercise after it serves its purpose for development, and time comes to focus on finding food, watching out for predators, and mating. With chimps, however, adult play serves to cement social bonds.

Why do some primates play throughout life and other mammals don't? "I think what sets primates apart is that they spend more time growing up compared to other mammals," said Machanda. "They also have highly developed brains and live in structured groups, with very specific rules governing interactions between individuals. Play permits them to build not only physical skills, but also the skills of social interaction."

Social structure in the chimpanzee world may also explain why mother chimps sometimes become the primary play partners for their young. The chimpanzees have a very fluid social system called fission-fusion, which means a group of 60 chimps, for example, may have smaller groups break away for days or weeks, which then merge again while other groups break off.

When food becomes scarce, chimp mothers tend to break away into smaller groups or solo with their babies. "But when they're doing that, they are also limiting the ability of their young ones to play with others, and the moms become the primary playmates," said Sabbi. "They're trading off that lower feeding competition in the larger group for more time and energy being spent playing with their little ones."

By comparison, a troop of 60 baboons always sticks together, so baby baboons always have other baboons close to their age nearby to play with. Baboon mothers usually do not play with their babies.

Types of Play

Play among the chimps often divides depending on their sex. "It's not uncommon to see male chimps to engage in more aggressive types of play, while females are doing a type of play related to parenting," said Machanda. "You see them practice carrying things -- a kind of preparation for future maternal behavior. Males often size each other up, and when they hit their second birthday, play style changes and can get rougher."

Mothers are often the ones that juveniles and older infants come back to. "If they're playing with somebody and it starts to get a little bit too rough, they'll switch it up and go back to playing with mom, because at the end of the day it's a very safe place," said Sabbi.

"If we compare to humans, it's very easy to find lots of evidence in the child psychology literature for how important it is for human mothers and fathers to be playing with their children, especially at really young ages. Moms and dads are important first play partners before kids branch out into their own social networks," she said.

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Humans are unique but not exceptional species of mammal

In modern society, one parent may take a daughter to ballet class and fix dinner so the other parent can get to exercise class before picking up the son from soccer practice. To an observer, they seem to be cooperating in their very busy, co-parenting, monogamous relationship.

These people may think they are part of an evolved society different from the other mammals that inhabit earth. But their day-to-day behavior and child-rearing habits are not much different than other mammals who hunt, forage for food, and rear and teach their children, researchers suggest.

"For a long time it has been argued that humans are an exceptional, egalitarian species compared to other mammals," said Monique Borgerhoff Mulder, professor emerita of anthropology at the University of California, Davis, and corresponding author of a new study. But, she said, this exceptionalism may have been exaggerated.

"Humans appear to resemble mammals that live in monogamous partnerships and to some extent, those classified as cooperative breeders, where breeding individuals have to rely on the help of others to raise their offspring," she said.

The UC Davis-led study, with more than 100 researchers collaborating from several institutions throughout the world, is the first to look at whether human males are more egalitarian than are males among other mammals, focusing on the numbers of offspring they produce.

The article, "Reproductive inequality in humans and other mammals," was published this week (May 22) in the Proceedings of the National Academy of Sciences. Co-authors include researchers from UC Davis, The Santa Fe Institute, the National Institute for Mathematical and Biological Synthesis, and the Max Planck Institute for Evolutionary Anthropology, Germany.

The researchers amassed data from 90 human populations comprising 80,223 individuals from many parts of the world -- both historical and contemporary. They compared the records for men and women to lifetime data for 45 different nonhuman, free-ranging mammals.

The researchers found that humans are by no means exceptional, merely another unique species of mammal. Furthermore, as first author Cody Ross, former UC Davis graduate student in the Department of Anthropology now at the Max Planck Institute, points out "we can quite successfully model reproductive inequality in humans and nonhumans using the same predictors."

Egalitarianism in polygynous societies

Somewhat unexpectedly, when focusing specifically on women, the researchers found greater reproductive egalitarianism in societies that allow for polygynous marriage than in those where monogamous marriage prevails. In polygynous systems, in which men take several wives at the same time, women tend to have more equal access to resources, such as land, food and shelter -- and parenting help. This is because women, or their parents on their behalf, favor polygynous marriages with wealthy men who have more resources to share.

Researchers observed something else in their work.

"It turns out that monogamous mating (and marriage) can drive significant inequalities among women," Borgerhoff Mulder said. Monogamy, practiced in agricultural and market economies, can promote large differences in the number of children couples produce, researchers found, resulting from large differences in wealth in such economies.

How humans may differ

The fact men are relatively egalitarian compared to other animals reflects our patterns of child rearing. Human children are heavily dependent on the care and resources provided by both mothers and fathers -- a factor that is unusual, but not completely absent -- in other mammals, researchers said.

The critical importance of the complementary nature of this care -- that that each parent provides different and often non-substitutable resources and care throughout long human childhoods -- is why we don't show the huge reproductive variability seen in some of the great apes, said researcher Paul Hooper, from the University of New Mexico.

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How selfish genes succeed

New findings from the Stowers Institute for Medical Research uncover critical insights about how a dangerous selfish gene -- considered to be a parasitic portion of DNA -- functions and survives. Understanding this dynamic is a valuable resource for the broader community studying meiotic drive systems.

A new study, published in PLoS Genetics on Dec. 7, 2022, reveals how a selfish gene in yeast uses a poison-antidote strategy that enables its function and likely has facilitated its long-term evolutionary success. This strategy is an important addition for scientists studying similar systems including teams that are designing synthetic drive systems for pathogenic pest control. Collective and collaborative advancement on understanding drive may one day lead to the eradication of pest populations that harm crops or even humans in the case of vector borne diseases.

"It's quite dangerous for a genome to encode a protein that has the capacity to kill the organism," said Stowers Associate Investigator SaraH Zanders, Ph.D. "However, understanding the biology of these selfish elements could help us build synthetic drivers to modify natural populations."

Drivers are selfish genes that can spread in a population at higher rates than most other genes, without benefiting the organism. Previous research from the Zanders Lab revealed that a driver gene in yeast, wtf4, produces poison protein capable of destroying all offspring. However, for a given parent cell's chromosome pair, drive is achieved when wtf4 is found only on one chromosome. The effect is a simultaneous rescue of only those offspring that inherit the drive allele, by delivering a dose of a very similar protein that counteracts the poison, the antidote.

Building upon this work, the study, led by former Predoctoral Researcher Nicole Nuckolls, Ph.D., and current Predoctoral Researcher Ananya Nidamangala Srinivasa in the Zanders Lab, discovered that differences in the timing of generating poison and antidote proteins from wtf4 and their unique distribution patterns within developing spores are fundamental to the drive process.

The team has developed a model they are continuing to investigate for how the poison acts to kill the spore -- the equivalent of a human egg or sperm in yeast. Their results indicate that poison proteins cluster together, potentially disrupting proper folding of other proteins required for the cell to function. Because the wtf4 gene encodes both poison and antidote, the antidote is very similar in form and groups together with the poison. However, the antidote has an extra part that appears to isolate the poison-antidote clusters by bringing them to the cell's garbage can, the vacuole.

To understand how selfish genes function during reproduction, the researchers looked at the beginning of spore formation and found poison protein expressed within all developing spores and the sac surrounding them, while the antidote protein was only seen in low concentration throughout the sac. Later in development, the antidote was enriched inside of the spores that inherited wtf4 from the parent yeast cell.

The researchers found that spores that inherited the driver gene manufactured additional antidote protein inside the spore to neutralize the poison and ensure their survival.

The team also discovered that a particular molecular switch that controls many other genes involved in spore formation also controls the expression of poison, but not antidote, from the wtf4 gene. The switch is essential for yeast reproduction and is inextricably linked to wtf4, helping to explain why this selfish gene is so successful at evading any attempts by the host to disable the switch.

"One of the reasons we are thinking these things have stuck around for so long -- they've used this sneaky strategy of exploiting the same essential switch that turns on yeast reproduction," said Nidamangala Srinivasa.

"If we could manipulate these DNA parasites to be expressed in mosquitoes and drive their destruction, it may be a way to control pest species," said Nuckolls.

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Plants use their epigenetic memories to adapt to climate change

Animals can adapt quickly to survive adverse environmental conditions. Evidence is mounting to show that plants can, too. A paper publishing in the journal Trends in Plant Science on November 17 details how plants are rapidly adapting to the adverse effects of climate change, and how they are passing down these adaptations to their offspring.

"One day I thought how the living style and experience of a person can affect his or her gametes transmitting molecular marks of their life into their children," says Federico Martinelli, a plant geneticist at the University of Florence. "Immediately I thought that even more epigenetic marks must be transmitted in plants, being that plants are sessile organisms that are subjected to many more environmental stresses than animals during their life."

Plants are facing more environmental stressors than ever. For example, climate change is making winters shorter and less severe in many locations, and plants are responding. "Many plants require a minimum period of cold in order to set up their environmental clock to define their flowering time," says Martinelli. "As cold seasons shorten, plants have adapted to require less period of cold to delay flowering. These mechanisms allow plants to avoid flowering in periods where they have less chances to reproduce."

Because plants don't have neural networks, their memory is based entirely on cellular, molecular, and biochemical networks. These networks make up what the researchers term somatic memory. "These mechanisms allow plants to recognize the occurrence of a previous environmental condition and to react more promptly in presence of the same consequential condition," says Martinelli.

These somatic memories can then be passed to the plants' progeny via epigenetics. "We have highlighted key genes, proteins, and small oligonucleotides, which previous studies have shown play a key role in the memory of abiotic stresses such as drought, salinity, cold, heat, and heavy metals and pathogen attacks," says Martinelli. "In this peer-reviewed opinion piece, we provide several examples that demonstrate the existence of molecular mechanisms modulating plant memory to environmental stresses and affecting the adaptation of offspring to these stresses."

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Mothers pass on allergies to offspring

 Mothers can pass allergies to offspring while they are developing in the womb, researchers from the Agency for Science, Technology and Research (A*STAR), KK Women's and Children's Hospital (KKH) and Duke-NUS Medical School in Singapore reported this week in the journal Science.

The study, which employed an animal model conducted according to the National Advisory Committee for Laboratory Animal Research (NACLAR) guidelines, shows that the key antibody responsible for triggering allergic reactions, immunoglobulin E (IgE), can cross the placenta and enter the fetus. When inside the fetus, the antibody binds to fetal mast cells, a type of immune cell that releases chemicals that trigger allergic reactions, from runny noses to asthma. After birth, newborn mice develop allergic reactions to the same type of allergen as their mothers at the time of first exposure -- unlike adult mice, which require two exposures. Studies in the laboratory also showed that maternal IgE can bind to human fetal mast cells, indicating they might cross the placenta in humans in a similar way.

Dr Florent Ginhoux, Senior Principal Investigator at A*STAR's Singapore Immunology Network (SIgN), a senior co-author of the study, said, "There is currently a significant lack of knowledge on mast cells that are present early on in the developing fetus. Here, we discovered that fetal mast cells phenotypically mature through the course of pregnancy, and can be sensitised by IgE of maternal origin that cross the placental barrier. The study suggests that a highly allergic pregnant mother may potentially transfer her IgE to her baby that consequently develop allergic reactions when exposed to the first time to the allergen."

"Allergies begin very early in life," said Associate Professor Ashley St. John, an immunologist at Duke-NUS' Emerging Infectious Diseases Programme and a senior co-author of the study. "Infants experience allergic responses closely linked with the mother's allergic response in ways that cannot only be explained by genetics. This work emphasises one way that allergic responses can pass from the mother to the developing fetus, and shows how allergies can then persist after birth."

As part of the study, following NACLAR guidelines, researchers exposed mice to ragweed pollen, a common allergen, prior to pregnancy. Mice that developed a sensitivity to the pollen had offspring that also showed an allergic reaction to ragweed. The sensitivity is allergen-specific; the offspring did not react to dust mites, another common allergen.

Notably, the transfer of sensitivity appears to fade with time. The newborn mice had allergic reactions when tested at four weeks, but less or none at six weeks.

The experimental studies were backed up with cellular tests and imaging, which showed maternal IgE bound to fetal mast cells, triggering the mast cells to release chemicals in reaction to an allergen, a process called degranulation.

This study further showed that the IgE transfer across the placenta requires the help of another protein, FcRN. Mice with FcRN knocked out lacked maternal IgE attached to their mast cells, and did not develop allergies after birth.

The study findings potentially open new intervention strategies to limit such transfer to minimise the occurrence of neonatal allergies. Currently, between 10 to 30 per cent of the world's population are affected by allergies. This number is set to continue rising and a solution preventing allergies being passed from mother to child could potentially bring those numbers down over time.

"Our research has really exciting findings that may explain the high incidence of early onset atopic dermatitis (eczema) in children of mothers with clinically proven eczema, which parallel findings in our local birth cohort findings," said Professor Jerry Chan, Senior Consultant, Department of Reproductive Medicine at KKH, Senior National Medical Research Council Clinician Scientist, and Vice Chair of Research with the Obstetrics and Gynaecology Academic Clinical Programme at the SingHealth Duke-NUS Academic Medical Centre. "From a clinical point of view, developing a further understanding in placental transfer of IgE, and the mechanism of fetal mast cell activation would be key to developing strategies to reduce the chance of eczema or other allergies from being transferred from mother to baby."

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