The study also found that although the public health burden of large trucks has been greatly reduced, passenger light-duty vehicles, such as SUVs and pickup trucks, continue to contribute a significant amount of air pollution in major metropolitan areas.

The study will be published online on December 13, 2021 in the journal PNAS.

“Recent reductions in vehicle emissions have yielded major health benefits, even though only small progress has been made on reducing their climate impact,” said first author Ernani Choma, a research fellow in Harvard Chan School’s Department of Environmental Health. “Our results indicate that to achieve further public health and climate gains, even more stringent policies will be required.”

Although the health and climate burden of vehicle emissions in the U.S. has been widely studied, the benefits of recent reductions in vehicle emissions — spurred by federal air pollution regulations and technological innovations by car manufacturers — were not well known. The new study provides estimates that compare the actual health and climate impact of reduced vehicle emissions with what that impact would have been had emissions not been reduced. Researchers calculated the so-called “social benefits” attributable to decreasing emissions — in this case, the monetary value to society of the reduction in deaths attributable to air pollution and climate impacts avoided.

Using recent national emissions data, the researchers modeled four scenarios for emissions in 2017: actual emissions as well as three alternative scenarios in which county-level emissions were the same as they were in 2014, 2011, and 2008. Each of the scenarios factored in the types of vehicles being driven and how many miles they traveled, detailed data about air pollution levels across the U.S., mortality rates, and trends in demographics — including an aging population that is becoming more susceptible to air pollution over time.

The researchers estimated that reductions in emissions yielded $270 billion in social benefits in the U.S. in 2017 — mostly due to the estimated value of reduced mortality risk from fine particulate matter (PM2.5) air pollution — and, to a lesser degree, to reduced “social costs” from greenhouse gas emissions, which are calculated from a range of factors such as human health impacts, changes in agricultural productivity, natural disasters, risk of conflict, and more.

The researchers also estimated that deaths attributable to air pollution due to vehicle emissions dropped from 27,700 in 2008 to 19,800 in 2017. The decrease in deaths was not as large as researchers expected, because many factors offset the progress in reducing emissions, such as a larger and aging population, larger vehicles replacing smaller ones, and more miles traveled per vehicle. On the other hand, the authors noted, if vehicles were still emitting at 2008 levels, those emissions would have caused 48,200 deaths attributable to air pollution in 2017 — which would have represented a 74% increase between 2008 and 2017.

The study found significant recent progress in reducing emissions from heavy-duty trucks, but less progress with passenger light-duty vehicles, including cars, SUVs, and pickup trucks. Passenger light-duty vehicles accounted for two-thirds of the public health burden from transportation-related air pollution in 2017, the authors said. They noted that emissions from these vehicles in large metropolitan areas are so harmful that they are responsible for 30% more attributable deaths than all heavy-duty trucks across the nation.

“If the trends of increased population density with an aging population, and a shift to larger passenger vehicles continue, emissions, especially in urban areas, will continue to become more harmful and it will be harder to achieve further public health gains by small incremental improvements in new vehicles,” said John Spengler, Akira Yamaguchi Professor of Environmental Health and Human Habitation and senior author of the study. “Our study findings strengthen the case for policies at the municipal level that encourage electric vehicles while discouraging conventional gasoline vehicles and for making our cities more accessible for non-motorized transportation such as biking or walking.”

Other Harvard Chan School co-authors of the study included John Evans, Joel Schwartz, and James Hammitt.

Funding for the study was provided by Harvard University, from which Choma received financial support during his doctoral program.

The team of Prof. Dr. William Martin in the Institute for Molecular Evolution at the HHU investigates how and where life arose on the early Earth. Their approach is experimental and computational. In the laboratory, they run chemical experiments to investigate reactions between hydrogen and carbon dioxide, CO₂, using catalysts and conditions found in submarine hydrothermal vents. At the computer, they have developed a form of molecular archaeology that allows them to uncover the many different traces of primordial life that are preserved in the proteins, DNA and chemical reactions of modern cells.

In their latest work, they investigated the question of what kind of chemical environment fostered the chemical reactions that gave rise to metabolism, and later to LUCA itself, and where the energy came from that was needed to drive those reactions forward. To do that, they looked not at genes, but at the information contained within the chemical reactions of life themselves. They identified 402 metabolic reactions that have gone virtually unchanged since the origin of life roughly 4 billion years ago. Because these reactions are common to all cells, they were also present in LUCA. They shed light on how primordial life dealt with energy in metabolism and where it obtained the energy needed to make life’s chemical reactions go forward.

Jessica Wimmer, a PhD student in the institute and lead author on the new paper, was particularly interested in the energy balance of LUCA’s metabolic reactions, because all life requires energy. For that she made a catalogue of the 402 reactions that the simple and ancient among modern cells — bacteria and archaea — use to construct the building blocks of life: the 20 amino acids, the bases of DNA and RNA, and the 18 vitamins (cofactors) that are essential for metabolism. In the most primitive of modern cells, and in Wimmer’s computer analyses, these compounds are synthesized from simple molecules that are present in the modern environment and that were also present in hydrothermal vents on the early Earth: hydrogen (H₂), carbon dioxide (CO₂) and ammonia (NH₃). The result was the metabolic network of LUCA.

When asked about the motivation behind the central question of the new study, Jessica Wimmer says: “We wanted to know where the energy came from that drove primordial metabolism forward. At the very onset of metabolic reactions some 4 billion years ago, there were no proteins or enzymes to catalyze reactions because they had not yet evolved. Metabolism had to arise from reactions that could take place in the environment, perhaps with help from inorganic catalysts. But catalysts or not, in order to go forward, the reactions have to release energy. Where did that energy come from? There have been lots of suggestions for possible sources of metabolic energy in the literature. But nobody ever looked into the reactions of metabolism itself.” To find sources of energy in metabolic reactions, the team calculated the amount of free energy, also called Gibbs energy, that is released or consumed in each reaction.

The result: LUCA’s metabolism required no external source of energy such as UV light, meteorite impacts, volcanic eruptions, or radioactivity. On the contrary, in an environment typical of many modern submarine hydrothermal vents, the energy needed for the reactions of metabolism to go forward stems from within metabolism itself. Stated another way, almost all of LUCA’s metabolic reactions liberate energy all by themselves: the energy for life stems from life itself. Martin, senior author of the study, says: “That is exciting, because the 400 interconnected reactions of central metabolism, which seem so hopelessly complex upon first encounter, suddenly reveal a natural tendency to unfold all by themselves under the right conditions.”

To arrive at that conclusion, the team had to first investigate the energetics of the 402 reactions using computer programs that simulate different environmental conditions, so as to distinguish energetically favorable from unfavorable combinations. This is important because whether or not a reaction releases energy often depends upon environmental conditions. They surveyed conditions ranging from pH 1 (acidic) to pH 14 (alkaline), temperatures from 25 to 100 °C, and different relative amounts of reactants to products. They looked with particular care at the energetic role of hydrogen. Wimmer: “Without hydrogen, nothing happens at all, because hydrogen is required to get carbon from CO₂ incorporated into metabolism in the first place.”

The energetically optimal conditions fall within an alkaline pH range around pH 9 and a temperature around 80 °C, with hydrogen required for CO₂ fixation. Putting this result in context, Martin explains: “This is almost exactly what we see at Lost City, a H₂-producing hydrothermal field in the Mid-Atlantic. In an environment like that, about 95-97 % of LUCA’s metabolic reactions could go forward spontaneously, that is, without the need for any other source of energy. In the abyssal darkness of hydrothermal systems, H₂ is chemical sunlight. Modern energy research exploits exactly the same properties of hydrogen as life does. It is just that life has four billion years of experience with hydrogen technology, while we are just getting started.”

Jessica Wimmer adds: “Regarding energy at life’s origin, we can say that pure chemical energy is sufficient. We need no sunlight, no meteorites, no UV light: just H₂ and CO₂, plus some ammonia and salts. Because of the extremely conserved nature of the chemical reactions in our biosynthetic network, we can obtain some interesting insights into the reactions that gave rise to LUCA, even though it lived four billion years ago.”

During embryonic development, hundreds of genes must be precisely activated or repressed for organs to build properly. This control of activity is directed by short DNA sequences that, by binding certain proteins in the cell nucleus, act as true ON/OFF switches. “When the switch is turned on, it initiates the transcription of a gene into RNA, which in turn is translated into a protein that can then perform a specific task,” explains Guillaume Andrey, professor in the Department of Genetic and Developmental Medicine at the UNIGE Faculty of Medicine, who led this research. “Without this, genes would be continuously switched on or off, and therefore unable to act selectively, in the right place and at the right time.” In general, each gene has several switches to ensure that the mechanism is robust. “However, could the loss of one of these switches have consequences? This is what we wanted to test here by taking as a model the Pitx1 gene, whose role in the construction of the lower limbs is well known,” says Raquel Rouco, a post-doctoral researcher in Guillaume Andrey’s laboratory and co-first author of this study.

A decrease in cellular activation that leads to clubfoot

To do this, the scientists modified mouse stem cells using the genetic engineering tool CRISPR-CAS 9, which makes it possible to add or remove specific elements of the genome. “Here, we removed one of Pitx1’s switches, called Pen, and added a fluorescence marker that allows us to visualise the gene activation,” explains Olimpia Bompadre, a doctoral student in the research team and co-first author. “These modified cells are then aggregated with mouse embryonic cells for us to study their early stages of development.”

Usually, about 90% of cells in future legs activate the Pitx1 gene, while 10% of cells do not. “However, when we removed the Pen switch, we found that the proportion of cells that did not activate Pitx1 rose from 10 to 20%, which was enough to modify the construction of the musculoskeletal system and to induce a clubfoot,” explains Guillaume Andrey. Indeed, the proportion of inactive cells increased particularly in the immature cells of the lower limbs and in the irregular connective tissue, a tissue that is essential for building the musculoskeletal system.

The same mechanism in many genes

Beyond the Pitx1 gene and clubfoot, the UNIGE scientists have discovered a general principle whose mechanism could be found in a large number of genes. Flawed genetic switches could thus be at the origin of numerous malformations or developmental diseases. Moreover, a gene does not control the development of a single organ in the body, but is usually involved in the construction of a wide range of organs. “A non-lethal malformation, such as clubfoot for example, could be an indicator of disorders elsewhere in the body that, while not immediately visible, could be much more dangerous. If we can accurately interpret the action of each mutation, we could not only read the information in the genome to find the root cause of a malformation, but also predict effects in other organs, which would silently develop, in order to intervene as early as possible,” the authors conclude.

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