It is precisely here that the interdisciplinary project “GreenToxiConomy,” which is part of the scientific alliance Bioeconomy Science Center (BioSC), comes into play. The objective was to examine bio-based substances and innovative technologies with a view to their toxic impact on the environment at an early stage in product development and to incorporate the resulting findings into product design. Project partners from Aachen, Jülich and Düsseldorf provided two of their bio-based product candidates for the analyses: microgel containers for crop protection agents and biosurfactants.

The wash-active biosurfactants for use in shampoos and detergents at BioSC are based on the synthesis abilities of the Pseudomonas putida bacterium and the Ustilago maydis fungus, respectively, rather than on crude oil. The microgel technology allows for the controlled delivery of crop protection agents because the containers ensure that the active ingredients still adhere to the plants in the event of rain.

Dr. Sarah Johann, the lead author for the study and the head of a working group in the department of evolutionary ecology and environmental toxicology at the Institute for Ecology, Evolution and Diversity at Goethe University Frankfurt, explains: “For the analysis of novel substances and technologies we have selected a broad range of concentration to be able to adequately estimate potential hazards for humans and the environment. We wanted to examine whether the bio-based surfactants were more environmentally friendly than conventional chemical surfactants. In addition, we investigated whether the microgel containers per se induce any toxicity.”

To ensure the ecotoxicological evaluation was as precise as possible, the project team combined two elements in the determination of the toxicity: computer-aided prognoses (in silico) and experiments in the laboratory (in vitro and in vivo). The computer models work with the toxicity data of known chemicals, whose structure they compared with the structure of the new bio-based substances to forecast the toxicity. The experiments were conducted on aquatic and terrestrial organisms that represent specific organism groups, among them earthworms, springtails, water fleas and zebrafish embryos at a very early stage.

The result: both biosurfactants and microgels are highly promising candidates for use in a future bioeconomy whose products must be sustainably manufactured while not causing any environmental damage or harm to humans both during and after their utilisation. “We can only make statements within certain limits, however, as the transfer of laboratory results to the reality in the open field or in other applications is complicated,” says Johann. More research is necessary for a holistic assessment of the risk potential, which is why follow-up projects are planned.

Prof. Henner Hollert, head of the evolutionary ecology and environmental toxicology department at Goethe University Frankfurt, underlines the significance of the close interdisciplinary collaboration on “GreenToxiConomy.” In the project biotechnologists and engineers jointly designed a new product, and this was evaluated during the development stages by eco-toxicologists from Goethe University together with a team at RWTH Aachen headed by Prof. Dr. Martina Roß-Nickoll. “This continuous process is the major strength of the project.” Although it is only a first step towards a bioeconomy that is safe in eco-toxicological terms, for Hollert it is already clear that eco-toxicology and green toxicology will play a key role in the plans being drawn up by the EU. “Whenever it is a question of future bio-based product development and product design, we have to clarify the consequences for humans and the environment at an early stage. In this respect our approach can provide valuable results.”

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Many of the craters are clustered in groups and are aligned along rays. Furthermore, several craters are elliptical, allowing the reconstruction of the incoming paths of the impactors. The reconstructed trajectories have a radial pattern.

“The trajectories indicate a single source and show that the craters were formed by ejected blocks from a large primary crater,” said project leader Thomas Kenkmann, professor of geology at the University of Freiburg, Germany. “Secondary craters around larger craters are well known from other planets and moons but have never been found on Earth,”

The team calculated the ballistic trajectories and used mathematical simulations to model the formation of the craters. All of the craters found so far are located 150-200 km from the presumed primary crater and were formed by blocks that were 4-8-m in size that struck the Earth at speeds of 700-1000 m/s. The team estimate that the source crater is about 50-65 km in diameter and should be deeply buried under younger sediments in the northern Denver basin near the Wyoming-Nebraska border.

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Journal Reference:

1. Thomas Kenkmann, Louis Müller, Allan Fraser, Doug Cook, Kent Sundell, Auriol S.P. Rae. Secondary cratering on Earth: The Wyoming impact crater field. GSA Bulletin, 2022; DOI: 10.1130/B36196.1

The research was conducted primarily in the laboratory of Sarkis Mazmanian, Luis B. and Nelly Soux Professor of Microbiology and affiliated faculty member with the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech. A paper describing the study appears on February 14 in the journal Nature.

Decades of research have shown that the communities of bacteria that inhabit the intestines of animals (the microbiome) influence the immune system and metabolism; studies in the last few years have linked the microbiome to brain function and mood. People with certain neurological conditions have distinctly different gut bacteria communities. Further, studies in mice have shown that manipulating these communities can alter neurodevelopmental and neurodegenerative states, either ameliorating or exacerbating symptoms.

“It’s been really difficult to show causation between something that’s happening in the gut and the brain, rather than just associations between the disease states and the presence or absence of certain microbes,” says Brittany Needham, first author of the new study and a postdoctoral scholar in the Mazmanian lab. “We were interested in trying to understand the molecular messages that are going between the gut and the brain, and how these signals may lead to changes in behavior.”

This study focused on a bacterial metabolite (a by-product of microbes) called 4-ethylphenyl sulfate, or 4EPS. Initially produced by microbes in the intestines, 4EPS is then absorbed into the bloodstream and circulates throughout the body in both humans and mice. In 2013, the Mazmanian lab showed that this particular molecule was present in higher levels in mice with altered neurological development, specifically, a mouse model of autism and schizophrenia. Though other aspects of the altered microbiome differed from the healthy microbiome, 4EPS levels were by far the most different. Additionally, in a screen of human blood samples from 231 individuals, 4EPS levels were about seven times higher in children on the autism spectrum than in neurotypical children.

In this work, the team focused on the effects of 4EPS on mouse models of anxiety. While anxiety disorders in humans are complex, animal models provide a way to study the precise changes in the brain and body that lead to anxious behaviors. “Anxiety” in mice is measured by their willingness to explore or hide in a new space as well as the time spent in a risky environment. Bold mice will explore a new space, sniffing around, but anxious mice will hide, as if facing a predator, instead of exploring.

The study compared two groups of laboratory mice: one group was colonized with a pair of bacteria that were genetically engineered to produce 4EPS; the control group of mice were colonized with bacteria that were identical except lacked the ability to produce 4EPS. Then, the mice were introduced to a new arena, and researchers measured each mouse’s behavior.

The mice with 4EPS spent much less time exploring the area and more time hiding as compared to their non-4EPS counterparts, indicating higher levels of anxiety. Brain scans of the 4EPS mice also showed that some of the brain regions associated with fear and anxiety were more activated in addition to overall changes in brain activity and functional connectivity.

Looking closer at brain cells within these altered regions, the team found that particular cells called oligodendrocytes were altered. These cells are important in part because they produce a protein called myelin, which acts as a protective coating around neurons and nerve fibers called axons, like insulation around an electrical wire. The team found that in the presence of 4EPS, oligodendrocytes are less mature and consequently produce less myelin, leading to thinner insulation around axons.

However, when the 4EPS mice were treated with a drug known to increase myelin production in oligodendrocytes, the drug was able to overpower the negative effects of 4EPS — the mice regained normal myelin production, and the anxious behaviors were reduced.

In a related study appearing simultaneously in the journal Nature Medicine, Needham showed that treating mice with an oral drug to soak up and remove 4EPS from their systems led to reductions in anxious behaviors. This result enabled a small clinical study that also gave humans the drug in an open-label trial (no placebo or control group). Sequestering 4EPS in the human gut led to reduced levels of 4EPS in the blood and urine, and many of the 26 study participants displayed overall decreased levels of anxiety.

“It’s an exciting proof-of-concept finding that a specific microbial metabolite alters the activity of brain cells and complex behaviors in mice, but how this is happening remains unknown,” says Mazmanian. “The basic framework for brain function includes integration of sensory and molecular cues from the periphery and even the environment. What we show here is similar in principle but with the discovery that the neuroactive molecule is of microbial origin. I believe this work has implications for human anxiety or other mood conditions.”

The next steps for the work are to examine the mechanisms through which 4EPS affects oligodendrocytes — which proteins it may be interacting with, whether 4EPS is affecting changes directly in the brain, or if it is affecting another part of the body and those effects are making their way up to the brain. Also, it will be critical to show that the human data have an effect in a well-powered and controlled clinical trial, which is now underway.

In addition to Needham and Mazmanian, Caltech co-authors are former research technician Mark Adame; research technician Joseph Boktor; former postdoctoral scholar Wei-Li Wu (now of National Cheng Kung University in Taiwan); postdoctoral scholar Claire Rabut; EM scientist Mark Ladinsky; lecturer in chemistry Son-Jong Hwang; graduate student Jessica Griffiths; Pamela Bjorkman, David Baltimore Professor of Biology and Bioengineering, Merkin Institute Professor, and executive officer for biology and biological engineering; and Mikhail Shapiro, professor of chemical engineering and Howard Hughes Medical Institute Investigator.

Additional co-authors are Masanori Funabashi of Stanford University and Daiichi Sankyo RD Novare Co.; Zhuo Wang, Yumei Guo, and Daniel Holschneider of USC; Jillian Haney and Daniel Geschwind of UCLA; Qiyun Zhu of UC San Diego and Arizona State University; Rob Knight of UC San Diego; and Michael Fischbach of Stanford University.

Funding was provided by the Center for Environmental Microbial Interactions, the National Science Foundation, the Human Frontier Science Program, the National Institutes of Health, the Ministry of Science and Technology in Taiwan, the Heritage Medical Research Institute, and Lynda and Blaine Fetter. Sarkis Mazmanian is co-founder of Axial Therapeutics, which conducted the clinical trial.