How caloric restriction prevents negative effects of aging in cells

Peas on plate, dieting concept (stock image).

If you want to reduce levels of inflammation throughout your body, delay the onset of age-related diseases, and live longer, eat less food. That's the conclusion of a new study by scientists from the US and China that provides the most detailed report to date of the cellular effects of a calorie-restricted diet in rats. While the benefits of caloric restriction have long been known, the new results show how this restriction can protect against aging in cellular pathways, as detailed in Cell on February 27, 2020.

"We already knew that calorie restriction increases life span, but now we've shown all the changes that occur at a single-cell level to cause that," says Juan Carlos Izpisua Belmonte, a senior author of the new paper, professor in Salk's Gene Expression Laboratory and holder of the Roger Guillemin Chair. "This gives us targets that we may eventually be able to act on with drugs to treat aging in humans."

Aging is the highest risk factor for many human diseases, including cancer, dementia, diabetes and metabolic syndrome. Caloric restriction has been shown in animal models to be one of the most effective interventions against these age-related diseases. And although researchers know that individual cells undergo many changes as an organism ages, they have not known how caloric restriction might influence these changes.

In the new paper, Belmonte and his collaborators -- including three alumni of his Salk lab who are now professors running their own research programs in China -- compared rats who ate 30 percent fewer calories with rats on normal diets. The animals' diets were controlled from age 18 months through 27 months. (In humans, this would be roughly equivalent to someone following a calorie-restricted diet from age 50 through 70.)

At both the start and the conclusion of the diet, Belmonte's team isolated and analyzed a total of 168,703 cells from 40 cell types in the 56 rats. The cells came from fat tissues, liver, kidney, aorta, skin, bone marrow, brain and muscle. In each isolated cell, the researchers used single-cell genetic-sequencing technology to measure the activity levels of genes. They also looked at the overall composition of cell types within any given tissue. Then, they compared old and young mice on each diet.

Many of the changes that occurred as rats on the normal diet grew older didn't occur in rats on a restricted diet; even in old age, many of the tissues and cells of animals on the diet closely resembled those of young rats. Overall, 57 percent of the age-related changes in cell composition seen in the tissues of rats on a normal diet were not present in the rats on the calorie restricted diet.

"This approach not only told us the effect of calorie restriction on these cell types, but also provided the most complete and detailed study of what happens at a single-cell level during aging," says co-corresponding author Guang-Hui Liu, a professor at the Chinese Academy of Sciences.

Some of the cells and genes most affected by the diet related to immunity, inflammation and lipid metabolism. The number of immune cells in nearly every tissue studied dramatically increased as control rats aged but was not affected by age in rats with restricted calories. In brown adipose tissue -- one type of fat tissue -- a calorie-restricted diet reverted the expression levels of many anti-inflammatory genes to those seen in young animals.

"The primary discovery in the current study is that the increase in the inflammatory response during aging could be systematically repressed by caloric restriction" says co-corresponding author Jing Qu, also a professor at the Chinese Academy of Sciences.

When the researchers homed in on transcription factors -- essentially master switches that can broadly alter the activity of many other genes -- that were altered by caloric restriction, one stood out. Levels of the transcription factor Ybx1 were altered by the diet in 23 different cell types. The scientists believe Ybx1 may be an age-related transcription factor and are planning more research into its effects.

"People say that 'you are what you eat,' and we're finding that to be true in lots of ways," says Concepcion Rodriguez Esteban, another of the paper's authors and a staff researcher at Salk. "The state of your cells as you age clearly depends on your interactions with your environment, which includes what and how much you eat."

The team is now trying to utilize this information in an effort to discover aging drug targets and implement strategies towards increasing life and health span.

Other researchers on the study were Shuai Ma, Shuhui Sun, Lingling Geng, Moshi Song, Wei Wang, Yanxia Ye, Qianzhao Ji, Zhiran Zou, Si Wang and Qi Zhou of the Chinese Academy of Sciences; Xiaojuan He, Wei Li, Piu Chan and Weiqi Zhang of Xuanwu Hospital Capital Medical University; Xiao Long of Peking Union Medical College Hospital; and Guoji Guo of Zhejiang University School of Medicine.

The work and researchers involved were supported by grants from the National Key Research and Development Program of China, the Strategic Priority Research Program of the Chinese Academy of Sciences, the National Natural Science Foundation of China, Beijing Natural Science Foundation, Beijing Municipal Commission of Health and Family Planning, Advanced Innovation Center for Human Brain Protection, the State Key Laboratory of Membrane Biology, the Moxie Foundation, and the Glenn Foundation.

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Materials provided by Salk Institute. Note: Content may be edited for style and length.

Living robots built using frog cells

African clawed frog, Xenopus laevis (stock image).

A book is made of wood. But it is not a tree. The dead cells have been repurposed to serve another need.

Now a team of scientists has repurposed living cells -- scraped from frog embryos -- and assembled them into entirely new life-forms. These millimeter-wide "xenobots" can move toward a target, perhaps pick up a payload (like a medicine that needs to be carried to a specific place inside a patient) -- and heal themselves after being cut.

"These are novel living machines," says Joshua Bongard, a computer scientist and robotics expert at the University of Vermont who co-led the new research. "They're neither a traditional robot nor a known species of animal. It's a new class of artifact: a living, programmable organism."

The new creatures were designed on a supercomputer at UVM -- and then assembled and tested by biologists at Tufts University. "We can imagine many useful applications of these living robots that other machines can't do," says co-leader Michael Levin who directs the Center for Regenerative and Developmental Biology at Tufts, "like searching out nasty compounds or radioactive contamination, gathering microplastic in the oceans, traveling in arteries to scrape out plaque."

The results of the new research were published January 13 in the Proceedings of the National Academy of Sciences.

Bespoke Living Systems

People have been manipulating organisms for human benefit since at least the dawn of agriculture, genetic editing is becoming widespread, and a few artificial organisms have been manually assembled in the past few years -- copying the body forms of known animals.

But this research, for the first time ever, "designs completely biological machines from the ground up," the team writes in their new study.

With months of processing time on the Deep Green supercomputer cluster at UVM's Vermont Advanced Computing Core, the team -- including lead author and doctoral student Sam Kriegman -- used an evolutionary algorithm to create thousands of candidate designs for the new life-forms. Attempting to achieve a task assigned by the scientists -- like locomotion in one direction -- the computer would, over and over, reassemble a few hundred simulated cells into myriad forms and body shapes. As the programs ran -- driven by basic rules about the biophysics of what single frog skin and cardiac cells can do -- the more successful simulated organisms were kept and refined, while failed designs were tossed out. After a hundred independent runs of the algorithm, the most promising designs were selected for testing.

Then the team at Tufts, led by Levin and with key work by microsurgeon Douglas Blackiston -- transferred the in silico designs into life. First they gathered stem cells, harvested from the embryos of African frogs, the species Xenopus laevis. (Hence the name "xenobots.") These were separated into single cells and left to incubate. Then, using tiny forceps and an even tinier electrode, the cells were cut and joined under a microscope into a close approximation of the designs specified by the computer.

Assembled into body forms never seen in nature, the cells began to work together. The skin cells formed a more passive architecture, while the once-random contractions of heart muscle cells were put to work creating ordered forward motion as guided by the computer's design, and aided by spontaneous self-organizing patterns -- allowing the robots to move on their own.

These reconfigurable organisms were shown to be able move in a coherent fashion -- and explore their watery environment for days or weeks, powered by embryonic energy stores. Turned over, however, they failed, like beetles flipped on their backs.

Later tests showed that groups of xenobots would move around in circles, pushing pellets into a central location -- spontaneously and collectively. Others were built with a hole through the center to reduce drag. In simulated versions of these, the scientists were able to repurpose this hole as a pouch to successfully carry an object. "It's a step toward using computer-designed organisms for intelligent drug delivery," says Bongard, a professor in UVM's Department of Computer Science and Complex Systems Center.

Living Technologies

Many technologies are made of steel, concrete or plastic. That can make them strong or flexible. But they also can create ecological and human health problems, like the growing scourge of plastic pollution in the oceans and the toxicity of many synthetic materials and electronics. "The downside of living tissue is that it's weak and it degrades," say Bongard. "That's why we use steel. But organisms have 4.5 billion years of practice at regenerating themselves and going on for decades." And when they stop working -- death -- they usually fall apart harmlessly. "These xenobots are fully biodegradable," say Bongard, "when they're done with their job after seven days, they're just dead skin cells."

Your laptop is a powerful technology. But try cutting it in half. Doesn't work so well. In the new experiments, the scientists cut the xenobots and watched what happened. "We sliced the robot almost in half and it stitches itself back up and keeps going," says Bongard. "And this is something you can't do with typical machines."

Cracking the Code

Both Levin and Bongard say the potential of what they've been learning about how cells communicate and connect extends deep into both computational science and our understanding of life. "The big question in biology is to understand the algorithms that determine form and function," says Levin. "The genome encodes proteins, but transformative applications await our discovery of how that hardware enables cells to cooperate toward making functional anatomies under very different conditions."

To make an organism develop and function, there is a lot of information sharing and cooperation -- organic computation -- going on in and between cells all the time, not just within neurons. These emergent and geometric properties are shaped by bioelectric, biochemical, and biomechanical processes, "that run on DNA-specified hardware," Levin says, "and these processes are reconfigurable, enabling novel living forms."

The scientists see the work presented in their new PNAS study -- "A scalable pipeline for designing reconfigurable organisms," -- as one step in applying insights about this bioelectric code to both biology and computer science. "What actually determines the anatomy towards which cells cooperate?" Levin asks. "You look at the cells we've been building our xenobots with, and, genomically, they're frogs. It's 100% frog DNA -- but these are not frogs. Then you ask, well, what else are these cells capable of building?"

"As we've shown, these frog cells can be coaxed to make interesting living forms that are completely different from what their default anatomy would be," says Levin. He and the other scientists in the UVM and Tufts team -- with support from DARPA's Lifelong Learning Machines program and the National Science Foundation -- believe that building the xenobots is a small step toward cracking what he calls the "morphogenetic code," providing a deeper view of the overall way organisms are organized -- and how they compute and store information based on their histories and environment.

Future Shocks

Many people worry about the implications of rapid technological change and complex biological manipulations. "That fear is not unreasonable," Levin says. "When we start to mess around with complex systems that we don't understand, we're going to get unintended consequences." A lot of complex systems, like an ant colony, begin with a simple unit -- an ant -- from which it would be impossible to predict the shape of their colony or how they can build bridges over water with their interlinked bodies.

"If humanity is going to survive into the future, we need to better understand how complex properties, somehow, emerge from simple rules," says Levin. Much of science is focused on "controlling the low-level rules. We also need to understand the high-level rules," he says. "If you wanted an anthill with two chimneys instead of one, how do you modify the ants? We'd have no idea."

"I think it's an absolute necessity for society going forward to get a better handle on systems where the outcome is very complex," Levin says. "A first step towards doing that is to explore: how do living systems decide what an overall behavior should be and how do we manipulate the pieces to get the behaviors we want?"

In other words, "this study is a direct contribution to getting a handle on what people are afraid of, which is unintended consequences," Levin says -- whether in the rapid arrival of self-driving cars, changing gene drives to wipe out whole lineages of viruses, or the many other complex and autonomous systems that will increasingly shape the human experience.

"There's all of this innate creativity in life," says UVM's Josh Bongard. "We want to understand that more deeply -- and how we can direct and push it toward new forms."

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Materials provided by University of Vermont. Original written by Joshua E. Brown. Note: Content may be edited for style and length.

Bacteria made to mimic cells, form communities

Bacteria made to mimic cells, form communities

Rice University scientists have found a way to engineer a new kind of cell differentiation in bacteria, inspired by a naturally occurring process in stem cells.

They have created a genetic circuit able to produce genetically distinguished cells of Escherichia coli as the bacterium divides. By controlling this process, it is possible to create diverse communities of microbes that exhibit complex, non-native behaviors.

Rice synthetic biologist Matthew Bennett and Sara Molinari, a former student in the university's Systems, Synthetic and Physical Biology Ph.D. program, led the project to show how manipulating the genetic code of plasmids -- free-floating pieces of circular DNA in cells -- can be used to obtain stem cell-like differentiation in bacteria.

"Stem cells have the remarkable ability to divide asymmetrically," Bennett said. "Upon division, the original stem cell stays the same, but the new daughter cell has a completely new phenotype. That's asymmetric cell division, and multicellular organisms use it to help control their cellular makeup.

"As a synthetic biologist, I think a lot about creating and controlling differentiated cell types within a multicellular population," he said. "Here, we've taken what we know about stem cells and engineered the means to do it in bacteria."

The researchers reported the development, which they call asymmetric plasmid partitioning (APP), in Nature Chemical Biology.

Molinari first discovered how to force plasmids in E. coli to aggregate in a single cluster so they do not distribute homogeneously during cell division, but rather are inherited by only one of the two daughter cells. The plasmid-laden daughter cell remains identical to the progenitor cell, while its sibling becomes genetically distinct as it loses the genetic information present on the plasmids.

She then expanded the synthetic circuit to induce the simultaneous asymmetric partitioning of two plasmid species in a single cell, resulting in four genetically distinct E. coli. Some of the cells have motility programmed in; they can literally go their own way and help form patterns in the resulting colony.

"When we started, we were thinking about creating materials that have to be able to sense and adapt to an environment," said Molinari, who recently earned her doctorate at Rice. "We thought if we could mimic this feature of higher-order tissues, we would increase the robustness of our colonies and their ability to perform tasks. The challenge was to engineer a population of bacteria that becomes something else whenever it's needed."

Molinari and her colleagues hit the jackpot on their first try with E. coli. "There was no canonical way to engineer asymmetrical cell division," she said. "It was a crazy idea, and it magically worked the first time.

"But there was something we couldn't completely figure out about the system," Molinari said. "It took two years to find out I made a cloning mistake when I got this protein and put it in my plasmid. I had randomly added 17 amino acids at the beginning of the protein, and that made the whole system work."

With that knowledge, she proceeded to improve upon the hydrophobic proteins that cluster in cells while they bind to target plasmids, holding them in place.

Bennett noted natural processes either load enough plasmids into a cell to ensure some land in each daughter cell or actively pull plasmids into each of the new cells to ensure they remain identical. "We have shown we can outcompete those processes," he said.

APP could turn simple organisms into complicated systems that enhance understanding of multicellular life. "We're pretty good at designing bacteria," Bennett said. "We've been doing that for years now. I think the field has evolved to the point where we can do amazing things with bacteria and people are asking what else we can do."

The new discovery, he said, provides a path forward.

"There are three main hallmarks to multicellular life," he said. "One is differentiation through asymmetric cell division. Another is intercellular communication, which synthetic biologists have been engineering for years. And the third is cell adhesion, so cells stay where they're supposed to and stick to each other. If we can control all those things together, we can talk about engineering interesting multicellular lifeforms.

"It starts to feel a bit like science fiction, for sure," he said.

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Story Source:

Materials provided by Rice University. Original written by Mike Williams. Note: Content may be edited for style and length.

Lack of oxygen doesn't kill infant brain cells

Nearly 15 million babies are born prematurely, or before 37 weeks of pregnancy, around the world each year. When born too early, a baby's immature respiratory center in the brain often fails to signal it to breathe, resulting in low oxygen levels, or hypoxia, in the brain.

Research published in the Journal of Neuroscience shows that even a brief 30-minute period of hypoxia is enough to persistently disrupt the structure and function of the brain region known as the hippocampus, which is vital for learning and memory.

"Our findings raise new concerns about the vulnerability of the preterm brain to hypoxia. They are concerning for the long-term impact that oxygen deprivation can have on the ability of these preterm babies to learn as they grow to school age and adulthood," said the study's principal investigator, Stephen Back, M.D., Ph.D., Clyde and Elda Munson Professor of Pediatric Research and Pediatrics, OHSU School of Medicine, OHSU Doernbecher Children's Hospital.

In the neonatal intensive care unit, preemies can experience up to 600 short, but impactful periods of hypoxia each week. Consequently, more than one-third of babies who survive preterm birth are likely to have smaller brains, presumably due to brain cell loss, compared with the brains of full-term infants. This can increase the risk of significant life-long neurodevelopmental challenges that will affect learning, memory, attention and behavior.

Using a twin preterm fetal sheep model, Back and colleagues studied the impact of both hypoxia alone, as well as in combination with ischemia -- or insufficient blood flow -- on the developing hippocampus. The results confirm that, similar to human preterm survivors, growth of the hippocampus is impaired. However, brain cells do not die as previously believed. Rather, hippocampal cells fail to mature normally, causing a reduction in long-term potentiation, or the cellular basis of how the brain learns.

Remarkably, the severity of the hypoxia predicted the degree to which cells in the hippocampus failed to mature normally, explains Back. These findings are all the more unexpected because it was not appreciated that the preterm hippocampus was already capable of these learning processes.

"We want to understand next how very brief or prolonged exposure to hypoxia affects the ability for optimal learning and memory, " says Back. "This will allow us to understand how the hippocampus responds to a lack of oxygen, creating new mechanisms of care and intervention both at the hospital, and at home."

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Materials provided by Oregon Health & Science University. Note: Content may be edited for style and length.

Milk from teeth: Dental stem cells can generate milk-producing cells

Milk from teeth

The ability of adult stem cells to generate various tissue-specific cell populations is of great interest in the medical and dental research fields. These cells can replace damaged cells and therefore represent a good alternative to classical medical treatments for tissue regeneration. This may even allow the de novo formation of entire tissues and organs in the future.

Dental stem cells capable of regenerating mammary gland

Dental epithelial stem cells are able to generate all epithelial cell types of the teeth; however, it was not yet clear whether these cells could also produce non-dental cell populations. In a recent paper published in the open access journal Cells, a team of researchers led by Thimios Mitsiadis, professor at the Institute of Oral Biology of the University of Zurich (UZH), has shown for the first time that epithelial stem cells isolated from the continuously growing incisors of young mice are indeed able to form mammary glands in female mice.

In a first set of experiments, after removing all cells of mammary origin, dental epithelial stem cells and mammary epithelial cells were directly injected into the areas where the mammary glands normally develop. The researchers used advanced genetic, molecular and imaging tools that allow the precise follow-up of the transplanted dental stem cells in the mammary gland fat pad of the animals. "The results show that the dental stem cells contribute to mammary gland regeneration, and are able to generate all mammary cell populations and, even more strikingly, milk-producing cells," says Mitsiadis.

This work demonstrates the exceptional plasticity of dental epithelial stem cells to generate not only dental tissues but also other tissues of the body. "These findings represent a major contribution to the understanding of the cellular and molecular mechanisms involved in the regenerative capacity of dental stem cells, and, furthermore, indicate the clinical potential of these specific stem cell populations," Mitsiadis adds.

Stem cell-based therapies could be used for breast tissue regeneration

In a second set of experiments, dental epithelial stem cells were injected alone, without mammary epithelial cells. In this case, the dental stem cells were also able to form small ductal systems consisting of branching rudiments. However, in some cases this resulted in the formation of cysts. "This plasticity might be unique for dental epithelial stem cells, since all other non-mammary epithelial cells examined so far have never shown the ability to generate mammary ducts without the support of mammary epithelial cells," states co-author Pierfrancesco Pagella from the Institute of Oral Biology.

One of the most severe pathological conditions is breast cancer, which is often treated with surgery. "Our discovery that dental epithelial stem cells are able to replace cells from the mammary gland opens up new paths for developing stem cell-based therapies that could be used for breast regeneration in the future," says Thimios Mitsiadis.

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Materials provided by University of Zurich. Note: Content may be edited for style and length.

Bacteria made to mimic cells, form communities

Bacteria made to mimic cells

Rice University scientists have found a way to engineer a new kind of cell differentiation in bacteria, inspired by a naturally occurring process in stem cells.

They have created a genetic circuit able to produce genetically distinguished cells of Escherichia coli as the bacterium divides. By controlling this process, it is possible to create diverse communities of microbes that exhibit complex, non-native behaviors.

Rice synthetic biologist Matthew Bennett and Sara Molinari, a former student in the university's Systems, Synthetic and Physical Biology Ph.D. program, led the project to show how manipulating the genetic code of plasmids -- free-floating pieces of circular DNA in cells -- can be used to obtain stem cell-like differentiation in bacteria.

"Stem cells have the remarkable ability to divide asymmetrically," Bennett said. "Upon division, the original stem cell stays the same, but the new daughter cell has a completely new phenotype. That's asymmetric cell division, and multicellular organisms use it to help control their cellular makeup.

"As a synthetic biologist, I think a lot about creating and controlling differentiated cell types within a multicellular population," he said. "Here, we've taken what we know about stem cells and engineered the means to do it in bacteria."

The researchers reported the development, which they call asymmetric plasmid partitioning (APP), in Nature Chemical Biology.

Molinari first discovered how to force plasmids in E. coli to aggregate in a single cluster so they do not distribute homogeneously during cell division, but rather are inherited by only one of the two daughter cells. The plasmid-laden daughter cell remains identical to the progenitor cell, while its sibling becomes genetically distinct as it loses the genetic information present on the plasmids.

She then expanded the synthetic circuit to induce the simultaneous asymmetric partitioning of two plasmid species in a single cell, resulting in four genetically distinct E. coli. Some of the cells have motility programmed in; they can literally go their own way and help form patterns in the resulting colony.

"When we started, we were thinking about creating materials that have to be able to sense and adapt to an environment," said Molinari, who recently earned her doctorate at Rice. "We thought if we could mimic this feature of higher-order tissues, we would increase the robustness of our colonies and their ability to perform tasks. The challenge was to engineer a population of bacteria that becomes something else whenever it's needed."

Molinari and her colleagues hit the jackpot on their first try with E. coli. "There was no canonical way to engineer asymmetrical cell division," she said. "It was a crazy idea, and it magically worked the first time.

"But there was something we couldn't completely figure out about the system," Molinari said. "It took two years to find out I made a cloning mistake when I got this protein and put it in my plasmid. I had randomly added 17 amino acids at the beginning of the protein, and that made the whole system work."

With that knowledge, she proceeded to improve upon the hydrophobic proteins that cluster in cells while they bind to target plasmids, holding them in place.

Bennett noted natural processes either load enough plasmids into a cell to ensure some land in each daughter cell or actively pull plasmids into each of the new cells to ensure they remain identical. "We have shown we can outcompete those processes," he said.

APP could turn simple organisms into complicated systems that enhance understanding of multicellular life. "We're pretty good at designing bacteria," Bennett said. "We've been doing that for years now. I think the field has evolved to the point where we can do amazing things with bacteria and people are asking what else we can do."

The new discovery, he said, provides a path forward.

"There are three main hallmarks to multicellular life," he said. "One is differentiation through asymmetric cell division. Another is intercellular communication, which synthetic biologists have been engineering for years. And the third is cell adhesion, so cells stay where they're supposed to and stick to each other. If we can control all those things together, we can talk about engineering interesting multicellular lifeforms.

"It starts to feel a bit like science fiction, for sure," he said.

---

Story Source:

Materials provided by Rice University. Original written by Mike Williams. Note: Content may be edited for style and length.

Bacteria made to mimic cells, form communities

Bacteria

Rice University scientists have found a way to engineer a new kind of cell differentiation in bacteria, inspired by a naturally occurring process in stem cells.

They have created a genetic circuit able to produce genetically distinguished cells of Escherichia coli as the bacterium divides. By controlling this process, it is possible to create diverse communities of microbes that exhibit complex, non-native behaviors.

Rice synthetic biologist Matthew Bennett and Sara Molinari, a former student in the university's Systems, Synthetic and Physical Biology Ph.D. program, led the project to show how manipulating the genetic code of plasmids -- free-floating pieces of circular DNA in cells -- can be used to obtain stem cell-like differentiation in bacteria.

"Stem cells have the remarkable ability to divide asymmetrically," Bennett said. "Upon division, the original stem cell stays the same, but the new daughter cell has a completely new phenotype. That's asymmetric cell division, and multicellular organisms use it to help control their cellular makeup.

"As a synthetic biologist, I think a lot about creating and controlling differentiated cell types within a multicellular population," he said. "Here, we've taken what we know about stem cells and engineered the means to do it in bacteria."

The researchers reported the development, which they call asymmetric plasmid partitioning (APP), in Nature Chemical Biology.

Molinari first discovered how to force plasmids in E. coli to aggregate in a single cluster so they do not distribute homogeneously during cell division, but rather are inherited by only one of the two daughter cells. The plasmid-laden daughter cell remains identical to the progenitor cell, while its sibling becomes genetically distinct as it loses the genetic information present on the plasmids.

She then expanded the synthetic circuit to induce the simultaneous asymmetric partitioning of two plasmid species in a single cell, resulting in four genetically distinct E. coli. Some of the cells have motility programmed in; they can literally go their own way and help form patterns in the resulting colony.

"When we started, we were thinking about creating materials that have to be able to sense and adapt to an environment," said Molinari, who recently earned her doctorate at Rice. "We thought if we could mimic this feature of higher-order tissues, we would increase the robustness of our colonies and their ability to perform tasks. The challenge was to engineer a population of bacteria that becomes something else whenever it's needed."

Molinari and her colleagues hit the jackpot on their first try with E. coli. "There was no canonical way to engineer asymmetrical cell division," she said. "It was a crazy idea, and it magically worked the first time.

"But there was something we couldn't completely figure out about the system," Molinari said. "It took two years to find out I made a cloning mistake when I got this protein and put it in my plasmid. I had randomly added 17 amino acids at the beginning of the protein, and that made the whole system work."

With that knowledge, she proceeded to improve upon the hydrophobic proteins that cluster in cells while they bind to target plasmids, holding them in place.

Bennett noted natural processes either load enough plasmids into a cell to ensure some land in each daughter cell or actively pull plasmids into each of the new cells to ensure they remain identical. "We have shown we can outcompete those processes," he said.

APP could turn simple organisms into complicated systems that enhance understanding of multicellular life. "We're pretty good at designing bacteria," Bennett said. "We've been doing that for years now. I think the field has evolved to the point where we can do amazing things with bacteria and people are asking what else we can do."

The new discovery, he said, provides a path forward.

"There are three main hallmarks to multicellular life," he said. "One is differentiation through asymmetric cell division. Another is intercellular communication, which synthetic biologists have been engineering for years. And the third is cell adhesion, so cells stay where they're supposed to and stick to each other. If we can control all those things together, we can talk about engineering interesting multicellular lifeforms.

"It starts to feel a bit like science fiction, for sure," he said.

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Story Source:

Materials provided by Rice University. Original written by Mike Williams. Note: Content may be edited for style and length.