Friday, 30 August 2024

Bacterial cells transmit memories to offspring

 

Temporary stress can cause heritable changes without altering the genetics, study finds

Date:
August 28, 2024
Source:
Northwestern University
Summary:
Bacterial cells can 'remember' brief, temporary changes to their bodies and immediate surroundings, a new 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.

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."

The study, "Irreversibility in bacterial regulatory networks," was supported by the National Science Foundation (award number MCB-2206974).



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Thursday, 29 August 2024

Hydrogels can play Pong by 'remembering' previous patterns of electrical simulation

 

Date:
August 22, 2024
Source:
Cell Press
Summary:
Non-living hydrogels can play the video game Pong and improve their gameplay with more experience, researchers report. The researchers hooked hydrogels up to a virtual game environment and then applied a feedback loop between the hydrogel's paddle -- encoded by the distribution of charged particles within the hydrogel -- and the ball's position -- encoded by electrical stimulation. With practice, the hydrogel's accuracy improved by up to 10%, resulting in longer rallies. The researchers say that this demonstrates the ability of non-living materials to use 'memory' to update their understanding of the environment, though more research is needed before it could be said that hydrogels can 'learn.'

Non-living hydrogels can play the video game Pong and improve their gameplay with more experience, researchers report August 23 in the Cell Press journal Cell Reports Physical Science. The researchers hooked hydrogels up to a virtual game environment and then applied a feedback loop between the hydrogel's paddle -- encoded by the distribution of charged particles within the hydrogel -- and the ball's position -- encoded by electrical stimulation. With practice, the hydrogel's accuracy improved by up to 10%, resulting in longer rallies. The researchers say that this demonstrates the ability of non-living materials to use "memory" to update their understanding of the environment, though more research is needed before it could be said that hydrogels can "learn."

"Ionic hydrogels can achieve the same kind of memory mechanics as more complex neural networks," says first author and robotics engineer Vincent Strong of the University of Reading. "We showed that hydrogels are not only able to play Pong; they can actually get better at it over time."




The researchers were inspired by a previous study that showed that brain cells in a dish can learn to play Pong if they are electrically stimulated in a way that gives them feedback on their performance.

"Our paper addresses the question of whether simple artificial systems can compute closed loops similar to the feedback loops that allow our brains to control our bodies," says corresponding author and biomedical engineer Yoshikatsu Hayashi of the University of Reading. "The basic principle in both neurons and hydrogels is that ion migration and distributions can work as a memory function that can correlate with sensory-motor loops in the Pong world. In neurons, ions run within the cells; in the gel, they run outside."

Hydrogels are complex polymers that become jelly like when hydrated -- gelatin and agar are natural examples. In this case, the researchers used an "electro-active polymer," meaning a hydrogel that can respond to electrical stimulation thanks to the presence of ions (charged particles) in the media surrounding its polymer matrix. When the hydrogel is electrically stimulated, the ions move, dragging water molecules with them, and this movement causes the hydrogel to temporarily change shape.

"The rate at which the hydrogel de-swells takes much longer than the time it takes for it to swell in the first place, meaning that the ions' next motion is influenced by its previous motion, which is sort of like memory occurring," says Strong. "The continued rearrangement of ions within the hydrogel is based off of previous rearrangements within the hydrogel, continuing back to when it was first made and had a homogeneous distribution of ions."

To test whether the hydrogel's physical "memory" could enable it to play Pong, the researchers used electrodes to connect the hydrogel to a virtual game environment and started up the game by sending the ball in a random direction. They used electrical stimulation to inform the hydrogel of the ball's position and measured the movement of ions within the hydrogel to determine the position of its paddle.

As the Pong games played out, the researchers measured the gel's hit rate and examined whether its accuracy improved. They showed that, with more experience, the hydrogel was able to hit the ball more frequently, resulting in longer rallies. Whereas the Pong-playing neurons achieved their optimal ball-skills within around 10 minutes, the hydrogel took closer to 20 minutes to reach its maximum Pong potential.

"Over time, as the ball moves, the gel gathers a memory of all motion. And then the paddle moves to accommodate that ball within the simulated environment," says Strong. "The ions move in a way that maps a memory of all motion over time, and this "memory" results in improved performance."

Because most existing AI algorithms are derived from neural networks, the researchers say that hydrogels represent a different kind of "intelligence" that could be used to develop new, simpler algorithms. In the future, the researchers plan to further probe the hydrogel's "memory" by examining the mechanisms behind its memory and by testing its ability to perform other tasks.

"In our follow-up projects, we are thinking about how to extract the algorithm from the hydrogels that allows memory acquisition," says co-author William Holderbaum of the University of Reading.

"We've shown that memory is emergent within the hydrogels, but the next step is to see whether we can also show specifically that learning is occurring," says Strong.

This research was supported by Process Vision Ltd.



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Wednesday, 28 August 2024

 

These DNA insertions may be linked to early death

Date:
August 22, 2024
Source:
Columbia University Irving Medical Center
Summary:
A new study finds that mitochondria in our brain cells frequently fling their DNA into the cells' nucleus, where the mitochondrial DNA integrates into chromosomes, possibly causing harm.

As direct descendants of ancient bacteria, mitochondria have always been a little alien.

Now a study shows that mitochondria are possibly even stranger than we thought.

Mitochondria in our brain cells frequently fling their DNA into the nucleus, the study found, where the DNA becomes integrated into the cells' chromosomes. And these insertions may be causing harm: Among the study's nearly 1,200 participants, those with more mitochondrial DNA insertions in their brain cells were more likely to die earlier than those with fewer insertions.

"We used to think that the transfer of DNA from mitochondria to the human genome was a rare occurrence," says Martin Picard, mitochondrial psychobiologist and associate professor of behavioral medicine at Columbia University Vagelos College of Physicians and Surgeons and in the Robert N. Butler Columbia Aging Center. Picard led the study with Ryan Mills of the University of Michigan.



"It's stunning that it appears to be happening several times during a person's lifetime, Picard adds. "We found lots of these insertions across different brain regions, but not in blood cells, explaining why dozens of earlier studies analyzing blood DNA missed this phenomenon."

Mitochondrial DNA behaves like a virus

Mitochondria live inside all our cells, but unlike other organelles, mitochondria have their own DNA, a small circular strand with about three dozen genes. Mitochondrial DNA is a remnant from the organelle's forebears: ancient bacteria that settled inside our single-celled ancestors about 1.5 billion years ago.

In the past few decades, researchers discovered that mitochondrial DNA has occasionally "jumped" out of the organelle and into human chromosomes.

"The mitochondrial DNA behaves similar to a virus in that it makes use of cuts in the genome and pastes itself in, or like jumping genes known as retrotransposons that move around the human genome," says Mills.

The insertions are called nuclear-mitochondrial segments -- NUMTs ("pronounced new-mites") -- and have been accumulating in our chromosomes for millions of years.

"As a result, all of us are walking around with hundreds of vestigial, mostly benign, mitochondrial DNA segments in our chromosomes that we inherited from our ancestors," Mills says.

Mitochondrial DNA insertions are common in the human brain

Research in just the past few years has shown that "NUMTogenesis" is still happening today.

"Jumping mitochondrial DNA is not something that only happened in the distant past," says Kalpita Karan, a postdoc in the Picard lab who conducted the research with Weichen Zhou, a research investigator in the Mills lab. "It's rare, but a new NUMT becomes integrated into the human genome about once in every 4,000 births. This is one of many ways, conserved from yeast to humans, by which mitochondria talk to nuclear genes."

The realization that new inherited NUMTs are still being created made Picard and Mills wonder if NUMTs could also arise in brain cells during our lifespan.

"Inherited NUMTs are mostly benign, probably because they arise early in development and the harmful ones are weeded out," says Zhou. But if a piece of mitochondrial DNA inserts itself within a gene or regulatory region, it could have important consequences on that person's health or lifespan. Neurons may be particularly susceptible to damage caused by NUMTs because when a neuron is damaged, the brain does not usually make a new brain cell to take its place.

To examine the extent and impact of new NUMTs in the brain, the team worked with Hans Klein, assistant professor in the Center for Translational and Computational Neuroimmunology at Columbia, who had access to DNA sequences from participants in the ROSMAP aging study (led by David Bennett at Rush University). The researchers looked for NUMTs in different regions of the brain using banked tissue samples from more than 1,000 older adults.

Their analysis showed that nuclear mitochondrial DNA insertion happens in the human brain -- mostly in the prefrontal cortex -- and likely several times over during a person's lifespan.

They also found that people with more NUMTs in their prefrontal cortex died earlier than individuals with fewer NUMTs. "This suggests for the first time that NUMTs may have functional consequences and possibly influence lifespan," Picard says. "NUMT accumulation can be added to the list of genome instability mechanisms that may contribute to aging, functional decline, and lifespan."

Stress accelerates NUMTogenesis

What causes NUMTs in the brain, and why do some regions accumulate more than others?

To get some clues, the researchers looked at a population of human skin cells that can be cultured and aged in a dish over several months, enabling exceptional longitudinal "lifespan" studies.

These cultured cells gradually accumulated several NUMTs per month, and when the cells' mitochondria were dysfunctional from stress, the cells accumulated NUMTs four to five times more rapidly.

"This shows a new way by which stress can affect the biology of our cells," Karan says. "Stress makes mitochondria more likely to release pieces of their DNA and these pieces can then 'infect' the nuclear genome," Zhou adds. It's just one way mitochondria shape our health beyond energy production.

"Mitochondria are cellular processors and a mighty signaling platform," Picard says. "We knew they can control which genes are turned on or off. Now we know mitochondria can even change the nuclear DNA sequence itself."



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Tuesday, 27 August 2024

Origins of creativity in the brain

Date:
July 15, 2024
Source:
University of Utah Health
Summary:
New results could ultimately help lead to interventions that spark creative thought or aid people who have mental illnesses that disrupt these regions of the brain.

Have you ever had the solution for a tough problem suddenly hit you when you're thinking about something entirely different? Creative thought is a hallmark of humanity, but it's an ephemeral, almost paradoxical ability, striking unexpectedly when it's not sought out.



And the neurological source of creativity -- what's going on in our brains when we think outside the box -- is similarly elusive.

But now, a research team led by a University of Utah Health researcher and based in Baylor College of Medicine has used a precise method of brain imaging to unveil how different parts of the brain work together in order to produce creative thought.

Their findings published in BRAIN on June 18.

The new results could ultimately help lead to interventions that spark creative thought or aid people who have mental illnesses that disrupt these regions of the brain.

Outside the bo

Higher cognitive processes like creativity are especially hard to study. "Unlike motor function or vision, they're not dependent on one specific location in the brain," says Ben Shofty, MD, PhD, assistant professor of neurosurgery in the Spencer Fox Eccles School of Medicine and senior author on the paper. "There's not a creativity cortex."

But there's evidence that creativity is a distinct brain function. Localized brain injury caused by stroke can lead to changes in creative ability -- both positive and negative. That discovery suggests that narrowing down the neurological basis of creativity is possible.

Shofty suspected that creative thought might rely strongly on parts of the brain that are also activated during meditation, daydreaming, and other internally focused types of thinking. This network of brain cells is the default mode network (DMN), so called because it's associated with the "default" patterns of thought that happen in the absence of specific mental tasks. "Unlike most of the functions that we have in the brain, it's not goal-directed," Shofty says. "It's a network that basically operates all the time and maintains our spontaneous stream of consciousness."

The DMN is spread out across many dispersed brain regions, making it more difficult to track its activity in real time. The researchers had to use an advanced method of brain activity imaging to understand what the network was doing moment-to-moment during creative thought. In a strategy most commonly used to pinpoint the location of seizures in patients with severe epilepsy, tiny electrodes are implanted in the brain to precisely track the electrical activity of multiple brain regions.

Participants in the study were already undergoing this kind of seizure monitoring, which meant that the research team could also use the electrodes to measure brain activity during creative thinking. This provided a much more detailed picture of the neural basis of creativity than researchers had been able to capture before. "We could see what's happening within the first few milliseconds of attempting to perform creative thinking,"Shofty says.

Two steps toward originality

The researchers saw that during a creative thinking task in which participants were asked to list novel uses for an everyday item, like a chair or a cup, the DMN lit up with activity first. Then, its activity synchronized with other regions in the brain, including ones involved in complex problem-solving and decision-making. Shofty believes this means that creative ideas originate in the DMN before being evaluated by other regions.

What's more, the researchers were able to show that parts of the network are required specifically for creative thought. When the researchers used the electrodes to temporarily dampen the activity of particular regions of the DMN, people brainstormed uses for the items they saw that were less creative. Their other brain functions, like mind wandering, remained perfectly normal.

Eleonora Bartoli, PhD, assistant professor of neurosurgery at Baylor College of Medicine and co-first author on the paper, explains that this result shows that creativity isn't just associated with the network but fundamentally depends on it. "We moved beyond correlational evidence by using direct brain stimulation," she says. "Our findings highlight the causal role of the DMN in creative thinking."

The activity of the network is changed in several disorders, such as ruminative depression, in which the DMN is more active than normal, possibly related to increased dwelling on negative internally directed thoughts. Shofty says that a better understanding of how the network operates normally may lead to better treatments for people with such conditions.

By characterizing the brain regions involved in creative thought, Shofty hopes to ultimately inspire interventions that can help spark creativity. "Eventually, the goal would be to understand what happens to the network in such a way that we can potentially drive it toward being more creative."


Story Source:

Materials provided by University of Utah Health.


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Thursday, 22 August 2024

Life from a drop of rain: New research suggests rainwater helped form the first protocell walls

 

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