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A new approach to stabilizing protein structures could be key to an efficient vaccine

 

Despite decades of malaria research, the disease still afflicts hundreds of millions and kills around half a million people each year – most of them children in tropical regions. Part of the problem is that the malaria parasite is a shape-shifter, making it hard to target. But another part of the problem is that even the parasite’s proteins that could be used as vaccines are unstable at tropical temperatures and require complicated, expensive cellular systems to produce them in large quantities. Unfortunately, the vaccines are most needed in areas where refrigeration is lacking and funds to buy vaccines are scarce. A new approach developed at the Weizmann Institute of Science, recently reported in Proceedings of the National Academy of Science (PNAS), could, in the future, lead to an inexpensive malaria vaccine that can be stored at room temperature.

 

The RH5 protein is one of the malaria parasite’s proteins that have been tested for use as a vaccine. This protein is used by the parasite to anchor itself to the red blood cells it infects. Using the protein as a vaccine alerts the immune system to the threat without causing disease, thus enabling it to mount a rapid response when the disease strikes, and to disrupt the parasite’s cycle of infection. Research student Adi Goldenzweig and Dr. Sarel Fleishman of the Institute’s Biomolecular Sciences Department decided to use the computer-based protein design tools they have been developing in Fleishman’s lab to improve the usefulness of this protein.

 

Based on software they have been creating for stabilizing protein structures, Goldenzweig developed a new program for “programming” proteins used in vaccines against infectious diseases. Such proteins, because they are under constant attack by the immune system, tend to mutate from generation to generation. So the program she developed uses all the known information on different configurations of the protein sequence in different versions of the parasite. “The parasite deceives the immune system by mutating its surface proteins. Paradoxically, the better the parasite is at evading the immune system, the more clues it leaves for us to use in designing a successful artificial protein,” she says.

 

The researchers sent the programmed artificial protein to a group in Oxford that specializes in developing a malaria vaccine. This group, led by Prof. Matthew Higgins and Simon Draper, soon had good news: The results showed that, in contrast with the natural ones, the programmed protein can be produced in simple, inexpensive cell cultures, and in large quantities. This could significantly lower production costs. In addition, it is stable at temperatures of up to 50o C, so it won’t need refrigeration. Best of all, in animal trials, the proteins provoked a protective immune response. “The method Adi developed is really general,” says Fleishman. “It has succeeded where others have failed, and because it is so easy to use, it might be applied to emerging infectious diseases like Zika or Ebola, when quick action can stop an epidemic from developing.”

 

Fleishman and his group are currently using their method to test a different strategy for treating malaria, based on targeting the RH5 protein itself and blocking its ability to mediate the contact between the parasite and human red blood cells.

Dr. Sarel Fleishman’s research is supported by the Rothschild Caesarea Foundation; Sam Switzer, Canada; and the European Research Council. Dr. Fleishman is the incumbent of the Martha S. Sagon Career Development Chair.

 

A Rusty Green Early Ocean?

Though they may seem rock solid, the ancient sedimentary rocks called iron formations – the world’s chief economic source of iron ore – were once dissolved in seawater. How did that iron go from a dissolved state to banded iron formations? Dr. Itay Halevy and his group in the Weizmann Institute of Science’s Earth and Planetary Sciences Department suggest that billions of years ago, the “rust” that formed in the seawater and sank to the ocean bed was green – an iron-based mineral that is rare on Earth today but might once have been relatively common.

 

We know there was dissolved iron in the early oceans, and this is a strong indication that Earth’s free oxygen (O2) concentrations were exceedingly low. Otherwise, the iron would have reacted with oxygen to form iron oxides, which are the rusty red deposits familiar to anyone who’s left a bike out in the rain. Today, says Halevy, iron is delivered from the land to the oceans as small insoluble oxide particles in rivers. But this mode of sedimentation only came about as free oxygen accumulated in Earth’s atmosphere, about 2.5 billion years ago. With almost no oxygen, the oceans were iron-rich, but that did not mean that iron remained dissolved in seawater indefinitely: It ultimately formed insoluble compounds with other elements and settled to the seabed to give rise to banded iron formations.

 

The idea that one of those insoluble compounds could be a rusty green mineral, says Halevy, occurred to him during his doctoral research, when he was trying to recreate the conditions on early Mars, including its rusty-red iron sediments. “I got some green stuff I didn’t recognize at first, which quickly turned orange when I exposed it to air. With a little more careful experimentation, I found that this was a mineral called green rust, which is extremely rare on Earth today, owing to its affinity for oxygen.” Today green rust quickly transforms into the familiar red rust, but with not much free oxygen around, Halevy reasoned, it could have been an important way for dissolved iron to form solid compounds and settle to the seafloor.

 

Support for these ideas comes from Sulawesi, Indonesia, where green rust forms today in iron-rich, oxygen-poor Lake Matano, thought to be similar to the seawater that existed during extended periods of Earth’s early history. To test his ideas in detail and explore their significance, Halevy set up experiments in which he and his team recreated, as closely as possible, the conditions of the ancient, oxygen-free, Precambrian ocean. They found that green rust not only forms under these conditions, but that when left to age, it transforms into the minerals found in Precambrian iron formations – a combination of iron-bearing oxides, carbonates and silicates.

 

Could green rust have been a main vehicle for settling iron out of seawater? Halevy and his team developed models to depict the iron cycle in Earth’s early oceans, including the possibility of green rust formation and competition with other mineral shuttles of iron to the seafloor. Their findings suggest that green rust was probably a major player in the iron cycle. The iron in the green rust later transformed into the minerals we can now observe in the geologic record. “Of course, it would have been one of several means of iron deposition, just as a number of different processes are involved in chemical sedimentation in the oceans today,” says Halevy. “But as far as we can tell, green rust should have delivered a substantial proportion of iron to the very early ocean sediments.”

 

Dr. Itay Halevy’s research is supported by the Helen Kimmel Center for Planetary Science; the Deloro Institute for Advanced Research in Space and Optics; and the Wolfson Family Charitable Trust. Dr. Halevy is the incumbent of the Anna and Maurice Boukstein Career Development Chair in Perpetuity.

 

Uncovering the Secrets of White Cell Power

 

White blood cells push their way through barriers to get to infection sites

 

One of the mysteries of the living body is the movement of cells – not just in the blood, but through cellular and other barriers. New research in the Weizmann Institute of Science has shed light on the subject, especially on the movement of immune cells that race to the sites of infection and inflammation. The study revealed that these cells – white blood cells – actively open large gaps in the internal lining of the blood vessels, so they can exit through the vessel walls and rapidly get to areas of infection.

 

Prof. Ronen Alon and his group in the Weizmann Institute’s Immunology Department discovered how various white blood cells push their way through the lining of the blood vessels when they reach their particular “exit ramps.” Using their nuclei to exert force, they insert themselves between – as well as into – the cells in the vessel walls called endothelial cells. Dismantling structural filaments within the cytoskeletons – the internal skeletons – of the endothelial cells creates the large holes – several microns in diameter.

 

Alon explains that the nucleus is the largest, most rigid structure in the cell. When driven by motors specifically engaged for this function, is tough enough to push through the barrier imposed by the blood vessel walls.  

 

The scientists tracked the cytoskeletons of endothelial cells as they were crossed by immune cells in real time, the behavior of the nuclei of various white blood cells during active squeezing and the fate of the various types of actin fibers that make up the endothelial cell skeletons. The researchers used a number of methods, including fluorescence and electron microscopy, in collaboration with Dr. Eugenia Klein of the Microscopy Unit; a unique system in Alon’s lab for simulating blood vessels in a test tube; and in vivo imaging with Prof. Sussan Nourshargh of Queen Mary University of London. The results of this research, conducted in Alon’s lab by research students Sagi Barzilai and Francesco Roncato and postdoctoral fellow Dr. Sandeep Kumar Yadav, were recently reported in Cell Reports.

 

Common wisdom in this field had held that the endothelial cells must help immune cells squeeze through by contracting themselves like small muscles, but the present study found no evidence for such contraction-based help. Alon says: “Our study shows that the endothelial cells, which were thought to be dynamic assistants in this process of crossing of blood vessel walls, are really more responders to the ‘physical work’ invested by the white blood cell motors and nuclei in generating gaps and crossing through blood vessels.”

 

Significance for cancer research

In addition to increasing the basic understanding of how the various arms of the immune system reach their sites of differentiation and activity, these findings may aid in cancer research. “We believe that small subsets of metastatic tumor cells have the ability to adopt the mechanisms used by immune cells to exit the blood vessels into the lungs, the bone marrow, the brain and other organs. If this is true, we might be able to identify these subsets and target them before these cells leave their original tumor sites and invade distant organs,” says Alon.

 

Prof. Ronen Alon’s research is supported by the Herbert L. Janowsky Lung Cancer Research Fund; Mr. and Mrs. William Glied, Canada; and Carol A. Milett, Aventura, FL. Prof. Alon is the incumbent of the Linda Jacobs Professorial Chair in Immune and Stem Cell Research.

 

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