During the winter of 1944, the Nazis blocked food supplies to the western Netherlands, creating a period of widespread famine and devastation. The impact of starvation on expectant mothers produced one of the first known epigenetic “experiments” — changes resulting from external rather than genetic influences — which suggested that the body’s physiological responses to hardship could be inherited. The underlying mechanism, however, remained a mystery.
In a paper published recently in the journal Cell, Dr. Oded Rechavi, Dr. Leah Houri-Ze’ev, and Dr. Sarit Anava of Tel Aviv University’s Faculty of Life Sciences and Sagol School of Neuroscience, Prof. Oliver Hobert and Dr. Sze Yen Kerk of Columbia University Medical Center and the Howard Hughes Medical Institute, and Dr. Wee Siong Sho Goh and Dr. Gregory J. Hannon of the Cold Spring Harbor Laboratory and the Howard Hughes Medical Institute, explore a genetic mechanism that passes on the body’s response to starvation to subsequent generations of worms, with potential implications for humans also exposed to starvation and other physiological challenges, such as anorexia nervosa.
“There are possibly several different genetic mechanisms that enable inheritance of traits in response to changes in the environment. This is a new field, so these mechanisms are only now being discovered,” said Dr. Rechavi. “We identified a mechanism called ‘small RNA inheritance’ that enables worms to pass on the memory of starvation to multiple generations.”
Does RNA have a memory?
RNA molecules are produced from DNA templates in response to the needs of specific cells. “Messenger” RNA molecules (mRNAs) contain instructions for the production of proteins, which service cells and allow them to function. But other RNA molecules have different regulatory functions. Small RNAs are one species of these regulatory RNAs — short molecules that regulate gene expression, mostly by shutting genes off, but sometimes by turning them on.
Dr. Rechavi first became interested in studying starvation-induced epigenetic responses following a discovery made as a post doctorate in Prof. Hobert’s lab at Columbia University Medical Center in New York. “Back then, we found that small RNAs were inherited, and that this inheritance affected antiviral immunity in worms. It was obvious that this was only the tip of the iceberg,” he said.
In the course of the new study, worms (C.elegans nematodes) were starved early in their development. They responded by producing small RNAs, which function by regulating genes through a process that is known as RNA interference (RNAi). The researchers discovered that the starvation-responsive small RNAs target genes that are involved in nutrition. More important, the starvation-induced small RNAs were inherited by at least three subsequent generations of worm specimens.
“We were also surprised to find that the great-grandchildren of the starved worms had an extended life span,” said Dr. Rechavi. “To the best of our knowledge, our paper provides the first concrete evidence that it’s enough to simply experience a particular environment — in this case, an environment without food — for small RNA inheritance and RNA interference to ensue. In this case, the environmental challenge is starvation, a very physiologically relevant challenge, and it is likely that other environments induce transgenerational inheritance of small RNAs as well.
“We identified genes that are essential for production and for the inheritance of starvation-responsive small RNAs. RNA inheritance could prove to be an important genetic mechanism in other organisms, including humans, acting parallel to DNA. This could possibly allow parents to prepare their progeny for hardships similar to the ones that they experience,” Dr. Rechavi said.
The researchers are currently researching a wide variety of traits affected by inherited small RNAs.
Reducing the amount of alcoholic beverages consumed, even for light-to-moderate drinkers, may improve cardiovascular health, including a reduced risk of coronary heart disease, lower body mass index (BMI) and blood pressure, according to a new multi-center study published in The BMJ and co-led by the Perelman School of Medicine at the University of Pennsylvania. The latest findings call into question previous studies which suggest that consuming light-to-moderate amounts of alcohol (0.6-0.8 fluid ounces/day) may have a protective effect on cardiovascular health.
The new research reviewed evidence from more than 50 studies that linked drinking habits and cardiovascular health for over 260,000 people. Researchers found that individuals who carry a specific gene which typically leads to lower alcohol consumption over time have, on average, superior cardiovascular health records. Specifically, the results show that individuals who consume 17 percent less alcohol per week have on average a 10 percent reduced risk of coronary heart disease, lower blood pressure and a lower Body Mass Index.
“These new results are critically important to our understanding of how alcohol affects heart disease. Contrary to what earlier reports have shown, it now appears that any exposure to alcohol has a negative impact upon heart health,” says co-lead author Michael Holmes, MD, PhD, research assistant professor in the department of Transplant Surgery at the Perelman School of Medicine at the University of Pennsylvania. “For some time, observational studies have suggested that only heavy drinking was detrimental to cardiovascular health, and that light consumption may actually be beneficial. This has led some people to drink moderately based on the belief that it would lower their risk of heart disease. However, what we’re seeing with this new study, which uses an investigative approach similar to a randomized clinical trial, is that reduced consumption of alcohol, even for light-to-moderate drinkers, may lead to improved cardiovascular health.”
In the new study, researchers examined the cardiovascular health of individuals who carry a genetic variant of the ‘alcohol dehydrogenase 1B’ gene, which is known to breakdown alcohol at a quicker pace. This rapid breakdown causes unpleasant symptoms including nausea and facial flushing, and has been found to lead to lower levels of alcohol consumption over time. By using this genetic marker as an indicator of lower alcohol consumption, the research team was able to identify links between these individuals and improved cardiovascular health.
The study was funded by the British Heart Foundation and the Medical Research Council, and was an international collaboration that included 155 investigators from the UK, continental Europe, North America, and Australia.
Several years ago, Georgia Institute of Technology researchers created a technology-enhanced glove that can teach beginners how to play piano melodies in 45 minutes. Now they’ve advanced the same wearable computing technology to help people learn how to read and write Braille. The twist is that people wearing the glove don’t have to pay attention. They learn while doing something else.
“The process is based on passive haptic learning (PHL),” said Thad Starner, a Georgia Tech professor and wearable computer pioneer. “We’ve learned that people can acquire motor skills through vibrations without devoting active attention to their hands.”
In their new study, Starner and Ph.D. student Caitlyn Seim examined how well these gloves work to teach Braille. Each study participant wore a pair of gloves with tiny vibrating motors stitched into the knuckles. The motors vibrated in a sequence that corresponded with the typing pattern of a pre-determined phrase in Braille. Audio cues let the users know the Braille letters produced by typing that sequence. Afterwards, everyone tried to type the phrase one time, without the cues or vibrations, on a keyboard.
The sequences were then repeated during a distraction task. Participants played a game for 30 minutes and were told to ignore the gloves. Half of the participants felt repeated vibrations and heard the cues; the others only heard the audio cues. When the game was over, participants tried to type the phrase without wearing the gloves.
“Those in the control group did about the same on their second attempt (as they did in their pre-study baseline test),” said Starner. “But participants who felt the vibrations during the game were a third more accurate. Some were even perfect.”
The researchers expected to see a wide disparity between the two groups based on their successful results while using the piano glove. But they were surprised the passive learners picked up an additional skill.
“Remarkably, we found that people could transfer knowledge learned from typing Braille to reading Braille,” said Seim. “After the typing test, passive learners were able to read and recognize more than 70 percent of the phrase’s letters.”
No one in the study had previously typed on a Braille keyboard or knew the language. The study also didn’t include screens or visual feedback, so participants never saw what they typed. They had no indication of their accuracy throughout the study.
“The only learning they received was guided by the haptic interface,” said Seim.
Seim is currently in the middle of a second study that uses PHL to teach the full Braille alphabet during four sessions. Of the eight participants so far, 75 percent of those receiving PHL reached perfect typing performance. None of the control group had zero typing errors. PHL participants have also been able to recognize and read more than 90 percent of all the letters in the alphabet after only four hours.
Nearly 40 million people worldwide are blind. However, because Braille instruction is widely neglected in schools, only 10 percent of those who are blind learn the language. Braille is also difficult to learn later in life, when diabetics, wounded veterans or older people are prone to lose their sight.
The Braille studies will be presented in Seattle this September at the 18th International Symposium on Wearable Computers (ISWC).
In addition to teaching the piano, the researchers have previously demonstrated that the glove can improve sensation and mobility for people with spinal cord injury.
In the Lewis Carroll classic, Through the Looking Glass, Humpty Dumpty states, “When I use a word, it means just what I choose it to mean — neither more nor less.” In turn, Alice (of Wonderland fame) says, “The question is, whether you can make words mean so many different things.” All organisms on Earth use a genetic code, which is the language in which the building plans for proteins are specified in their DNA. It has long been assumed that there is only one such “canonical” code, so each word means the same thing to every organism. While a few examples of organisms deviating from this canonical code had been serendipitously discovered before, these were widely thought of as very rare evolutionary oddities, absent from most places on Earth and representing a tiny fraction of species. Now, this paradigm has been challenged by the discovery of large numbers of exceptions from the canonical genetic code, published by a team of researchers from the U.S. Department of Energy Joint Genome Institute (DOE JGI) in the May 23, 2014 edition of the journal Science.
“All along, we presumed that the code or vocabulary used by organisms was universal, applying to all branches of the tree of life, with vanishingly few exceptions,” said DOE JGI Director Eddy Rubin, and senior author on the Science paper. “We have now confirmed that this just isn’t so. There is a significant portion of life that uses different vocabularies where the same word means different things in different organisms.”
This research was conducted under the DOE JGI’s continuing effort to explore the biological frontier known as “microbial dark matter.” These are the vast number of microbes that are difficult-to-impossible to grow and study in the laboratory but populate nearly all environments from the human gut to the hot vents at the bottom of the ocean. Approximately 99% of all microbial species on Earth fall in this category, defying culture in the laboratory but profoundly influencing the most significant environmental processes from plant growth and health, to the carbon and other nutrient cycles on land and sea, and even climate processes.
“The tools of metagenomics and single-cell genomics, with which we determine the genetic blueprints of microbes without the need to grow them in the laboratory, provide us a window into the unexplored, uncultured microbial world,” Rubin said. “The metaphor we use is that up until very recently we have just been looking under the lamppost for new life, studying organisms that we can grow in the laboratory while we know most microbial life is very resistant to being grown in the lab. In this project, using metagenomics and single-cell genomics to explore uncultured microbes, we really had the opportunity to see how the genetic code operates in the wild. It is helping us get an unbiased view of how nature operates and how microbes manage our planet.”
It has been 60 years since the discovery of the structure of DNA and the emergence of the central dogma of molecular biology, wherein DNA serves as a template for RNA and these nucleotides form triplets of letters called codons. There are 64 codons, and all but three of these triplets encode actual amino acids — the building blocks of protein. The remaining three are “stop codons,” that bring the molecular machinery to a halt, terminating the translation of RNA into protein. Each has a given name: Amber, Opal and Ochre. When an organism’s machinery reads the instructions in the DNA, builds a protein composed of amino acids, and reaches Amber, Opal or Ochre, this triplet would signal that they have arrived at the end of a protein.
“This is sort of a ‘stop sign,’” Rubin said. “But what we saw in the study was that in certain organisms, the stop sign was not interpreted as stop, rather it signaled to continue adding amino acids and expand the protein.”
The particular observation that caught the team’s interest in looking for breakdowns in the canonical genetic code was when the study’s lead investigator, DOE JGI’s Natalia Ivanova, came across an anomaly: bacteria with extraordinarily short genes of only 200 base pairs in length. Typically, genes from microbes are about 800-900 base pairs long.
“When trying to interpret the sequence of these bacteria using the canonical codon table, Opal, normally interpreted as a stop sign, resulted in the bacteria having unbelievably short genes. When Natalia applied a different vocabulary where Opal, instead of be interpreted as a stop, was assumed to encode the amino acid glycine, the genes in the bacteria suddenly appeared to be of normal length,” Rubin said. Their interpretation of the finding was that “Opal-recoded” organisms, instead of stopping, incorporated an amino acid into the polypeptide, which kept growing and eventually produced normal-sized proteins.
Following this finding they wanted to see how frequently this occurs in nature and looked for similar occurrences in enormous amounts of sequence data from uncultured microbes. Computationally they sifted through a massive “haystack” of sequence data, 5.6 trillion letters of genetic code (the equivalent of nearly 2,000 human genomes). These came from over 1,700 samples sourced from far-flung and esoteric locations that span the globe — marine, fresh water, and terrestrial environments — to those much closer to home and more prosaic — from the human mouth and gut.
“We were surprised to find that an unprecedented number of bacteria in the wild possess these codon reassignments, from “stop” to amino-acid encoding “sense,” up to 10 percent of the time in some environments,” said Rubin.
Another observation the researchers made was that beyond bacteria, these reassignments were also happening in phage, viruses that attack bacterial cells. Phage infect bacteria, injecting their DNA into the cell and exploiting the translational machinery of the cell to create more of themselves, to the point when the bacterial cell explodes, releasing more progeny phage particles to spread to neighboring bacteria and run amok.
“To make this all happen, the established dogma was that phage needed to employ the exact genetic code that the host cell uses, otherwise, whatever DNA they inject wouldn’t be properly translated,” Rubin said. “But we observed phage with codon vocabularies that did not match any we found in their bacterial hosts. We scratched our heads at this result, because we wondered about what was up with the host. The dogma tells us that the phage to need to share the same code as the host, but we saw no Amber in bacteria. So what were these phage doing?”
The punch line, Rubin said, is that the dogma is wrong.
“Phage apparently don’t really ‘care’ about the codon usage of the host. They have ways to get around that, and in fact they use differences to attack the host.” The phage use certain molecular tricks, just those slight changes in the codon table, to suppress the host cell’s protective mechanisms to conduct a ‘hostile takeover’ of the cell. “We call this strategy ‘codon warfare’,” Rubin said. “We need to keep this in mind when characterizing environments and how their resident microbes contribute to biochemical and biogeochemical processes. Now that our assumptions about the canonical nature of the codon table are shaken up, we will be able to devise new analysis methods that take this phenomenon of unexpected complexity into consideration so we can obtain a better understanding of how these environments function.”
Additional food for thought, Rubin noted, is whether adequate controls can effectively be established for those emergent organisms developed through synthetic biology. Some of these organisms have been engineered with an intentionally altered genetic code, designed as a “firewall” to prevent the exchange of genetic information between laboratory-engineered microbes and their cousins in the wild.
Alice in Wonderland certainly captured the vexations of nature’s complexity: “If I had a world of my own, everything would be nonsense.”
Babies begin to learn about the connection between pictures and real objects by the time they are nine-months-old, according to a new study by scientists at Royal Holloway, University of London, and the University of South Carolina.
The research, published today in Child Development, found that babies can learn about a toy from a photograph of it well before their first birthday.
“The study should interest any parent or caregiver who has ever read a picture book with an infant,” said Dr Jeanne Shinskey, from the Department of Psychology at Royal Holloway. “For parents and educators, these findings suggest that, well before their first birthdays and their first words, babies are capable of learning about the real world indirectly from picture books, at least those that have very realistic images like photographs.”
Researchers familiarized 30 eight and nine-month-olds with a life-sized photo of a toy for about a minute. The babies were then placed before the toy in the picture and a different toy and researchers watched to see which one the babies reached for first.
In one condition, the researchers tested infants’ simple object recognition for the target toy by keeping both objects visible, drawing infants’ attention to the toys and then placing the toys inside clear containers. In another condition, they tested infants’ ability to create a continued mental idea of the target toy by hiding both toys from view, drawing infants’ attention to the toys and then placing the toys inside opaque containers.
When the toys were visible in clear containers, babies reached for the one that had not been in the picture, suggesting that they recognized the pictured toy and found it less interesting than the new toy because its novelty had worn off. But when the toys were hidden in opaque containers, babies showed the opposite preference — they reached more often for the one that had been in the photo, suggesting that they had formed a continued mental idea of it.
Dr Shinskey said: “These findings show that one brief exposure to a picture of a toy affects infants’ actions with the real toy by the time they reach nine-months-old. It also demonstrates that experience with a picture of something can strengthen babies’ ideas of an object so they can maintain it after the object disappears — so out of sight is not out of mind.”
The study, which was carried out at the Baby Lab at Royal Holloway’s campus, in Egham, Surrey, was published online today in Child Development, the journal of the Society for Research in Child Development.
Delivering chemotherapy drugs in nanoparticle form could help reduce side effects by targeting the drugs directly to the tumors. In recent years, scientists have developed nanoparticles that deliver one or two chemotherapy drugs, but it has been difficult to design particles that can carry any more than that in a precise ratio.
Now MIT chemists have devised a new way to build such nanoparticles, making it much easier to include three or more different drugs. In a paper published in the Journal of the American Chemical Society, the researchers showed that they could load their particles with three drugs commonly used to treat ovarian cancer.
“We think it’s the first example of a nanoparticle that carries a precise ratio of three drugs and can release those drugs in response to three distinct triggering mechanisms,” says Jeremiah Johnson, an assistant professor of chemistry at MIT and the senior author of the new paper.
Such particles could be designed to carry even more drugs, allowing researchers to develop new treatment regimens that could better kill cancer cells while avoiding the side effects of traditional chemotherapy. In the JACS paper, Johnson and colleagues demonstrated that the triple-threat nanoparticles could kill ovarian cancer cells more effectively than particles carrying only one or two drugs, and they have begun testing the particles against tumors in animals.
Longyan Liao, a postdoc in Johnson’s lab, is the paper’s lead author.
Putting the pieces together
Johnson’s new approach overcomes the inherent limitations of the two methods most often used to produce drug-delivering nanoparticles: encapsulating small drug molecules inside the particles or chemically attaching them to the particle. With both of these techniques, the reactions required to assemble the particles become increasingly difficult with each new drug that is added.
Combining these two approaches — encapsulating one drug inside a particle and attaching a different one to the surface — has had some success, but is still limited to two drugs.
Johnson set out to create a new type of particle that would overcome those constraints, enabling the loading of any number of different drugs. Instead of building the particle and then attaching drug molecules, he created building blocks that already include the drug. These building blocks can be joined together in a very specific structure, and the researchers can precisely control how much of each drug is included.
Each building block consists of three components: the drug molecule, a linking unit that can connect to other blocks, and a chain of polyethylene glycol (PEG), which helps protect the particle from being broken down in the body. Hundreds of these blocks can be linked using an approach Johnson developed, called “brush first polymerization.”
“This is a new way to build the particles from the beginning,” Johnson says. “If I want a particle with five drugs, I just take the five building blocks I want and have those assemble into a particle. In principle, there’s no limitation on how many drugs you can add, and the ratio of drugs carried by the particles just depends on how they are mixed together in the beginning.”
For this paper, the researchers created particles that carry the drugs cisplatin, doxorubicin, and camptothecin, which are often used alone or in combination to treat ovarian cancer.
Each particle carries the three drugs in a specific ratio that matches the maximum tolerated dose of each drug, and each drug has its own release mechanism. Cisplatin is freed as soon as the particle enters a cell, as the bonds holding it to the particle break down on exposure to glutathione, an antioxidant present in cells. Camptothecin is also released quickly when it encounters cellular enzymes called esterases.
The third drug, doxorubicin, was designed so that it would be released only when ultraviolet light shines on the particle. Once all three drugs are released, all that is left behind is PEG, which is easily biodegradable.
This approach “represents a clever new breakthrough in multidrug release through the simultaneous inclusion of different drugs, through distinct chemistries, within the same … platform,” says Todd Emrick, a professor of polymer science and engineering at the University of Massachusetts at Amherst who was not involved in the study.
Working with researchers in the lab of Paula Hammond, the David H. Koch Professor of Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research, the team tested the particles against ovarian cancer cells grown in the lab. Particles carrying all three drugs killed the cancer cells at a higher rate than those that delivered only one or two drugs.
Johnson’s lab is now working on particles that carry four drugs, and the researchers are also planning to tag the particles with molecules that will allow them to home to tumor cells by interacting with proteins found on the cell surfaces.
Johnson also envisions that the ability to reliably produce large quantities of multidrug-carrying nanoparticles will enable large-scale testing of possible new cancer treatments. “It’s important to be able to rapidly and efficiently make particles with different ratios of multiple drugs, so that you can test them for their activity,” he says. “We can’t just make one particle, we need to be able to make different ratios, which our method can easily do.”