Culture

In a paper in Science this week, Penn researchers report the first detailed molecular characterization of how every cell changes during animal embryonic development. The work, led by the laboratories of Perelman School of Medicine's John I. Murray, the School of Arts and Sciences' Junhyong Kim, and Robert Waterston of the University of Washington (UW), used the latest technology in the emergent field of single cell biology to profile more than 80,000 cells in the embryo of the nematode Caenorhabditis elegans.

"Over the past few years, new single cell genomics methods have revolutionized the study of animal development," says Murray. "Our study takes advantage of the fact that the C. elegans embryo has a very small number of cells produced by a known and completely reproducible pattern of cell divisions. Using single cell genomics methods, we were able to identify over 87 percent of embryonic cells from gastrulation (when there are about 50 cells present) through the end of embryogenesis."

C. elegans is an animal that hatches with only 558 cells in its body. In a multicellular organism, every cell is derived by cell division from a single fertilized egg, resulting in a "cell lineage tree" that shows the division history of every cell, and describes their relationships to each other, akin to a genealogy. The Nobel prize winning work of Sydney Brenner, H. Robert Horvitz, and John Sulston worked out the cell lineage tree of C. elegans more than 40 years ago, and showed that every C. elegans animal develops through identical patterns of cell division.

To further elucidate the process of development, the Penn and UW teams characterized what happens at the molecular level by measuring the transcriptome--all the RNAs in a cell--of individual cells during development using a single cell genomics approach. These methods allow scientists to determine which genes are expressed, or turned on, in each of tens or hundreds of thousands of cells and to identify rare cell types based on their expression of similar subsets of the genes. However, it is difficult to know in these studies whether all cell types have been identified, or how the identified cells are related to each other through cell division.  

The lead authors, graduate students Jonathan Packer of UW and Qin Zhu of Penn, developed sophisticated data analysis programs and algorithms to trace the changes in the transcriptome to the temporal sequences in the cell lineage tree, revealing detailed dynamics of molecular changes required to generate the full body of C. elegans.

The resulting dataset will be a powerful tool for the thousands of labs that study C. elegans as a model organism and reinforces the limitations of using single cell genomics alone to infer relationships between cells in other species.

"Penn has been one of the pioneers of single cell genomics, which really helped make this work possible," says Kim.

The investigation helps reveal fundamental mechanisms involved in how cells specialize their function during development. For example, the researchers showed that cells with very different lineage histories can rapidly converge to the same molecular state, such that they can no longer be distinguished. The researchers also found that, during differentiation, some cells undergo strikingly rapid changes in their transcriptomes.

In addition, this work will contribute to applications in regenerative medicine and cellular engineering, such as controlling the cell-differentiation process involved in using patient's own cells for therapy.

HOUSTON -- (Sept. 5, 2019) -- When physicians integrate with hospitals, the cost of health care rises even though there's no evidence patients get better treatment, according to a new paper by experts at Rice University and Blue Cross and Blue Shield of Texas (BCBSTX).

As hospitals gain more control over physicians, they may incentivize delivery of more services but not necessarily higher quality care, the researchers said in the paper, which appears in the Journal of General Internal Medicine.

"When we launched this study, we hypothesized that tighter integration of physicians with hospitals would improve care coordination," said Vivian Ho, lead author and the James A. Baker III Institute Chair in Health Economics and director of the Center for Health and Biosciences at Rice's Baker Institute for Public Policy. "For example, less duplicate testing might occur, which would lower costs. That hypothesis didn't play out in the data."

The tightest form of integration occurs when hospitals directly employ physicians, but physicians also become integrated with hospitals when they jointly contract for services with an insurer.

In 2003, approximately 29% of U.S. hospitals employed physicians, a number that rose to 42% by 2012. The share of physician practices owned by hospitals rose from 14% in 2012 to 29% in 2016. Economists refer to these relationships between hospitals and physicians as vertical integration, because they represent hospitals exerting more control over physicians as an essential part of inpatient care.

The researchers analyzed all preferred provider organization (PPO) insurance claims processed for care through BCBSTX from 2014 through 2016 in Texas' four largest metropolitan areas -- Dallas, Houston, San Antonio and Austin. The population in these areas totaled 18.9 million in 2017, greater than the population of 46 U.S. states. The sample included all claims for health care services for patients aged 19 to 64 except for prescription drugs.

Several studies have found that vertical integration of physicians with hospitals is associated with higher annual spending, but none of these studies concurrently measured the relation between vertical integration and quality, the researchers said.

In their study, they examined claims to determine whether patients had visited a primary care physician (PCP) and, if so, which PCP they saw most frequently. The researchers attributed roughly 500,000 to 600,000 patients to a PCP for each year and used BCBSTX contracting data to determine whether each of these physicians worked in a physician-owned practice or one that was hospital-owned. The researchers then compared the annual spending for patients treated by doctors in physician- versus hospital-owned practices.

They found patients with PPO insurance coverage incur spending that is 5.8 percentage points higher when treated by doctors in hospital-owned versus physician-owned practices. The difference appears attributable to greater service use rather than higher prices. For four out of five common diagnostic tests (for example, X-rays and MRIs), claims per patient were equal to or higher in hospital- versus physician-owned practices. There was no consistent difference in quality of care (for example, 30-day hospital readmission rates, diabetic care or screening mammography) for hospital-owned versus physician-owned practices.

"Healthcare costs continue to rise faster than the growth rate of the overall economy," said Ho, who is also a professor of economics at Rice and a professor of medicine at Baylor College of Medicine. "Tighter integration of physicians with hospitals appears to be contributing to that cost growth, with no evidence of better quality."

Higher spending ultimately translates into higher insurance premiums for customers, said Leanne Metcalfe, executive director of research and strategy at BCBSTX and a co-author of the study.

"Centers for Medicare and Medicaid Services regulators should be wary of the burden that increasing reporting requirements place on physicians in small, independent practices," Metcalfe said. "In the long run, these requirements may have the unintended consequence of raising health care costs."

A genome-wide analysis of ancient DNA from more than 500 individuals from across South and Central Asia sheds light on the complex genetic ancestry of the region's modern people. "The scale of this data set enables [the authors] to compare genomes across more space and time points than ever before, allowing them to hone in on increasingly specific questions that would have been unanswerable even a few years ago," write Nathan Shaefer and Beth Shapiro in a related Perspective. Not only does the study document genetic exchanges between Asian populations and those from the European Steppe, the Near East and southeast Asia, it also reveals a population history that reflects similar and parallel genomic patterns to those found in ancient Europe - findings that illustrate the cultural spread of Indo-European languages. The preserved genetic remains of people who lived long ago can offer a clear window into the movements and interactions of ancient populations, as well as into the spread of major cultural innovations, like farming, herding or language. Vagheesh Narasimhan, David Reich and colleagues analyzed ancient DNA from 523 individuals who lived over the past 8,000 years to better understand the prehistory of human dispersals into and throughout Central and South Asia. According to Narasimhan et al., the primary source of ancestry in modern Asians stems from near-eastern farmers who arrived following the decline of Indus Valley Civilization and from a group of Bronze Age pastoralists from the European Steppe known as the 'Yamnaya.' Previous research has shown that these same people also moved into areas of Eastern Europe, which likely contributed to the wide dispersion of closely related features of Indo-Iranian and Balto-Slavic languages.

Scientists have designed an ultra-miniaturised device that could directly image single cells without the need for a microscope or make chemical fingerprint analysis possible from a smartphone.

The device, made from a single nanowire 1000 times thinner than a human hair, is the smallest spectrometer ever designed. It could be used in potential applications such as assessing the freshness of foods, the quality of drugs, or even identifying counterfeit objects, all from a smartphone camera. Details are reported in the journal Science.

In the 17th century, Isaac Newton, through his observations on the splitting of light by a prism, sowed the seeds for a new field of science studying the interactions between light and matter - spectroscopy. Today, optical spectrometers are essential tools in industry and almost all fields of scientific research. Through analysing the characteristics of light, spectrometers can tell us about the processes within galactic nebulae, millions of light years away, down to the characteristics of protein molecules.

However, even now, the majority of spectrometers are based around principles similar to what Newton demonstrated with his prism: the spatial separation of light into different spectral components. Such a basis fundamentally limits the size of spectrometers in respect: they are usually bulky and complex, and challenging to shrink to sizes much smaller than a coin. Four hundred years after Newton, University of Cambridge researchers have overcome this challenge to produce a system up to a thousand times smaller than those previously reported.

The Cambridge team, working with colleagues from the UK, China and Finland, used a nanowire whose material composition is varied along its length, enabling it to be responsive to different colours of light across the visible spectrum. Using techniques similar to those used for the manufacture of computer chips, they then created a series of light-responsive sections on this nanowire.

"We engineered a nanowire that allows us to get rid of the dispersive elements, like a prism, producing a far simpler, ultra-miniaturised system than conventional spectrometers can allow," said first author Zongyin Yang from the Cambridge Graphene Centre. "The individual responses we get from the nanowire sections can then be directly fed into a computer algorithm to reconstruct the incident light spectrum."

"When you take a photograph, the information stored in pixels is generally limited to just three components - red, green, and blue," said co-first author Tom Albrow-Owen. "With our device, every pixel contains data points from across the visible spectrum, so we can acquire detailed information far beyond the colours which our eyes can perceive. This can tell us, for instance, about chemical processes occurring in the frame of the image."

"Our approach could allow unprecedented miniaturisation of spectroscopic devices, to an extent that could see them incorporated directly into smartphones, bringing powerful analytical technologies from the lab to the palm of our hands," said Dr Tawfique Hasan, who led the study.

One of the most promising potential uses of the nanowire could be in biology. Since the device is so tiny, it can directly image single cells without the need for a microscope. And unlike other bioimaging techniques, the information obtained by the nanowire spectrometer contains a detailed analysis of the chemical fingerprint of each pixel.

The researchers hope that the platform they have created could lead to an entirely new generation of ultra-compact spectrometers working from the ultraviolet to the infrared range. Such technologies could be used for a wide range of consumer, research and industrial applications, including in lab-on-a-chip systems, biological implants, and smart wearable devices.

The Cambridge team has filed a patent on the technology, and hopes to see real-life applications within the next five years.

ROCKVILLE, MD - The American Society of Human Genetics (ASHG) today affirmed the crucial role of genetic and genomic data sharing to advance medicine and health research, and asserted core principles about privacy protections that should apply to all human genetics and genomics research regardless of funding source. The Society's views appear today in The American Journal of Human Genetics (AJHG).

Genetic and genomic data from research participants is helping scientists better understand the health of individuals and populations, and this new knowledge drives improved diagnosis and treatments as well as growing insight into our shared human origins. Biobanks and other growing research resources with shared data enable researchers to work at larger scale and could enable more accurate understanding of the genetic and genomic underpinnings of disease.

"To sustain these advances, it is essential to encourage broad public participation, continue research investments, and promote privacy protections," the Society stated. To realize the benefits of genetics and genomics research, the field must pursue strategies for the use and sharing of data sets and the need to protect confidential information, they explained.

The Perspective comes at a time of broad global discussions about consumer data privacy, and many countries are considering new broad citizen privacy protections. Given this context, ASHG's position urges recognition of important protections already in place for federally funded research and the field's commitment to those protections. Yet it also notes that, within the United States, many genetic privacy laws apply only to federally funded research. Increasingly, researchers in the genetics and genomics community--both in academia and industry--recognize the potentially useful role of data generated by entities that are not federally funded to pursue shared health goals.

The statement outlines current laws protecting participant privacy covering federally funded research in the U.S. Most genetics and genomics research is federally funded, and is thus subject to these laws. Yet as an increasing number of private entities join the field and work directly with consumers, those research participants may not have the same privacy protections.

"Where there is appropriate consent and oversight, consumer data collected by private testing services can be a valuable resource for genetic and genomic research," the Society noted. "ASHG encourages opportunities to engage with consumer genomics companies developing customer privacy policies related to their research."

The statement articulates five essential privacy principles that the Society believes should apply to all genetics and genomics research, whether publicly or privately funded:

Individuals should have a right to maintain the confidentiality of their own genetic information and should not be compelled to disclose it.

Entities holding human genomic data must take robust measures to protect the confidentiality of individuals' medical and genetic information.

Decisions about privacy protections and data-sharing practices should be based upon an assessment of risks and benefits for both the participants and for society.

When establishing policies and practices, it is important to consider when genetic information should be treated like other health data and when it should be treated differently.

Research policies should both facilitate data-sharing and protect confidentiality in a way that both advances research and respects participants' preferences.

Looking forward, the Society will continue to engage with policymakers on measures that encourage research participation and help to advance genetics and genomics research; as well as work to ensure that new, broad data privacy policies applied outside of the research arena do not negatively affect research and medicine.

KANSAS CITY, MO--Small-cell clones in proliferating epithelia - tissues that line all body surfaces - organize very differently than their normal-sized counterparts, according to a recent study from the Stowers Institute for Medical Research. Published online September 5, 2019, in Developmental Cell, these findings from the laboratory of Matthew Gibson, PhD, may contribute to a better understanding of how some human diseases progress.

"A common feature of many cancer types is the pleomorphic nature - or variability in size and shape - of cells in a tumor," says first author and Postdoctoral Research Associate Subramanian P. Ramanathan, PhD. "What's not exactly known is whether differential cell size is the driver for, or the result of, cancer progression."

Cells in an epithelial sheet are normally connected by Velcro-like structures called adhesive junctions and have a near-uniform size distribution. As a result, cells related by descent tend to stick together in mosaic patches referred to as cell clones. In the fruit fly Drosophila melanogaster, epithelial cell clones that have smaller cells can lose contact with each other and disperse among their neighbors.

The striking dispersal of small cells carrying mutations in a gene called Tor was first observed over a decade ago by Gibson when he was a postdoctoral researcher. "I puzzled over it, but just couldn't make sense of why the mutant cells dispersed within the cell layer," says Gibson. Not until 2015, when Ramanathan joined the lab, did they begin to piece together the science behind this observation.

Ramanathan has a background in the biomechanics of cell division. He recalls, "we were very excited about the prospect of applying my interest in single-cell mechanics in the context of how epithelial cells organize."

"We initially thought we were going to be studying cell division and its relationship to junction formation," says Gibson. "But based on Subramanian's experiments, we determined that the Tor cells divide and make a junction that later becomes unstable. He was able to rule out cytoskeletal or biophysical explanations, and that led to a mathematical treatment of the problem."

"The eureka moment was the soap bubbles experiment," says Ramanathan, citing D'Arcy Wentworth Thompson's, On Growth and Form. "About a hundred years ago, Thompson documented the similarity between how soap foam and biological tissue organize. Soap cells grow and shrink in an extremely predictable fashion. We found that the junctions shared by smaller soap cells frequently collapsed separating the small cells. This was strikingly similar to what we saw in epithelial tissue," says Ramanathan.

Ramanathan reasoned that the Tor cell dispersal could be a geometrical consequence. "We had to convince ourselves that this is what was happening," he admits. To explore it in the purely in silico framework, they reached out to co-author Matej Krajnc, PhD, from Princeton University, who has experience with these types of models. "He was excited to modulate cell size, to see if we could see similar patterns emerging in silico. And that is indeed what we saw."

One of the most astounding feats of developmental biology is the transformation of an epithelial sheet into a functionally specialized three-dimensional structure. To do so, epithelial systems rely on uniformity among cells. Developmental processes shape and sculpt epithelia by creating region-specific properties that are classically understood to be driven by molecular pathways.

"In the human body, which is primarily made up of epithelial cell layers, the vast majority of mutations we accumulate are not germline, but rather somatic, and therefore clonal in nature," says Gibson. "In a pathogenesis context, because mutations create clonal effects, we don't have a framework for thinking about how clones of cells behave when they're genetically distinct from the surrounding wild type cells, but it's extremely important." The Gibson Lab continues to build off this study and related work to understand the interaction between physically and genetically heterogeneous epithelial cell populations.

NEW ORLEANS, September 5, 2019 -- High blood pressure appears to accelerate cognitive decline among middle-aged and older adults and treating high blood pressure may slow down the process, according to a preliminary research presented at the American Heart Association's Hypertension 2019 Scientific Sessions.

The findings are important because high blood pressure and cognitive decline are two of the most common conditions associated with aging, and more people are living longer worldwide.

According to the American Heart Association's 2017 Hypertension Guidelines, high blood pressure is a global health threat, affecting approximately 80 million U.S. adults and one billion people globally. Moreover, the relationship between brain health and high blood pressure is a growing interest as researchers examine how elevated blood pressure affects the brain's blood vessels, which in turn, may impact memory, language and thinking skills.

In this observational study, researchers from Columbia University analyzed data collected on nearly 11,000 adults from the China Health and Retirement Longitudinal Study (CHARLS) between 2011-2015, to assess how high blood pressure and its treatment may influence cognitive decline. High blood pressure was defined as having a systolic blood pressure of 140 mmHg or higher and a diastolic blood pressure of 90 mmHg or higher, and/or taking antihypertensive medications. (Note: The American Heart Association guidelines define high blood pressure as 130 mmHg or higher or a diastolic reading of 80 mmHg or higher.)

Researchers in China interviewed study participants at home about their high blood pressure treatment, education level and noted if they lived in a rural or urban environment. They were also asked to perform cognitive tests, such as immediately recalling words as part of a memory quiz.

Among the study's findings:

Overall cognition scores declined over the four-year study;

Participants ages 55 and older who had high blood pressure showed a more rapid rate of cognitive decline compared with participants who were being treated for high blood pressure and those who did not have high blood pressure; and

The rate of cognitive decline was similar between those receiving high blood pressure treatment and those who did not have high blood pressure.

The study did not evaluate why or how high blood pressure treatments may have contributed to slower cognitive decline or if some treatments were more effective than others.

"We think efforts should be made to expand high blood pressure screenings, especially for at-risk populations, because so many people are not aware that they have high blood pressure that should be treated," said presenting study author Shumin Rui, a biostatistician at the Mailman School of Public Health, Columbia University in New York. "This study focused on middle-aged and older adults in China, however, we believe our results could apply to populations elsewhere as well. We need to better understand how high blood pressure treatments may protect against cognitive decline and look at how high blood pressure and cognitive decline are occurring together."

The global health community is working to eliminate trachoma, a bacterial disease that causes blindness. Researchers reporting in PLOS Neglected Tropical Diseases have analyzed the costs of surveys that must track trachoma levels as part of these elimination efforts.

In the new work, Rachel Stelmach of RTI International, USA, and colleagues studied the financial costs to the national program of TSS and TIS in 11 countries from 2012 to 2018. Cost data was available for surveys supported by the ENVISION project funded by the US Agency for International Development (USAID) and led by RTI International. Financial costs of TT-only surveys in Cameroon, Tanzania, Uganda and Nepal were also included. Only incremental costs were studied-- costs that would have been incurred to the national program anyway were not included, nor were economic costs or costs to society such as the value of subjects' time.

The researchers were able to gather data on 228 TIS and 94 TSS, or 322 surveys in total. The surveys cost a median of $8,298 USD (IQR: $6,532 - $10,111) and did not differ significantly by survey type, data source, or years of implementation, though the authors found evidence of economies of scale from implementing surveys in a single year. Survey fieldwork accounted for a majority (80%) of costs, with training accounting for the next largest proportion of costs (13%). TT-only surveys appeared to cost about the same or slightly more than TIS and TSS in the same country. Cost differences between countries were mostly driven by how much it costs to pay surveyors and transport them to survey sites.

The World Health Organization requires that countries conduct trachoma impact surveys (TIS) to see whether a district has reached prevalence benchmarks that allow them to stop population-level prevention interventions, as well as trachoma surveillance surveys (TSS) to later ensure that trachoma has remained at bay.

"Costing studies like this one provide crucial planning data as countries advance toward the elimination of trachoma as a public health problem," the researchers say.

A trachomatous trachoma only (TT-only) survey, measuring one classification of the disease only, is also used in some contexts. Estimates of the costs of baseline trachoma prevalence surveys exist, but the costs of additional later surveys had not previously been studied.

Infection with parasitic helminths can reduce the susceptibility of T-cells to HIV-1 infection, according to a study published September 5 in the open-access journal PLOS Pathogens by Esther de Jong of the University of Amsterdam and William Paxton of the University of Liverpool, and colleagues.

Parasitic helminths such as Schistosoma mansoni (S. mansoni) have developed a number of strategies to evade, skew and dampen human immune responses, including the modulation of CD4+ T-lymphocyte responses. Since CD4+ T-lymphocytes are the main cell type infected with HIV-1, the immune responses mounted against the array of co-infecting pathogens will likely influence HIV-1 transmission and disease progression. Moreover, many areas endemic for S. mansoni infection have high HIV-1 prevalence rates, indicating that co-infection is likely. However, clear epidemiological evidence to date is lacking for the assumption that treating S. mansoni in co-infected individuals would be beneficial for their HIV-1 disease, as studies have reported contradictory findings.

In the new study, de Jong and Paxton analyzed the effect of soluble egg antigen (SEA) - an extract from the eggs of S. mansoni -- on HIV-1 infection. SEA efficiently blocked HIV-1 trans-infection -a process by which immune cells called dendritic cells capture HIV-1 and promote infection of CD4+ T-lymphocytes. The underlying mechanism involved the binding of Kappa-5 - a major molecular component of SEA -- to DC-SIGN - a molecule expressed on dendritic cells. Under certain conditions, exposure of dendritic cells to SEA reduced the susceptibility of T-cells to HIV-1 infection. They also found that omega-1 -- an abundant component of SEA -- can modulate HIV-1 infection and potentially influence disease course in co-infected individuals. According to the authors, these results should be considered in the context of HIV-1 vaccine trials being conducted in regions of the world where S. mansoni infections are endemic.

"Co-infection with HIV-1 and an array of pathogens can potentially modulate HIV-1 infection and therefore disease course," the authors add. "We demonstrate that specific molecules from the Schistosomula monsoni parasite can block both HIV-1 interactions with dendritic cells as well as induce CD4 lymphocytes which down-modulate infection with HIV-1."

Bioengineers at the University of California San Diego have developed a method to significantly extend the life of gene circuits used to instruct microbes to do things such as produce and deliver drugs, break down chemicals and serve as environmental sensors.

Most of the circuits that synthetic biologists insert into microbes break or vanish entirely from the microbes after a certain period of time--typically days to weeks--because of various mutations. But in the September 6, 2019 issue of the journal Science, the UC San Diego researchers demonstrated that they can keep genetic circuits going for much longer.

The key to this approach is the researchers' ability to completely replace one genetic-circuit-carrying sub-population with another, in order to reset the mutation clock, while keeping the circuit running.

"We've shown that we can stabilize genetic circuits without getting into the business of fighting evolution," said UC San Diego bioengineering and biology professor Jeff Hasty, the corresponding author on the study. "Once we stopped fighting evolution at the level of individual cells, we showed we could keep a metabolically-expensive genetic circuit going as long as we want."

The circuit the UC San Diego researchers used in the Science study is one that this team, and others, are actively using to develop new kinds of cancer therapies.

"As synthetic biologists our goal is to develop gene circuits that will enable us to harness microorganisms for a wide range of applications. However, the reality today is that the gene circuits we insert into microbes are prone to fail due to evolution. Whether it be days, weeks, or months, even with the best circuit-stabilization approaches, it's just a matter of time. And once you lose functionality in your genetic circuit, there is nothing to do but start over," said Michael Liao, a UC San Diego bioengineering PhD student and the first author on the Science paper. "Our work shows there is another path forward, not just in theory, but in practice. We've shown that it's possible to keep circuit-busting mutations at bay. We found a way to keep hitting reset on the mutation clock."

If the team's method can be optimized for living systems, the implications could be significant for many fields, including cancer therapy, bioremediation, and bioproduction of useful proteins and chemical components.

Rock Paper Scissors

To actually build a "reset button" for the mutation clock, the researchers focused on dynamics between strains of microbes, rather than trying to hold selective pressures at bay at the level of individual cells. The researchers demonstrated their community-level engineering system using three sub-populations of E. coli with a "rock-paper-scissors" power dynamic. This means that the "rock" strain can kill the "scissors" strain but will be killed by the "paper" strain.

Most published work tends to focus on stabilization strategies that act at the level of single cells. While some of these approaches may be sufficient in a given therapeutic context, evolution dictates that single cell approaches will naturally tend to stop working at some point. However, since the rock-paper-scissors (RPS) stabilization acts at a community level, it can also be coupled with any of the systems that act on a single cell level to drastically extend their lifespan.

Making Cancer Drugs and Delivering them to Tumors

In 2016 in Nature, UC San Diego researchers led by Hasty, along with colleagues at MIT, described a "synchronized lysis circuit" that could be used to deliver cancer-killing drugs that are produced by bacteria that accumulate in and around tumors. This led the UC San Diego group to focus on the synchronized lysis platform for the experiments published in Science.

These coordinated explosions only occur once a predetermined density of cells has been reached, thanks to "quorum sensing" functionality also baked into the genetic circuitry. After the explosion, the approximately 10% of the bacterial population that did not explode starts growing again. When the population density once again reaches the predetermined density (more "quorum sensing"), another drug-delivering explosion is triggered and the process encoded by the researchers' synchronized lysis circuit restarts.

The challenge, however, is that this cancer killing genetic circuit - and other genetic circuits created by synthetic biologists - eventually stop working in the bacteria. The culprit. Mutations driven by the process of evolution.

"The fact that some bugs naturally grow in tumors and we can engineer them to produce and deliver therapies in the body is a game-changer for synthetic biology," said Hasty. "But we have to find ways to keep the genetic circuits running. There is still work to do, but we're showing that we can swap populations and keep the circuit running. This is a big step forward for synthetic biology."

Biomedical Research Advances

One of the research teams working to further advance and implement the synchronized lysis circuit is run by Tal Danino, now a professor at Columbia University, who also published seminal work on the development of quorum sensing for synthetic biology as part of his Ph.D. at UC San Diego.

"Tal recently showed that synchronized lysis technology can be used to deliver an immunotherapy to tumors in mice. To my knowledge, they are the first to show that bacterial drug production and delivery within a treated tumor can modify the immune system to attack untreated tumors. The results are fascinating. They also highlight how important it is for us to figure out how to keep the lysis circuit running as long as possible," said Hasty.

The current approach is not limited to a three-strain system. Individual sup-populations of microbes, for example, could each be programmed to produce different drugs, offering the potential of precise combination drug therapies to treat cancer, for example.

The researchers studied the dynamics of the populations using microfluidic devices that allow for controlled interactions between the different sub-populations. They also demonstrated the system is robust when tested in larger wells.

One next step will be to combine the approach with standard stabilizing approaches and demonstrate the system works in live animal models.

"We are converging on an extremely stable drug delivery platform with wide applicability for bacterial therapies," said Hasty.

Hasty, Din, and Danino are co-founders of GenCirq, a company which seeks to transfer this and related work to the clinic.

Taxing sugar-sweetened beverages by the amount of sugar they contain, rather than by the liquid volume of these drinks, as several U.S. cities currently do, could produce even greater health benefits and economic gains, a team of researchers has concluded.

The analysis, by researchers at New York University, Harvard's TH Chan School of Public Health, the Wharton School at the University of Pennsylvania, and the University of California, Berkeley, appears in the journal Science.

Seven U.S. cities currently tax sugar-sweetened beverages, or SSBs, by the volume of the beverage--levies that don't take into account the amount of sugar these drinks contain.

"Despite their different sugar content and resulting different harms, all sugar-sweetened beverages are taxed at the same rate per liter under a volumetric tax," write Harvard's Anna Grummon, NYU's Hunt Allcott, Wharton's Benjamin Lockwood, and UC Berkeley's Dmitry Taubinsky. "This tax structure gives consumers no incentive to substitute from high-sugar to low-sugar SSBs, even though the latter are less harmful. Thus, while a volumetric tax reduces consumption of SSBs in general, it does not provide the maximum possible health benefits."

"A basic economic principle is that such corrective taxes should be proportional to the harm caused," the authors add. "The harm from sugary drinks comes from the sugar, and SSBs vary substantially in sugar per unit volume."

The researchers note, however, that a tax on liquid volume is beneficial. They estimate, for instance, that a 34-cent per liter volumetric tax causes the average U.S. adult to drink 2.9 fewer ounces of SSBs per day, a 22-percent reduction. This decrease in sugar intake would help the average adult to lose 2.3 pounds. In addition, a nationwide volumetric SSB tax would reduce obesity rates by 2 percent--a 2.1 million decline in adults with obesity--and would lower the number of new Type 2 diabetes cases by 2.3 percent, or approximately 36,000 new cases per year.

They add that such a tax would also result in economic gains--primarily through savings in health care costs--of about $1.4 billion per year nationwide.

However, in their assessment, a tax on the amount of sugar in SSBs would yield even greater health and economic gains. Such a tax would cause U.S. adults to consume 2.3 fewer grams of sugar per day from SSBs than they would under a volumetric tax, helping the average adult lose an additional 0.7 pounds. Across the U.S., a sugar tax instead of a volumetric tax would reduce obesity rates by an additional 630,000 adults and would cut the number of new Type 2 diabetes cases by another 0.7 percent--or approximately 11,000 people per year. Moreover, the additional annual economic gain would be another $400 million.

"Once there is agreement to tax SSBs, it seems natural to tax the harmful sugar, instead of the liquid that comes with the sugar," the authors conclude. "Our calculations suggest that this idea offers valuable low-hanging fruit for improving public health."

A previous study by Allcott, Lockwood, and Taubinsky concluded that soda taxes serve as a "net good," an assessment based on an examination of health benefits and consumer behavior. That analysis, which appeared in the Quarterly Journal of Economics earlier this year, estimated that a nationwide soda tax would yield $7 billion in net benefits to society each year.

Coral reefs are among the most diverse and productive ecosystems on our planet. But due to climate change and other human stressors, reef-building corals that reproduce by means of broadcast-spawning -- the simultaneous release of eggs and sperm into open water -- may now be under threat of extinction.

A new Tel Aviv University study finds that the highly synchronized, iconic spawning events of certain reef-building corals in the Gulf of Eilat/Aqaba, Red Sea, have completely changed over time and lost their vital synchrony, dramatically reducing chances of successful fertilization.

According to the research, led by Prof. Yossi Loya and PhD candidate Tom Shlesinger of TAU's School of Zoology and published in Science on September 6, the breakdown in coral spawning synchrony has led to a dearth of new recruits and stagnant aging populations, creating circumstances for extinction.

"Coral spawning, often described as 'the greatest orgy in the world,' is one of the greatest examples of synchronized phenomena in nature," explains Prof. Loya. "Once a year, thousands of corals along hundreds of kilometers of a coral reef release their eggs and sperm simultaneously into the open water, where fertilization will later take place. Since both the eggs and the sperm of corals can persist only a few hours in the water, the timing of this event is critical."

Successful fertilization, which can take place only within this narrow time window, has led to the evolution of a precise spawning synchrony. Such synchronicity relies on environmental cues: sea temperature, solar irradiance, wind, the phase of the moon and the time of sunset.

In 2015, the researchers initiated a long-term monitoring of coral spawning in the Gulf of Eilat/Aqaba. Over four years, they performed 225 night field surveys lasting three to six hours each during the annual coral reproductive season from June to September and recorded the number of spawning individuals of each coral species.

"We found that, in some of the most abundant coral species, the spawning synchrony had become erratic, contrasting both the widely accepted paradigm of highly synchronous coral spawning and studies performed on the exact same reefs decades ago," says Shlesinger.

The researchers then investigated whether this breakdown in spawning synchrony translated into reproductive failure. They mapped thousands of corals within permanent reef plots, then revisited these plots every year to examine and track changes in the coral community -- i.e., how many corals of a given species had died compared with new juveniles recruited to the reef.

"Although it appeared that the overall state of the coral reefs at Eilat was quite good and every year we found many new corals recruiting to the reefs, for those species that are suffering from the breakdown in spawning synchrony, there was a clear lack of recruitment of new juvenile generations, meaning that some species that currently appear to be abundant may actually be nearing extinction through reproductive failure," says Shlesinger.

"Several possible mechanisms may be driving the breakdown in spawning synchrony that we found," Prof. Loya concludes. "For example, temperature has a strong influence on coral reproductive cycles. In our study region, temperatures are rising fast, at a rate of 0.31 degrees Celsius per decade, and we suggest that the breakdown in spawning synchrony reported here may reflect a potential sublethal effect of ocean warming. Another plausible mechanism may be related to endocrine (hormonal) disrupting pollutants, which are accumulating in marine environments as a result of ongoing human activities that involve pollution."

"Regardless of the exact cause leading to these declines in spawning synchrony, our findings serve as a timely wake-up call to start considering these subtler challenges to coral survival, which are very likely also impacting additional species in other regions," says Shlesinger. "On a positive note, identifying early-warning signs of such reproductive mismatches will contribute to directing our future research and conservation efforts toward the very species that are at potential risk of decline, long before they even display any visible signs of stress or mortality."

For some, it is written in artifacts. For others, truth can be found in cool, hard genetic code.

Both kinds of data factor into an ambitious new study that reports genome-wide DNA information from 523 ancient humans collected at archaeological sites across the Near East and Central and South Asia. Washington University in St. Louis brought key partners to an international collaboration of more than 100 scholars who gathered archaeological skeletal samples -- and pooled their expertise -- to generate the largest study of ancient DNA published to date.

Their results, published this week in the journal Science, link the genetic and linguistic makeup of populations of Eurasia and India to the ebb and flow of people and cultures between 12,000 to 2,000 years ago that transformed Old World populations and civilizations.

"Often people assume populations change through simple migration processes, but regional genetic formation is nuanced, long-term and dynamic," said Michael Frachetti, co-senior author of the study and professor of archaeology in Arts & Sciences at Washington University.

"In some cases, we see centuries of regional mobility alongside stochastic population movements. We also document cases of prolonged, multidirectional interaction. Often, it's all of the above," Frachetti said. "So we made every effort to combine deep archaeological knowledge with the DNA results to illustrate how different mechanisms produced genetic diversity and change at different times."

Locking down the story

As the tools and methodologies for harvesting and analyzing DNA from bone samples improved and became more accessible, archaeologists and geneticists started to reshape the nature of their partnership in studying ancient societies.

"Early on, archaeologists were critical that ancient DNA studies were crafting huge narratives from limited data. That was a real limitation of early work, and I, too, had my concerns," Frachetti said. "This project was conceived to explicitly merge different methods and kinds of expertise, thus our approach was intentionally more inclusive of numerous voices in hopes of getting the best possible results."

Years in the making, the conceptual framework behind this research was sparked by David Reich, professor of genetics in the Blavatnik Institute at Harvard Medical School, the Howard Hughes Medical Institute, and the Broad Institute and Vagheesh Narashimhan, a postdoctoral scholar in his lab; Nick Patterson, a computational biologist at the Broad Institute of MIT and Harvard; Ron Pinhasi of the University of Vienna; and Frachetti. Their collaborative group grew to include dozens of archaeologists and geneticists around the world.

By focusing on Central Asia, the research addresses a huge gap in the world's ancient DNA dataset -- which was almost entirely restricted to Europe.

Said Reich, "The idea for this study grew out of a meeting we had in Cold Spring Harbor New York in May 2016, which was equally organized by geneticists and archaeologists. The goal of this meeting was explicitly to break down barriers between disciplines and find ways for these two communities with so many shared questions but different world views to come together. Michael's perspectives were challenging and stimulating to us geneticists. After multiple intense conversations, he and Ron Pinhasi and I decided to develop an ancient DNA study that was explicitly framed by Michael's archaeological questions, that would take advantage of innovations in ancient DNA technology that made it possible to massively increase the number of samples we could study, and that by focusing on Central Asia would address a huge gap in the world's ancient DNA dataset -- which until then was almost entirely restricted to Europe."

The result is a study that in one fell swoop increases the worldwide total of published ancient genomes by about 25 percent, and that shifts the center of gravity of the world's ancient DNA dataset far to the east.

"It's a significant addition to the literature," said Narasimhan, co-first author of the study. "We've been able to process and analyze samples at a scale that hadn't been possible before."

Pinhasi, a co-senior author, added, "We combined a wide range of approaches: linguistic data, archaeological data, modern-day genetic data and ancient DNA data. The new findings about the origins and spread of the Indo-European languages, in particular, highlights the power of studies that combine data, methods and perspectives from a diverse range of disciplines."

Frachetti has worked for over two decades in Kazakhstan and at archaeological sites linked to the Great Silk Road, the ancient trade route between China and the Mediterranean. Frachetti led much of the skeletal sampling for the Science paper; his close relationships in the region helped in developing ethical collection partnerships with colleagues and institutions across Central Asia.

"For decades, local archaeologists have been working to provide nuanced pictures of the underlying forces of social complexity and organization," Frachetti said.

"This study shows the explanatory power of relying on local scholars to help build the genetic datasets and shape the important questions on a variety of scales -- from individual excavation sites and individual specimens to wider, macro-regional narratives. It's a great example of how these collaborations should work."

"The history of Central Asia shows that connected ancient societies innovated rapidly due to exchanges of technology and ideas, whereas more isolated groups often faced longer-term economic stagnation. Likewise, current developments in academia benefit from active international exchange," said Farhod Maksudov, a study co-author and director of the Institute for Archaeological Research of the Uzbekistan Academy of Sciences. "For scholars from Uzbekistan (and likely other Central Asian countries) international academic collaboration is essential -- this study, which significantly advances our knowledge of Central Eurasia's deep history, shows the power of academic connectedness and cooperation on a large-scale."

A new dimension for work at Dali

Roughly 5,000 years ago, as the spread of herding required the movement of animals between summer and winter pastures, farmers and nomads came into greater contact across the region.

"Our maps in this study illustrate how transcontinental gene flow evolved over vast territory and thousands of years, but one must be careful not to view these genetic arrows as colonial invasions -- in fact, our data show that human mobility typically brought about gradual change over the span of centuries, and sometimes millennia," Frachetti said.

This new genetic information adds another dimension to human histories previously informed by archaeological work at particular sites.

A perfect example of this comes from an ancient site in Kazakhstan, where Frachetti has been excavating for many years.

Known as Dali, the mountainous site is located near the crossroads of cultural and genetic change during the Early and Late Bronze Age in a region that Frachetti calls the Inner Asia Mountain Corridor. At Dali, student researchers participating in the Washington University archaeological field school excavated skeletal samples that are a key part of the current ancient DNA study.

The genetic results from burials at Dali show movement and admixture between groups with North Eurasian hunter gatherer ancestry and farmers from the Iranian plateau -- defining a bi-directional flow of ancestry along the mountains and steppes of Eurasia approximately 5000 years ago.

Separately, Frachetti and collaborators also sampled DNA from individuals of the Bactria-Margiana Archaeological Complex (or BMAC), a Bronze Age civilization of southern Central Asia, found in present-day Uzbekistan and Turkmenistan, which was discovered for the first time in the 1970s by Soviet archaeologists.

Within the large number of samples from the BMAC included in the new genetic study (more than 100 individuals where previously there was no data), researchers were able to identify several key "outliers" -- individuals who reflect early steppe genetics, similar to those found at Dali -- living among an otherwise homogenous group.

The discovery of a range of these genetically distinct individuals intermixed among regional populations fits with the archaeological evidence collected by Frachetti and his students over the last decade. They had previously determined that people in the large urban centers of the BMAC were trading goods with pastoral communities living along the mountains and nearby plains.

"We had made the argument, as did many others, that steppe pastoralists were interacting with the BMAC on the basis of ceramics, metals, etc.," Frachetti said. "But there wasn't enough research, and the data were few. The new information we are getting from ancient DNA is critical to understanding the complex connectivity between these diverse communities across Asia."

"What we see in both in the isotopic information as well as the archeological information is trade and exchange of agricultural material and production happening in both directions: north and south along this corridor," Harvard's Narasimhan said.

"Now with the ancient DNA, we're actually seeing that in the people," he said. "It's giving us confidence to understand what happened in the past and how this process is happening."

Vivid narrative

The new genetic results also open up a wide array of additional questions that archaeologists can now probe with new eyes.

"The sort of questions you can ask now -- the sky's the limit," Frachetti said. "Working with this team has definitely opened up new ways of thinking for me. Questions about the degree to which trade and exchange versus important population movements brought innovation to various peoples, and how it shaped their future directions."

"I've asked a lot of these questions for 25 years without the benefit of the genetics," Frachetti said. "So, it's exciting to return to my laundry list of questions and say, 'Wow, a lot of these are now made that much more crystal clear.'"

The power of this study comes from its breadth and reach, made possible by samples from so many contributing archaeologists.

"If you only have one archeologist help to tell the story, then likely that one might be inclined to support his or her own theories," Frachetti said. "But if, for example, you bring together data and ideas from 10, 20, 50 archaeologists -- many of whom have different, competing theories on the same topic -- it forces everybody to look at the science, and that's how progress is made!

"That's really why teaming up with geneticists is so important. It's still not totally perfect in terms of how everyone wants things to be explained," Frachetti said. "But this paper brings us a rigorous, well-designed study with a massive baseline of ethically acquired data. Now all scholars can go back to it to focus on different sites or see how the data fit into their archaeological interpretation.

"This study, and the important genetic record it establishes, allows us to shade in the narrative so much more vividly," he said.

     After having issued an Editorial Expression of Concern on a 2016 Science study by Siddappa N. Byrareddy et al. in March of this year, to flag that the journal had learned the study had used a virus variant that could have affected results, Science is now issuing an official Correction to this study – to denote the virus used was not the wild-type. The study by Byrareddy and colleagues had reported that coupling an antibody targeting the integrin protein α4β7 with standard-of-care antiretroviral treatment (ART) kept SIV virus levels very low in nonhuman primates—including for more than nine months after all anti-viral agents were stopped. This result, significant for public health, motivated a clinical trial in humans using a similar, FDA-approved antibody (vedolizumab), as well as three replication studies—efforts initiated to confirm the study and to potentially give mechanistic insight into the antibody effects.
    

 The March 2019 Editorial Expression of Concern (EEoC) on Byrareddy et al. was published after Science learned that the virus used in the study featured a stop codon in the SIV nef gene, the presence of which was known by author Francois Villinger, who chose this strain intentionally; he believes it provides a better model for chronic HIV infection. However, use of this strain was not communicated to co-authors nor explicitly stated in the manuscript. Following the EEoC to flag this issue in March, Science is now correcting Byrareddy et al. to indicate the virus used was not wild-type SIVmac239, but SIVmac239-nef-stop (use of which introduces variation in the level of viral pathogenicity among animals).
     

Separately, all three attempts to replicate all or some aspects of Byrareddy et al. failed, three reports in this issue of Science will show. As such, Science is maintaining an Editorial Expression of Concern on this study to alert readers that current evidence suggests that the reported 2016 result “is not robust and therefore does not provide a good basis for guiding work on therapies for HIV.”Two of the replication attempts (Di Mascio et al. and Iwamoto et al.) used the same SIVmac239-nef-stop virus as in Byrareddy et al. but did not replicate the sustained low viral load, a result suggesting the nef-STOP virus was not the reason for the positive effect of antibody treatment reported in the 2016 paper. The third study (Abbink et al.) used a different SIV strain but a similar antibody approach but did not replicate the findings either.

     Science is not moving beyond Editorial Expression of Concern because neither the Byrareddy authors, the authors of the attempted replication studies, nor the editors can account for the differences between the 2016 study and the three failed replications. Moreover, there is a scientific basis supporting the idea that targeting α4 β7 may have a positive impact on the course of infection.
   

  Providing results from a phase 1 clinical trial using vedolizumab (an antibody currently approved as a therapy for ulcerative colitis and Crohn’s disease), a report in Science Translational Medicine reveals that the antibody did not show sustained antiviral effects in 19 HIV-positive individuals who stopped receiving ART after the seventh antibody infusion (at week 22). Although the antibody treatment was well-tolerated and showed no serious side effects, the results indicate that blocking α4β7 may not be an effective treatment for controlling the virus in HIV-positive patients. Thus, the results support the findings of the 3 replication studies described above. In their study, Michael Sneller and colleagues administered several infusions of vedolizumab antibody to 19 HIV-infected individuals over the course of 30 weeks and measured CD4+ T cell counts and viral loads in plasma every two weeks after ART was stopped at week 22. Halting ART was done in order to determine if the antibody alone could suppress viral load. With the exception of one subject, the treatment did not lead to a significant decline in CD4+ T cells carrying HIV DNA and RNA, the authors report.

  In a related Editorial, Science Editor-in-Chief Jeremy Berg highlights the importance of replicating experiments and comparing results “as a cornerstone of science.” He further elaborates on the events that followed publication of the study by Byrareddy et al. He also addresses the challenge it is for the scientific and publishing communities alike, to facilitate and communicate replications of important results.

Spanish may seem to be spoken at a higher speed than Vietnamese, but that doesn't make it any more "efficient". Researchers affiliated with the CNRS and Université Lumière Lyon 2 (Dynamique du Langage laboratory) have shown that human languages are equally effective at transmitting information, even if the speeds at which they are spoken differ. To come to this conclusion, they compared recordings in 17 languages (1) of 15 short texts describing daily situations, read out loud by 10 native speakers per language. For each of the languages, they measured speech rate, in number of syllables per second, and the average information density of the syllables uttered. (The more easily the utterance of a particular syllable may be predicted from the preceding one, the less information the former is deemed to provide.) The researchers found that higher speech rates are matched by lower information densities--as in Spanish--and slower speech rates with higher information densities--as is often the case with tonal Asian languages like Chinese and Vietnamese. In the end, by multiplying speech rate by information density, all languages, no matter how different, may be shown to convey information at a rate of roughly 39 bits per second.(2) This suggests a potentially optimal rate of language processing by the human brain. The findings appear in Science Advances (4 September 2019).