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The human body has sophisticated defenses against the deposition of calcium minerals that stiffen heart tissues, researchers at the University of Illinois Urbana-Champaign and collaborators at UCLA Health and the University of Texas at Austin found in a new study that provides the first detailed, step-by-step documentation of how calcification progresses. The human body has sophisticated defenses against the deposition of calcium minerals that stiffen heart tissues, researchers at the University of Illinois Urbana-Champaign and collaborators at UCLA Health and the University of Texas at Austin found in a new study that provides the first detailed, step-by-step documentation of how calcification progresses. "Heart disease is the leading killer annually -- about 18 million deaths per year -- and that number is growing. A large proportion is the result of calcification," said study leader Bruce Fouke, a U. of I. professor of earth science and environmental change and director of the Roy J. Carver Biotechnology Center at Illinois. "When the aortic valve calcifies, an ultra-invasive surgery to replace the valve is the only option currently. That heightens the urgency to get a handle on this process to more effectively move forward with drug development and testing." The aortic valve is the portal through which oxygenated blood gets pumped out of the heart to the body, opening and closing more than 3 billion times during the average lifespan. Calcium deposits can grow within the three tissue flaps that make up the valve, called leaflets, stiffening them and leaving them unable to open all the way. "With calcification in blood vessels, a stent can help, but you can't do that with the aortic valve. Every organ in the body can be in perfect condition, but if the aortic valve stops functioning, that's the end of that life," said Mayandi Sivaguru, the first author of the paper and the director of the Cytometry and Microscopy to Omics Facility in the Carver Biotechnology Center. Despite the prevalence and biological importance, little is known about how the calcium deposits form or grow. Fouke's group has pioneered the field of "GeoBioMed," a combination of geology, biology and medicine, and previously applied it to the study of kidney stones. In the new study, published in the journal Scientific Reports, Fouke's group at Illinois teamed up with colleagues at the UCLA School of Medicine and the Jackson School of Geoscience at Texas to study and document the steps of calcium deposit formation in aortic valves from human cadaver hearts. "We used more than 12 modalities of study, including optical microscopy, electron microscopy and spectroscopy, to investigate the nature and progression of mineralization and protein localization in the aortic valve for the first time. This multimodal analysis set us apart, uncovering a new line of evidence to better understand cardiovascular calcification," Sivaguru said. The starting point is healthy leaflet tissue. Then tiny spherules of calcium phosphate form in the smooth muscle layer of the leaflets. Crucially, the team found that the form of calcium phosphate in the mineral deposits is not the same type as found in bone, called apatite, as has been widely thought. Instead, the deposits consist predominately of amorphous calcium phosphate, which has the ability to morphologically shapeshift and atomically rearrange. As they grow, the spherules coalesce into layers that encrust and stiffen the collagen and smooth muscle fibers that give the leaflets their flexibility. These processes combine to form large nodules that rotate, touch each other and further stiffen the tissues. "Immediately, we saw that the reactions within the tissues of the valves were virtually identical to those we've studied in coral reefs, hot springs and many other natural environments that harbor life-water-mineral interactions," said Fouke, who is the Ralph E. Grim Professor at Illinois. "Our blood is saturated with calcium and phosphate. Calcification of collagen and growth of nodules is inevitable given our blood chemistry, biology and composition. "However, the silver lining to all of this is that we also found that our body has evolved these incredibly intricate and effective processes to fight mineralization. It can't stop it, but it can slow it down dramatically." The researchers found two defense mechanisms. As the tiny ACP spherules form and begin to coalesce, the heart tissues produce large amounts of the protein osteopontin. Osteopontin promotes apatite growth and calcification in bones and kidney stones, so the findings initially puzzled the researchers, Fouke said. But osteopontin has the opposite, inhibitory effect on ACP, slowing down collagen calcification and nodule aggregation. "That's why knowing it's ACP instead of apatite is so important. Enhancing the release of osteopontin could be an important new target to slow down calcification to a level that it won't be a threat or require surgical intervention," Fouke said. The body's second defense is the very collagen where the nodules form. The researchers found that as the nodules start growing, the collagen fibers stretch around and contain them, forming a water barrier that further slows nodule growth. In addition to investigating possible therapeutic applications of osteopontin to slow calcification, the researchers also hope their work opens new avenues of investigation into preventing initial growth and dissolving already-formed mineral deposits throughout the human body. In collaboration with Mayo Clinic, the team is now applying their multimodal GeoBioMed approach to studying calcification in human breast tumors, a hallmark of the disease. The Barbara and Ed Weil Foundation, the National Institutes of Health (grant OT2OD023848) and the UCLA Amara-Yad project supported this work.

A simple two-carbon compound may have been a crucial player in the evolution of metabolism before the advent of cells, according to a new study. The finding potentially sheds light on the earliest stages of prebiotic biochemistry, and suggests how ATP came to be the universal energy carrier of all cellular life today. A simple two-carbon compound may have been a crucial player in the evolution of metabolism before the advent of cells, according to a new study published October 4 in the open access journal PLOS Biology, by Nick Lane and colleagues of University College London, UK. The finding potentially sheds light on the earliest stages of prebiotic biochemistry, and suggests how ATP came to be the universal energy carrier of all cellular life today. ATP, adenosine triphosphate, is used by all cells as an energy intermediate. During cellular respiration, energy is captured when a phosphate is added to ADP (adenosine diphosphate) to generate ATP; cleavage of that phosphate releases energy to power most types of cellular functions. But building ATP's complex chemical structure from scratch is energy intensive and requires six separate ATP-driven steps; while convincing models do allow for prebiotic formation of the ATP skeleton without energy from already-formed ATP, they also suggest ATP was likely quite scarce, and that some other compound may have played a central role in conversion of ADP to ADP at this stage of evolution. The most likely candidate, Lane and colleagues believed, was the two-carbon compound acetyl phosphate (AcP), which functions today in both bacteria and archaea as a metabolic intermediate. AcP has been shown to phosphorylate ADP to ATP in water in the presence of iron ions, but a host of questions remained after that demonstration, including whether other small molecules might work as well, whether AcP is specific for ADP or instead could function just as well with diphosphates of other nucleosides (such as guanosine or cytosine), and whether iron is unique in its ability to catalyze ADP phosphorylation in water. In their new study, the authors explored all these questions. Drawing on data and hypotheses about the chemical conditions of the Earth before life arose, they tested the ability of other ions and minerals to catalyze ATP formation in water; none were nearly as effective as iron. Next, they tested a panel of other small organic molecules for their ability to phosphorylate ADP; none were as effective as AcP, and only one other (carbamoyl phosphate) had any significant activity at all. Finally, they showed that none of the other nucleoside diphosphates accepted a phosphate from AcP. Combining these results with molecular-dynamic modeling, the authors propose a mechanistic explanation for the specificity of the ADP/AcP/iron reaction, hypothesizing that the small diameter and high charge density of the iron ion, combined with the conformation of the intermediate formed when the three come together, provide a "just right" geometry that allows AcP's phosphate to switch partners, forming ATP. "Our results suggest that AcP is the most plausible precursor to ATP as a biological phosphorylator," Lane says, "and that the emergence of ATP as the universal energy currency of the cell was not the result of a 'frozen accident,' but arose from the unique interactions of ADP and AcP. Over time, with the emergence of suitable catalysts, ATP could eventually displace AcP as a ubiquitous phosphate donor, and promote the polymerization of amino acids and nucleotides to form RNA, DNA and proteins." Lead author Silvana Pinna adds, "ATP is so central to metabolism that I thought it might be possible to form it from ADP under prebiotic conditions. But I also thought that several phosphorylating agents and metal ion catalysts would work, especially those conserved in life. It was very surprising to discover the reaction is so selective -- in the metal ion, phosphate donor, and substrate -- with molecules that life still uses. The fact that this happens best in water under mild, life-compatible conditions is really quite significant for the origin of life."

September 8, 2017 By Mark Terry , BioSpace.com Breaking News Staff South San Francisco – Genentech a Roche company, announced that its lampalizumab failed to meet its primary endpoint in a Phase III trial for geographic atrophy (GA) due to age-related macular degeneration (AMD). Lampalizumab is being evaluated in two Phase III trials. In the first of the trial, Spectri, the drug didn’t reduce mean change in GA lesion area compared to “sham treatment” at 48 weeks. Because of the lack of results, dosing will be halted in patients until the data from the second Phase III trial are analyzed. “Geographic atrophy is a progressive and irreversible disease that impairs vision, and there are currently no available treatments,” said Sandra Horning , Genentech’s chief medical officer and head of Global Product Development, in a statement. “While this result is disappointing, we will continue to evaluate results from Spectri to get a clearer understanding of the data as we await the results of our second Phase III study, Chroma, anticipated in November.” The two trials have identical designs. They’re both double-masked, randomized, global studies looking at 10 mg doses of lampalizumab administered every four or six weeks by intravitreal injection compared to sham injections. The patients have geographic atrophy due to age-related macular degeneration. There are more than 1,800 people enrolled in the two studies in 275 sites in more than 20 countries. GA is a progressive and irreversible type of age-related macular degeneration (AMD). It affects more than 5 million people globally. Visual problems associated with GA typically affect both eyes. They report visual problems with activities of daily living, including reading, driving, recognizing faces, and anything done in dim or low light. There are no approved therapies. The symptoms of GA usually started when a patient can’t see one or more letters in a word while reading, or when looking at faces, part of the face isn’t seen. Once GA begins, the region of atrophy over several years tends to expand until central vision is gone. It doesn’t typically affect peripheral vision. Lampalizumab is an antigen-binding fragment (Fab) of a humanized, monoclonal antibody directed against complement factor D (CFD). CFD is an enzyme involved in the activation and amplification of the alternative complement pathway (ACP), which is part of the immune system. Malfunctions of the ACP has been linked via genetic studies to AMD. The primary endpoint was measured by fundus autofluorescence (FAF), which provides data about the size and type of GA lesions in the macula. The company did not report on secondary objectives, which will be evaluated at 96 weeks, and focused on lampalizumab’s effect on the patient’s visual function. The drug’s safety was consistent with previous trials and other intravitreal therapies. This news is striking in how much it differs from earlier trials. In an 18-month trial of 129 AMD patients, researchers observed a 20 percent reduction in lesion area progression in patients on the drug. In addition, genome analysis of a subgroup of patients with complement D variants showed a 44 percent cut in GA area progression. As such, there was speculation the drug would be a viable treatment option for patients with secondary geographic atrophy.