Weizmann Institute

Reading gut bacteria

(photo from wis-wander.weizmann.ac.il)

Our species’ waking and sleeping cycles – shaped in millions of years of evolution – have been turned upside down within a single century with the advent of electric lighting and airplanes. As a result, millions of people regularly disrupt their biological clocks – for example, shift workers and frequent flyers – and these have been known to be at high risk for such common metabolic diseases as obesity, diabetes and heart disease. A new study published in Cell, led by Weizmann Institute scientists, reveals for the first time that our biological clocks work in tandem with the populations of bacteria residing in our intestines, and that these micro-organisms vary their activities over the course of the day. The findings show that mice and humans with disrupted daily wake-sleep patterns exhibit changes in the composition and function of their gut bacteria, thereby increasing their risk for obesity and glucose intolerance.

A consensus has been growing in recent years that the populations of microbes living in and on our bodies function as an extra “organ” that has wide-ranging impacts on our health. Christoph Thaiss, a research student in the lab of Dr. Eran Elinav of the Weizmann Institute’s immunology department, led this research into the daily cycles of gut bacteria. Working together with David Zeevi in the lab of Prof. Eran Segal of the computer science and applied mathematics department, and Maayan Levy of Elinav’s lab, he found a regular day-night cycle in both the composition and the function of certain populations of gut bacteria in mice. Despite living in the total darkness of the digestive system, the gut microbes were able to time their activity to the mouse’s feeding cycles, coordinating daily microbial activities to those of their host.

Does this finding have any medical significance? To further investigate, the researchers looked at “jet-lagged” mice, whose day-night rhythms were altered by exposing them to light and dark at different intervals. The jet-lagged mice stopped eating at regular times, and this interrupted the cyclic rhythms of their internal bacteria, leading to weight gain and high blood sugar levels. To verify these results, the scientists transferred bacteria from the jet-lagged mice into sterile mice; those receiving the “jet-lagged microbes” also gained weight and developed high blood sugar levels.

The research group then turned to human gut bacteria, identifying a similar daily shift in their microbial populations and function. To conduct a jet-lag experiment in humans, the researchers collected bacterial samples from two people flying from the United States to Israel – once before the flight, once a day after landing when jet lag was at its peak, and once two weeks later when the jet lag had worn off. The researchers then implanted these bacteria into sterile mice. Mice receiving the jet-lagged humans’ bacteria exhibited significant weight gain and high blood sugar levels, while mice getting bacteria from either before or after the jet lag had worn off did not. These results suggest that the long-term disruption of the biological clock leads to a disturbance in their bacteria’s function that may, in turn, increase the risk for such common conditions as obesity and imbalances in blood sugar levels.

Segal: “Our gut bacteria’s ability to coordinate their functions with our biological clock demonstrates, once again, the ties that bind us to our bacterial population and the fact that disturbances in these ties can have consequences for our health.”

Elinav: “Our inner microbial rhythm represents a new therapeutic target that may be exploited in future studies to normalize the microbiota in people whose life style involves frequent alterations in sleep patterns, hopefully to reduce or even prevent their risk of developing obesity and its complications.”

Also participating in this research were Gili Zilberman-Schapira, Jotham Suez, Anouk Tengeler, Lior Abramson, Meirav Katz and Dr. Hagit Shapiro in Elinav’s lab; Tal Korem in Segal’s lab; Prof. Alon Harmelin, Dr. Yael Kuperman and Dr. Inbal Biton of the veterinary resources department, Dr. Shlomit Gilad of the Nancy and Stephen Grand Israel National Centre for Personalized Medicine; and Prof. Zamir Halpern and Dr. Niv Zmora of the Sourasky Medical Centre and Tel Aviv University.

Weizmann Institute news releases are posted at wis-wander.weizmann.ac.il and eurekalert.org.

Untangling the womb maze

Fluid-filled structures in the placenta. (photo from wis-wander.weizmann.ac.il)

The fetus in the womb totally depends on the blood bond with the mother. Spotting irregularities in the flow across the placenta could therefore be crucial for detecting fetal distress,

but currently no reliable method is available for monitoring the flow or detecting other signs of the distress in its early stages.

Magnetic resonance imaging, or MRI, can be safely performed during pregnancy, but currently available MRI methods are not suitable. Problems include the motion of the fetus or mothers’ breath, the varied structure of placental tissue and the tangled maze formed by maternal and fetal blood vessels.

In a new study in mice conducted with advanced MRI methods, Weizmann Institute scientists have now revealed in unprecedented detail the dynamics of the flow of fluids within the placenta. This feat was all the more impressive, as a mouse placenta is around the size of a dime. As reported recently in the Proceedings of the National Academy of Sciences, they managed to identify three different types of fluid-filled structures: maternal blood vessels, which account for two-thirds of blood flow in the placenta; fetal vessels, which account for about one-quarter of the flow; and embryo-derived cells infiltrating the mother’s vasculature, which account for the rest of the flow and in which the exchange of fluids between mother and fetus takes place. The researchers also found that in maternal vessels, blood flows by diffusion, whereas in fetal vessels, the flow, stimulated by the pumping of the growing fetus’ heart, is much faster. In the cells that have infiltrated the mother’s vasculature, the dynamics of the flow follows an intermediate pattern, driven by both diffusion and pumping.

Two sophisticated MRI methods were combined to enable the study: one geared toward monitoring diffusion and another directed at identifying structures with the help of a contrast material. They could be applied successfully in large part thanks to an innovative scanning approach, spatiotemporal encoding (SPEN), a Weizmann Institute technique. Because SPEN is ultra-fast and makes it possible to separately encode signals from such different materials as air or fat, it allowed the researchers to overcome disturbances created by movement and the variability of placental tissue. If developed further for safe and reliable use in humans, this combined approach holds great promise as a noninvasive means of detecting fetal distress caused by disruptions in the placental flow. It can be particularly valuable when fast decisions about inducing labor need to be made, for example, in such complications of pregnancy as preeclampsia.

The study was a joint effort of two laboratories: one headed by Prof. Michal Neeman of the biological regulation department and the other by Prof. Lucio Frydman of the chemical physics department. The research was performed by two graduate students, Reut Avni from Neeman’s lab and Eddy Solomon from Frydman’s lab, together with Ron Hadas and Dr. Tal Raz of the biological regulation department, and Dr. Peter Bendel of chemical research support, in collaboration with Prof. Joel Richard Garbow from Washington University in St. Louis.

For more Weizmann news, visit wis-wander.weizmann.ac.il.

How mammals respond to novelty

Measuring the response to novelty: A mouse repeatedly touches the object and pulls away (nose and whisker contacts are color-coded; d is the distance of the snout from the object). (photo from wis-wander.weizmann.ac.il)

Put a young child in a new playground and she may take awhile to start playing – approaching the slide and then running back to Mom before finally stepping on. A new model suggests that it is not fear that makes her run back and forth, but simply the fact that her brain is telling her to stop and take in the new information – the height of the slide or how slippery it appears – before going any further.

Drs. Goren Gordon and Ehud Fonio, and Prof. Ehud Ahissar, believe that this is a basic pattern in mammals that governs how we learn. The mathematical model they developed and tested in experiments suggests that our innate curiosity is tempered by mechanisms in our brains that curb our ability to absorb novelty.

In Ahissar’s lab in the institute’s neurobiology department, researchers investigate how animals sense their surroundings. Previous research in which Fonio participated showed that, in a new situation, a mouse would approach an unfamiliar space, retreat to familiar surroundings, and then approach again. When Gordon, Fonio and Ahissar examined how mice used their whiskers to feel out a novel object, a similar pattern ensued: the whisker would touch the object, pull back and then touch it again. Gradually, as the mouse became familiar with one part of its surroundings, it would begin to explore further, moving away from the known part. The pattern was so consistent, the researchers thought they could create a model to explain how a mouse – or another mammal – explores new surroundings.

The researchers based their model on the premise that novelty can be measured and that the amount of novelty could be a primary factor in shaping the way that a mouse – or its whisker – will move through an environment. This model successfully reproduced the results of the previous study, in which the movement of the mouse gradually became more complex through the addition of measurable degrees of freedom. For example, it began with movement along a wall, as opposed to traveling across the open space. Using data from the previous experiments and others for which such data were available, they were able to construct a model that required very few additional assumptions.

The model suggested that novelty, per se, was not the deciding factor, but rather how much the novelty varied within a given situation. Approaching and retreating appear to be a way to keep the amount of new information within a constant range. Like the wavering child in the playground, the mice would absorb a certain amount of new sensory input – the curve of a new wall, for example – retreat, and approach again once the novel information was already starting to become familiar.

To test the model, the researchers designed an experimental setup in which a family of mice was born and raised in a den, and then a gate was opened from the den to a new area in which the pups could freely explore and return to their familiar den. The researchers found that the model was able to predict how the mice would explore their new surroundings. It held true whether it was applied to locomotion or to the motion of whiskers in feeling out new objects. The initial movements explored the most novel features of the new environment. After those were learned, just as the model predicted, the animals moved further afield, exploring the still-unknown parts of their surroundings.

“The mice were not given rewards for their behavior – for them, as for humans, satisfying curiosity is its own reward,” said Gordon.

“This behavioral pattern enables the mice to control the level of sensory stimulus to their brains by regulating the amount of novelty they are exposed to,” added Fonio.

These limits to novelty and exploration may, of course, have another evolutionary advantage: while the urge to explore is necessary for animals that must seek out food, stopping to check out the surroundings a bit at a time could be a prudent survival strategy. In other words, curiosity may have killed the cat, but a whisker pulled back in time might save the mouse.

Does this model apply to humans? Gordon points out that when we learn a new subject, we often need time to think things over before going on to the next topic. Further research might reveal whether young children – babies just learning to crawl, for example – explore their new surroundings in the same way. Even an adult entering a new situation might undergo a similar process.

In the future, a mathematical model of learning might prove useful for teachers and students, as well as for research into neurological issues involving the ability to absorb new information. This model also might someday be used in the field of robotics: robots that learn on their own, like mice, to explore a new setting might be able to function in situations that are too dangerous for humans, such as the aftermath of an earthquake or a nuclear power plant accident, for example.

For more Weizmann Institute news releases, visit wis-wander.weizmann.ac.il.

Peering into universe’s past

A small black hole gains mass. Dense cold gas (green) flows toward the centre of a stellar cluster (red cross in blue circle) with stars (yellow); the erratic path of the black hole through the gas (black line) is randomized by the surrounding stars. (photo from wis-wander.weizmann.ac.il)

At the ends of the universe, there are black holes with masses equaling billions of our sun. These giant bodies – quasars – feed on interstellar gas, swallowing large quantities of it non-stop. Thus, they reveal their existence: the light that is emitted by the gas as it is sucked in and crushed by the black hole’s gravity travels for eons across the universe until it reaches our telescopes. Looking at the edges of the universe is, therefore, looking into the past. These far-off, ancient quasars appear to us in their “baby photos” taken less than a billion years after the Big Bang: monstrous infants in a young universe.

Normally, a black hole forms when a massive star, weighing tens of solar masses, explodes after its nuclear fuel is spent. Without the nuclear furnace at its core pushing against gravity, the star collapses. Much of the material is flung outwards in a great supernova blast, while the rest falls inward, forming a black hole of only about 10 solar masses.

Since these ancient quasars were first discovered, scientists have wondered what process could lead a small black hole to gorge and fatten to such an extent, so soon after the Big Bang.

In fact, several processes tend to limit how fast a black hole can grow. For example, the gas normally does not fall directly into the black hole, but gets sidetracked into a slowly spiraling flow, trickling in drop by drop. When the gas is finally swallowed by the black hole, the light it emits pushes out against the gas. That light counterbalances gravity, and it slows the flow that feeds the black hole.

So how, indeed, did these ancient quasars grow? Prof. Tal Alexander, head of the particle physics and astrophysics department at the Weizmann Institute of Science, proposes a solution in a paper written together with Prof. Priyamvada Natarajan of Yale University, which appeared in a recent issue of Science.

Their model begins with the formation of a small black hole in the very early universe. At that time, cosmologists believe, gas streams were cold, dense and contained much larger amounts of material than the thin gas streams we see in today’s cosmos. The hungry, newborn black hole moved around, changing direction all the time, as it was knocked about by other baby stars in its vicinity. By quickly zigzagging, the black hole continually swept up more and more of the gas into its orbit, pulling the gas directly into it so fast, the gas could not settle into a slow, spiraling motion. The bigger the black hole got, the faster it ate; this growth rate, explained Alexander, rises faster than exponentially. After around 10 million years – a blink of an eye in cosmic time – the black hole would have filled out to around 10,000 solar masses. From then, the colossal growth rate would have slowed to a somewhat more leisurely pace, but the black hole’s future path would already be set – leading it to eventually weigh in at a billion solar masses or more.

Alexander’s research is supported by the European Research Council. Visit wis-wander.weizmann.ac.il for more Weizmann news.

DNA’s not only factor

Epigenetics: environmental effects influence how genes are turned on or off. (photo by Yuval Robichek via wis-wander.weizmann.ac.il)

Blood stem cells have the potential to turn into any type of blood cell, whether it be the oxygen-carrying red blood cells or the many types of white blood cells of the immune system that help fight infection. How exactly is the fate of these stem cells regulated? Preliminary findings from research conducted by scientists from the Weizmann Institute and the Hebrew University are starting to reshape the conventional understanding of the way blood stem-cell fate decisions are controlled, thanks to a new technique for epigenetic analysis they have developed.

Understanding epigenetic mechanisms (environmental influences other than genetics) of cell fate could lead to the deciphering of the molecular mechanisms of many diseases, including immunological disorders, anemia, leukemia, and many more. It also lends strong support to findings that environmental factors and lifestyle play a more prominent role in shaping our destiny.

The process of differentiation – in which a stem cell becomes a specialized mature blood cell – is controlled by a cascade of events in which specific genes are turned “on” and “off” in a highly regulated and accurate order. The instructions for this process are contained within the DNA itself in short, regulatory sequences. These regulatory regions are normally in a “closed” state masked by special proteins called histones to ensure against unwarranted activation. Therefore, to access and “activate” the instructions, this DNA mask needs to be “opened” by epigenetic modifications of the histones so it can be read by the necessary machinery.

In a paper published in Science, Dr. Ido Amit and David Lara-Astiaso of the Weizmann Institute’s immunology department, together with Prof. Nir Friedman and Assaf Weiner of Hebrew University, charted for the first time histone dynamics during blood development. From the new technique for epigenetic profiling they developed, in which just a handful of cells – as few as 500 – can be sampled and analyzed accurately, they have identified the exact DNA sequences, as well as the various regulatory proteins, that are involved in regulating the process of blood stem-cell fate.

Their research also yielded unexpected results: as many as 50 percent of these regulatory sequences are established and opened during intermediate stages of cell development. This means that epigenetics is active at stages in which it had been thought that cell destiny was already set. “This changes our whole understanding of the process of blood stem-cell fate decisions,” said Lara-Astiaso, “suggesting that the process is more dynamic and flexible than previously thought.”

Although this research was conducted on mouse blood stem cells, the scientists believe that the mechanism may hold true for other types of cells. “This research creates a lot of excitement in the field, as it sets the groundwork to study these regulatory elements in humans,” said Weiner. Discovering the exact regulatory DNA sequence controlling stem-cell fate, as well as understanding its mechanism, holds promise for the future development of diagnostic tools, personalized medicine, potential therapeutic and nutritional interventions, and perhaps even regenerative medicine, in which committed cells could be reprogrammed to their full stem-cell potential.

For more Weizmann Institute news releases, visit wis-wander.weizmann.ac.il.

– Courtesy of Weizmann Institute