Though the first recorded use of rigid bone setting dates as far back as ancient Egypt, Prof. Elazar Zelzer and PhD student Chagai Rot of the Weizmann Institute’s Molecular Genetics Department now suggest, in a paper published in Developmental Cell, that constant movement of the bones could actually result in effective healing.

“In terms of evolution, the need for medical intervention just doesn’t make sense,” says Zelzer. “It’s a paradox: Evolution ‘invested’ great effort in affording bones with regenerative capabilities, and an intact skeleton is crucial for functioning and survival. Yet we are unaware of any natural mechanism able to align bones when they break.”

The medical literature has indicated the existence of such a natural system for some time. Some physicians are also aware of the phenomenon: They sometimes send very young children home with just a bandage wrapped around the limb. Even in cases of severe fracture, after some time the bones have often completely aligned and healed on their own. Until now, doctors and researchers have assumed that the bones initially rejoin at an angle and then are sculpted through a process of bone remodeling as the bone heals, mature bone being removed from one side and new bone being formed on the other to achieve the correct alignment.

 

To investigate the process, the Weizmann scientists allowed young mice with fractured bones to move around freely without any intervention, X-raying their bones on a daily basis. To their surprise, not only did the bones realign naturally, but this occurred within just a few days. This fast turnaround occurred while the bones were still separated, leading the scientists to believe that it is something other than the process of remodeling that brings about bone alignment.
 

 

 

 

Further analysis of the healing bones in the active mice revealed yet another surprise: New tissue similar to growth plates – an area at either end of growing bones from which new bone tissue is produced – had formed, but on the concave side of the fracture. The researchers observed that bone tissue is produced from both sides of the plate, acting like a “mechanical jack” to generate opposing forces that straighten the two bone fragments. Only once they are precisely realigned do the bone halves proceed with the modeling process to reunite and reshape.

Acting on previous research in Zelzer’s lab suggesting that muscle contraction may also play a role in the process, the scientists injected the mice with Botox to paralyze the muscles. They found that although the fractured bone had reunited, the halves were not aligned properly, remaining at an angle. The reason, they found, was that in the absence of muscle contraction, the new growth plate didn’t form.

The fact that this natural mechanism was found to be less effective in adults suggests that this newly discovered paradigm has helped solve the longstanding mystery of why fractures heal so much faster in the young. Rot: “In terms of evolution, a rapid and efficient fracture-healing process may be more important in the young, to ensure their ability to reproduce; while there is less ‘survival’ advantage for adults who have already passed on their genes to their offspring.”

The scientists suggest that a better understanding of spontaneous realignment in fracture healing may provide a new line of thinking – even in older children and adults – and help physicians reevaluate current bone-setting procedures.

 

Prof. Elazar Zelzer's research is supported by the Jeanne and Joseph Nissim Foundation for Life Sciences Research; the Irving and Dorothy Rom Charitable Trust; and the estate of David Levinson.

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, (PNAS), USA, 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’s heart, is much faster. In the cells that had 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 ultrafast 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.

Prof. Lucio Frydman’s research is supported by the Helen and Martin Kimmel Institute for Magnetic Resonance Research, which he heads; the Helen and Martin Kimmel Award for Innovative Investigation; the Ilse Katz Institute for Material Sciences and Magnetic Resonance Research; the Adelis Foundation; the Mary Ralph Designated Philanthropic Fund of the Jewish Community Endowment Fund; Gary and Katy Leff, Calabasas, CA; Paul and Tina Gardner, Austin TX; a Seventh Framework European Research Council Advanced Grant; and the Perlman Family Foundation.

Prof. Michal Neeman’s research is supported by the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics, which she heads; the Clore Center for Biological Physics,’which she heads; the Kirk Center for Childhood Cancer and Immunological Disorders, which she heads; the Leona M. and Harry B. Helmsley Charitable Trust; the Carolito Stiftung; the Foundation Adelis; Andrew Adelson, Canada; the US-Israel Binational Science Foundation; and a Seventh Framework European Research Council Advanced Grant. Prof. Neeman is the incumbent of the Helen and Morris Mauerberger Professorial Chair in Biological Sciences.
 

 

Mysterious brain cells called microglia are starting to reveal their secrets thanks to research conducted at the Weizmann Institute of Science.

 

Until recently, most of the glory in brain research went to neurons. For more than a century, these electrically excitable cells were believed to perform the entirety of the information processing that makes the brain such an amazing machine. In contrast, cells called glia – which together account for about half of the brain’s volume – were thought to be mere fillers that provided the neurons with support and protection but performed no vital function of their own. In fact, they had been named glia, the Greek for “glue,” precisely because they were considered so unsophisticated.
 

 

But in the past few years, the glia cells – particularly the tiny microglia that make up about one-tenth of the brain cells – have been shown to play critical roles both in the healthy and in the diseased brain.

The octopi-like microglia are immune cells that conduct ongoing surveillance, swallowing cellular debris or, in the case of infection, microbes, to protect the brain from injury or disease. But these remarkable cells are more than cleaners: In the past few years, they have been found to be involved in shaping neuronal networks by pruning excessive synapses – the contact points that allow neurons to transmit signals – during embryonic development. They are probably also involved in reshaping the synapses as learning and memory occurs in the adult brain. Defects in microglia are believed to contribute to various neurological diseases, among them Alzheimer’s disease and amyotrophic lateral sclerosis, or ALS. By clarifying how exactly the microglia operate on the molecular level, scientists might be able to develop new therapies for these disorders.

More than a decade ago, Weizmann Institute’s Prof. Steffen Jung developed a transgenic mouse model that for the first time enabled scientists to visualize the highly active microglia in the live brain. Now Jung has made a crucial next step: His laboratory developed a system for investigating the functions of microglia.

The scientists have equipped mice with a genetic switch: an enzyme that can rearrange previously marked portions of the DNA. The switch is activated by a drug: When the mouse receives the drug, the enzyme performs a genetic manipulation – for example, to disable a particular gene. The switch is so designed that over the long term, it targets only the microglia, but not other cells in the brain or in the rest of the organism. In this manner, researchers can clarify not only the function of the microglia, but the roles of different genes in their mechanism of action.

As reported in Nature Neuroscience, Weizmann scientists, in collaboration with the team of Prof. Marco Prinz at the University of Freiburg, Germany, recently used this system to examine the role of an inflammatory gene expressed by the microglia. They found that the microglia contribute to an animal disease equivalent of multiple sclerosis. Prof. Jung’s team included Yochai Wolf, Diana Varol and Dr. Simon Yona, all of Weizmann’s Immunology Department.

The system developed at the Weizmann Institute, currently applied in numerous other studies by researchers at Weizmann and elsewhere, promises to shed new light on the role of the microglia in the healthy brain as well as in Alzheimer’s, ALS and various other diseases.
 

Prof. Steffen Jung’s research is supported by the Leir Charitable Foundations; the Leona M. and Harry B. Helmsley Charitable Trust; the Adelis Foundation; Lord David Alliance, CBE; the Wolfson Family Charitable Trust; the estate of Olga Klein Astrachan; and the European Research Council.

In the midst of a combined clinical and postdoctoral fellowship in the lab of Prof. Brendan Lee in Baylor College of Medicine, in Texas, Dr. Ayelet Erez encountered a case that would set her on her present research path: A child was admitted to the hospital with high blood pressure that did not respond to treatment. That child suffered from a genetic disease; his body lacked an enzyme responsible for the production of a particular amino acid, called arginine. But the connection between the missing enzyme, known for short as ASL, and the symptoms of the disease was a riddle that left the doctors helpless. What took place next illustrates what can happen when science and medicine get together: Erez, who was on a double medical and research track, combined her knowledge from both fields to create a mouse model of the disease.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

That is how she discovered a previously unknown function for this enzyme: It is structurally required for the production of nitrous oxide (NO), a biological messenger that plays a role, among other things, in dilating blood vessels and the functioning of the nervous system. She showed that the child’s symptoms were caused by low NO levels in his body – the result of the lack of ASL enzymes. In this case, the path from lab bench to bedside was a short one: The child was treated with a drug supplement containing NO. His blood pressure returned to normal and has remained so until now – for more than three years – and his cognitive abilities eventually began to improve as well. Erez received the William K. Bowes Jr. Award in Medical Genetics, awarded by Harvard Medical School, for this work. “The combination of clinical experience and research enabled me to succeed,” she says, “and it gave me a lot of personal satisfaction – as a doctor, a scientist and a mother.”

Nitrous oxide research goes back to 1846, the year an Italian chemist invented the explosive nitroglycerin. One hundred years later, Ferid Murad, Louis J. Ignarro and Robert F. Furchgott, who received the 1998 Nobel Prize in Medicine for their work, discovered that the body can break down nitroglycerin into NO molecules and that this substance dilates the blood vessels. Since then, mounting evidence points to an important role for this molecule in maintaining blood vessel and nervous system health, but both the mechanisms by which it works and those that regulate its activities have remained unknown. Among the obstacles to research in this area is the fact that three different enzymes are known to produce NO. Results of experimental attempts to genetically manipulate these enzymes, in order to create disease models, for instance, have been inconclusive.

Erez’s solution to this problem is to focus on an earlier stage in the NO metabolic pathway – in which the enzyme she researched at Baylor comes into play. ASL is responsible for arginine production; this amino acid is the raw material that all three NO enzymes process to produce nitrous oxide. Erez later discovered that ASL is also vital for the assembly of the protein complexes needed to produce NO – a role that ranks it as a top regulatory factor for controlling crucial NO levels in the body.
 

Now, in her Weizmann Institute lab, Erez plans, among other things, to delve deeper into the workings of the ASL enzyme, as well as the metabolic cycles of arginine and NO. The diseases in which disruptions in these metabolic pathways figure include degenerative nerve diseases, kidney failure and cancer, and Erez hopes her findings will contribute to the development of new ways to treat them.

Relevance for real patients

Once a week, Erez forgoes her lab work in the Institute’s Biological Regulation Department to go to the Chaim Sheba Medical Center, in Ramat Gan (near Tel Aviv). There, she spends half a day working in pediatric genetics with families of children whose cancer has a genetic origin. Her work there ties in with another kind of metabolic process she intends to investigate: that which turns a healthy cell into a cancerous one. She believes that by taking both clinical and scientific approaches to fighting disease, the two will end up complementing and strengthening one another. To further this strategy, she and Dr. Eran Elinav of the Immunology Department have started organizing on-campus meetings between researchers and clinical physicians to discuss different topics. “As an MD-Ph.D., my starting and ending point is always the human being; it is important to me that my research questions have relevance for real patients. At the end of the day, over and above the satisfaction of my scientific curiosity, is the fulfillment that comes from understanding a disease mechanism and optimizing its therapy.”

Double studies

Dr. Ayelet Erez was born in Haifa and completed her medical studies at the Technion there. She undertook a residency in pediatrics at Chaim Sheba Medical Center and her doctoral research in cancer genetics was completed at Tel Aviv University while she worked in a pediatric clinic. Her postdoctoral research was conducted at Baylor College of Medicine, in Houston, Texas – a school that allowed her to pursue a medical sub-specialization in clinical genetics along with her postdoctoral work. In 2012, she joined the Weizmann Institute’s Biological Regulation Department.

Erez, her husband, who is a veterinarian, and their two daughters, live on Moshav Bnei Zion, north of Tel Aviv.

 

Dr. Ayelet Erez's research is supported by the Adelis Foundation; Joseph Piko Baruch, Israel; the Dukler Fund for Cancer Research; the Paul Sparr Foundation; and the estate of Fannie Sherr. Dr. Erez is the incumbent of the Leah Omenn Career Development Chair.