No matter how complex, all organisms – from the tiniest fruit fly to a human being – begin with a single cell. We know that this cell contains all the instructions for making every cell type in the body. The challenge is to uncover the overall plan laid out in the instruction book – the genome.  What makes a head at one end and a tail at the other, a front and back, and, continuing through embryonic development, all the complex and diverse patterns that make up the living creature?

 

Spaetzle, in its inactive form, is found encircling the entire inner membrane of the early embryo; the enzyme that activates it – by cleaving it into two parts – is active only in the belly region. Once spaetzle is activated, the two parts can diffuse out of the belly region, and they can also recombine in a different form that can then be reactivated in a new way. This interplay – between the elements that are able to diffuse past the edges of the belly region and those that are confined to it – creates a situation in which active spaetzle proteins are concentrated towards the belly region, thus producing the activation gradient.  Shilo: “We see, in our model, that the active form of the hormone is eventually driven in toward the center.”

With the mechanism proposed by the model in mind, the researchers turned back to experiments. They showed that the Spaetzle protein is indeed present in several distinct forms. When the team manipulated the genes for the elements in the model, they found they could direct the process of hormone concentration, even generating fruit fly embryos in which the belly region formed where the tail should be. These experiments convinced the researchers that the working model generated in computational approaches is truly valid.

The membrane receptors to which spaetzle binds are known as Toll receptors, and these were originally discovered in the 1980s in developing fruit fly embryos. The same Toll receptors were the subject of the 2011 Nobel Prize in Physiology or Medicine, but the prize was awarded for the discovery of a completely different role: They are vital for the innate immune response, our body’s first line of defense against invading pathogens. These receptors have been conserved over eons of evolution, and Shilo believes that the Toll receptor initially evolved for its crucial role in the immune system and was later co-opted for embryonic patterning in insects. Shilo: “It would be interesting to see whether the mechanism we discovered for concentrating the spaetzle proteins and creating a gradient might also apply to certain aspects of the innate immune response.”

 

 

 

 

 

 

Prof. Naama Barkai’s research is supported by the Azrieli Institute for Systems Biology, which she heads; the Helen and Martin Kimmel Award for Innovative Investigation; the Jeanne and Joseph Nissim Foundation for Life Sciences Research; Lorna Greenberg Scherzer, Canada; the Carolito Stiftung; the European Research Council; the estate of Hilda Jacoby-Schaerf; and the estate of John Hunter. Prof. Barkai is the incumbent of the Lorna Greenberg Scherzer Professorial Chair.
 

 

 

 

The researchers used the database to trace one of the ways in which sulfur exits ocean water into the underlying sediments – the formation of so-called sulfate evaporite minerals. These sulfur-bearing minerals, such as gypsum, settle to the bottom of shallow seas as seawater evaporates. The team found that the formation and burial of sulfate evaporites were highly variable over the last 550 million years, due to changes in shallow sea area, the latitude of ancient continents and sea level. More surprising to Halevy and colleagues was the discovery that only a relatively small fraction of the sulfur cycling through the oceans has exited seawater in this way. Their research showed that the formation and burial of a second sulfur-bearing mineral – pyrite – has apparently been much more important.

Pyrite is a shiny, yellow iron-sulfur mineral also known as "fools’ gold," which forms when microbes in seafloor sediments use the sulfur dissolved in seawater to digest organic matter. The microbes take up sulfur in the form of sulfate (bound to four oxygen atoms) and release it as sulfide (with no oxygen). Oxygen is emitted during this process, thus making it a source of oxygen in the air. This part of the sulfur cycle, however, was thought be minor. Since the other part – sulfur evaporite formation – does not release oxygen, sulfur's effect on oxygen levels was considered unimportant.
 

In testing various theoretical models of the sulfur cycle against the Macrostrat data, the team realized that the production and burial of pyrite has been much more significant than previously thought, accounting for more than 80% of all sulfur removed from the ocean – rather than the 30-40% in prior estimates. As opposed to the variability they saw for sulfate evaporite burial, pyrite burial has been relatively stable throughout the period. The analysis also revealed that most of the sulfur entering the ocean has been washed in from the weathering of pyrite exposed on land. In other words, there is a balance between pyrite formation and burial, which releases oxygen, and the weathering of pyrite on land, which consumes it. The implication of these findings is that the sulfur cycle regulates the atmospheric concentration of oxygen more strongly than previously appreciated.

“This is the first use of Macrostrat to quantify chemical fluxes in the Earth system,” said Peters. “I met my coauthors at a lecture I gave at Caltech, and we immediately began discussing how we might apply Macrostrat to understanding biogeochemical cycling. I think this study will open the door to many more uses of Macrostrat for constraining biogeochemical cycles.”

“For me, the truly surprising result is that pyrite weathering and burial appear to be such important processes in the sulfur cycle throughout all of Earth’s history. The carbon cycle is recognized as the central hub controlling redox processes on Earth, but our work suggests that nearly as many electrons are shuttled through the sulfur cycle,” said Fischer.

Halevy: “These findings, in addition to shedding new light on the role of sulfur in regulating oxygen levels in the atmosphere, represent an important step forward in developing a quantitative, mechanistic understanding of the processes governing the global sulfur cycle.”

 

Dr. Itay Halevy’s research is supported by the Sir Charles Clore Research Prize; and the estate of Olga Klein Astrachan.
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

One of the ways our cells keep things running smoothly is by recycling all sorts of proteins, especially those that are damaged or have outlived their usefulness. But how does the cell avoid consigning to the recycling bin those proteins that are still serving important functions? New research led by Dr. Michal Sharon of the Biological Chemistry Department reveals how one enzyme works to rescue vital proteins from unwanted demolition. Among other things, this enzyme saves from the cell’s protein recycler two proteins that help stop cancerous growth – p53 and p73 – and thus may play a role in protecting against cancer.

Dismantling proteins can be a “bureaucratic” process in which those slated for demolition are first labeled with special tags called ubiquitin and then sent off to the “Department of Protein Disassembly,” otherwise known as the proteasome. In the proteasome, the tags are read in one unit and then the protein is ushered into the next unit, where it is broken down for parts. The discovery of this bureaucratic process earned Rose, Hershko and Ciechanover a Nobel Prize in 2004. In recent years, however, researchers have come to realize that a parallel, more passive, dismantling process can occur in the same machinery. This process targets proteins that are unfolded – either along part of their lengths or completely. Such proteins can find themselves swept into the demolition unit without having first gone through the tagging and checking stage. Almost a third of the cell’s proteins contain unfolded segments and a fifth eventually undergo this type of disassembly, yet many of them play crucial roles in regulation and signaling. With no tagging system to sort them out, how does the cell protect the needed proteins from the degradation machinery?

Investigating this question was complicated, as the two pathways – the bureaucratic and the passive – exist side by side in the same machinery.

Several years ago, Prof. Yosef Shaul, Head of the Molecular Genetics Department, revealed a part of the answer: He identified the “rescuer” that prevents unwanted dismantling. This rescuer, an enzyme called NQO1, is an all-around protector of the cell: In addition to keeping vital proteins from being broken down, it was known to fight against reactive oxygen compounds, thus protecting the cell from oxidative damage.