In a study, published today in Science Advances, researchers from the Universities of Bristol and Ghent have shown how exploring the unknown may be the crucial step needed to realise the continual innovation needed for the biotechnologies of the future.

Recognising the role of open-endedness in achieving this goal and its growing importance in fields like computer science and evolutionary biology, the team mapped out how open-endedness is linked to bioengineering practice today and what would be required to achieve it in the lab.

For success, algorithms used for biological design should not solely focus on moving toward a specific goal — such as better yield – but also consider the creation and maintenance of novelty and diversity in the solutions that have been found.

Dr Thomas Gorochowski, co-author and Royal Society University Research Fellow in the School of Biological Sciences at Bristol, explained: “When we try to design a complex biological process, it’s often tempting to just tweak something that partially works rather than take the risk of trying something completely new.

“In this work we highlight that in these situations the best solutions often come from unexpected directions, because we don’t always fully understand how everything works. With biology, there are lots of unknowns and so we need a vast and diverse toolkit of building blocks to ensure we have the best chance of finding the solution we need.”

Professor Michiel Stock, lead author from Ghent University, added: “Biological systems have a natural capacity for innovation that has led to the overwhelming biodiversity we see in nature today.

“Our own attempts to engineer biology, in contrast, lack this creativity — they are far more rigid, less imaginative, and often doesn’t make the best use of what biology is capable of.

“With all life around us originating from the open-ended process of evolution, wouldn’t it be awesome if we could harness some of that power for our own biological designs.”

The ability to create new biotechnologies is becoming increasingly important for tackling global challenges spanning the sustainable production of chemicals, materials and food, to advanced therapeutics to combat emerging diseases. Fueling this progress are innovations in how biology can be harnessed in new ways. This work supports this goal by offering a fresh direction for new research and design approaches.

The study was made possible due to a travel grant from the FWO Flanders and funding from the Royal Society, BBSRC and EPSRC.

The findings, published in Science Advances, help explain the role oceans played in past glacial melting cycles and could improve predictions of how ocean carbon cycles will respond to global warming.

Oceans adjust atmospheric CO₂ as ice ages transition to warmer climates by releasing the greenhouse gas from carbon stored within the deep ocean. The research demonstrates a striking correlation between global ocean oxygen contents and atmospheric CO₂ from the last ice age to today — and how carbon release from the deep sea may rise as the climate warms.

“The research reveals the important role of the Southern Ocean in controlling the global ocean oxygen reservoir and carbon storage,” said Yi Wang, lead researcher and an assistant professor of Earth and Environmental Sciences at Tulane University School of Science and Engineering. Wang specializes in marine biogeochemistry and paleoceanography.

“This will have implications for understanding how the ocean, especially the Southern Ocean, will dynamically affect the atmospheric CO₂ in the future,” she said.

Wang conducted the study with colleagues from the Woods Hole Oceanographic Institution, the world’s leading independent nonprofit organization dedicated to ocean research, exploration and education. She worked for the institute before joining Tulane in 2023.

The team analyzed seafloor sediments collected from the Arabian Sea to reconstruct average global ocean oxygen levels thousands of years ago. They precisely measured isotopes of the metal thallium trapped in the sediments, which indicate how much oxygen was dissolved in the global ocean at the time the sediments formed.

“Study of these metal isotopes on glacial-interglacial transitions has never been looked at before, and these measurements allowed us to essentially recreate the past,” Wang said.

The thallium isotope ratios showed the global ocean lost oxygen overall during the last ice age compared to the current warmer interglacial period. Their study revealed thousand-year global ocean deoxygenation during abrupt warming in the Northern Hemisphere, whereas the ocean gained more oxygen when abrupt cooling occurred during the transition from the last ice age to today. The researchers attributed the observed ocean oxygen changes to Southern Ocean processes.

“This study is the first to present an average picture of how the oxygen content of the global oceans evolved as Earth transitioned from the last glacial period into the warmer climate of the last 10,000 years,” said Sune Nielsen, associate scientist at WHOI and co-author of the research. “These new data are a really big deal, because they show that the Southern Ocean plays a critical role in modulating atmospheric CO₂. Given that high latitude regions are those most affected by anthropogenic climate change, it is troubling that these also have an outsize impact on atmospheric CO₂ in the first place.”

Other authors include Kassandra Costa, Sophie Hines, and Wanyi Lu.

The Megalodon or megatooth shark is typically portrayed as a super-sized monster in popular culture, with recent examples in the sci-fi films “The Meg” (2018) and “Meg 2: The Trench” (2023). Previous studies assume that the shark likely reached lengths of at least 50 feet and possibly as much as 65 feet.

However, the Megalodon is largely known only from its teeth and vertebrae in the fossil record — a rather incomplete set of data from which to draw assumptions. Thus, the modern great white shark was traditionally used as a model for Megalodon bodies in previous studies. That model led researchers to conclude that the shark was round and stocky like great whites.

“Our team reexamined the fossil record, and discovered the Megalodon was more slender and possibly even longer than we thought. Therefore, a better model might be the modern mako shark,” said UCR biologist and paper first author Phillip Sternes. “It still would have been a formidable predator at the top of the ancient marine food chain, but it would have behaved differently based on this new understanding of its body.”

For the new study published in the journal Palaeontologia Electronica, a team of 26 scientists from around the world, co-led by Sternes and DePaul University paleobiology professor Kenshu Shimada, was inspired by differences in previously estimated body lengths for the Megalodon.

“It was a ‘eureka-moment’ when our research team realized the discrepancy between two previously published lengths for the same Megalodon specimen,” said Shimada.

The team then weighed in on a new comparison of Megalodon vertebra fossils to those of living lamniform shark relatives. “We measured the whole vertebral skeleton of a living great white shark with a CT scanner and compared that to the previous reconstruction of the Megalodon vertebral column,” Sternes said.

“It was still a giant, predatory shark. But the results strongly suggest that the Megalodon was not merely a larger version of the modern great white shark.”

A revised understanding of the Megalodon body type would in turn affect scientists’ understanding not only of the giant shark itself, but also of its impact on the ecology and evolution of marine ecosystems that shaped the present-day oceans.

There is no doubt the Megalodon is one of the largest marine predators ever to have lived. But a slimmer and more elongated body would suggest the Megalodon also had a longer digestive canal. Sternes explained that in this case, the sharks might have enjoyed enhanced absorption of nutrients, and may not have had to eat as often as previously believed.

“With increased ability to digest its food, it could have gone for longer without needing to hunt. This means less predation pressure on other marine creatures,” Sternes said. “If I only have to eat one whale every so often, whale populations would remain more stable over time.”

Some shark scientists have theorized that a natural decrease in prey led to the extinction of Megalodons. However, Sternes has another theory, in part supported by the revised understanding of its shape.

“I believe there were a combination of factors that led to the extinction, but one of them may have been the emergence of the great white shark, which was possibly more agile, making it an even better predator than the Megalodon,” Sternes said. “That competition for food may have been a major factor in its demise.”

The research team of shark experts from the U.S., UK, Austria, France, Japan, Mexico, Brazil, and Australia all feel that a revised understanding of ancient marine life would have a cascading effect on the oceans that are still visible today.

“Now that we know it was a thinner shark, we need to reinvestigate its lifestyle, how it really lived, and what caused it to die,” Sternes said. “This study represents a major stepping stone for others to follow up on.”

The tiny motor could help spark research into future applications such as building molecular factories for useful chemicals or medical probes of molecules inside the bloodstream to detect diseases such as cancer.

“Common macroscopic machines become inefficient at the nanoscale,” said study co-author professor Aleksei Aksimentiev, a professor of physics at the University of Illinois at Urbana-Champagne. “We have to develop new principles and physical mechanisms to realize electromotors at the very, very small scales.”

The experimental work on the tiny motor was conducted by Cees Dekker of the Delft University of Technology and Hendrik Dietz of the Technical University of Munich.

Dietz is a world expert in DNA origami. His lab manipulated DNA molecules to make the tiny motor’s turbine, which consisted of 30 double-stranded DNA helices engineered into an axle and three blades of about 72 base pair length. Decker’s lab work demonstrated that the turbine can indeed rotate by applying an electric field. Aksimentiev’s lab carried out all-atom molecular dynamics simulations on a system of five million atoms to characterize the physical phenomena of how the motor works.

The system was the smallest representation that could yield meaningful results about the experiment; however, “it was one of the largest ever simulated from the DNA origami perspective,” Aksimentiev said.

Mission Impossible to Mission Possible

The Texas Advanced Computing Center (TACC) awarded Aksimentiev a Leadership Resource Allocation to aid his study of mesoscale biological systems on the National Science Foundation (NSF)-funded Frontera, the top academic supercomputer in the U.S.

“Frontera was instrumental in this DNA nanoturbine work,” Aksimentiev said. “We obtained microsecond simulation trajectories in two to three weeks instead of waiting for a year or more on smaller computing systems. The big simulations were done on Frontera using about a quarter of the machine — over 2,000 nodes,” Aksimentiev said. “However, it’s not just the hardware, but also the interaction with TACC staff. It’s extremely important to make the best use of the resources once we have the opportunity.”

Aksimentiev was also awarded supercomputer allocations for this work by the NSF-funded Advanced Cyberinfrastructure Coordination Ecosystem: Services & Support (ACCESS) on Expanse of the San Diego Supercomputer Center and Anvil of Purdue University.

“We had up to 100 different nanomotor systems to simulate. We had to run them for different conditions and in a speedy manner, which the ACCESS supercomputers assisted with perfectly,” Aksimentiev said. “Many thanks to the NSF for their support — we would not be able to do the science that we do without these systems.”

DNA as a Building Block

The success with the working DNA nanoturbine builds on a previous study that also used Frontera and ACCESS supercomputers. The study showed that a single DNA helix is the tiniest electromotor that one can build — it can rotate up to a billion revolutions per minute.

DNA has emerged as a building material at the nanoscale, according to Aksimentiev.

“The way DNA base pair is a very powerful programming tool. We can program geometrical, three-dimensional objects from DNA using the Cadnano software just by programming the sequence of letters that make up the rungs of the double helix,” he explained.

Another reason for using DNA as the building block is that it carries a negative charge, an essential characteristic to make the electromotor.

“We wanted to reproduce one of the most spectacular biological machines — ATP synthase, which is driven by electric field. We chose to do our motor with DNA,” Aksimentiev said.

“This new work is the first nanoscale motor where we can control the rotational speed and direction,” he added. It’s done by adjusting the electric field across the solid state nanopore membrane and the salt concentrations of the fluid that surrounds the rotor.

“In the future, we might be able to synthetize a molecule using the new nanoscale electromotor, or we can use it to as an element of a bigger molecular factory, where things are moved around. Or we could imagine it as a vehicle for soft propulsion, where synthetic systems can go into a blood stream and probe molecules or cells one at a time,” Aksimentiev said.

If you think this sounds like something out of a 1960’s sci-fi movie, you are right. In the movie Fantastic Voyage, a team of Americans in a nuclear submarine is shrunk and injected into a scientist’s body to fix a blood clot and need to work quickly before the miniaturization wears off.

As far-fetched as this might sound, Aksimentiev says that the concept and the elements of the machines we are developing today could enable something like this to happen.

“We were able to accomplish this because of supercomputers,” Aksimentiev said. “Supercomputers are becoming more and more indispensable as the complexity of the systems that we build increases. They’re the computational microscopes, which at ultimate resolutions can see the motion of individual atoms and how that is coupled to a bigger system.”

Funding came from ERC Advanced Grant no. 883684 and the NanoFront and BaSyC programmes; ERC Consolidator Grant to H.D. (GA no. 724261), the Deutsche Forschungsgemeinschaft via the Gottfried-Wilhelm-Leibniz Programme (to H.D.) and the SFB863 Project ID 111166240 TPA9; National Science Foundation grant DMR-1827346; the Max Planck School Matter to Life and the MaxSynBio Consortium. Supercomputer time was provided through TACC Leadership Resource Allocation MCB20012 on Frontera and through ACCESS allocation MCA05S028.

The atmosphere contains many tiny solid particles. Scientists from the Max Planck Institute for Dynamics and Self-Organization (MPI-DS) and the University of Göttingen in collaboration with the Centre national de la recherche scientifique (CNRS) in France and the university of Gothenburg, Sweden, now studied how such non-spherical particles settle in air. For this, they used a new precision apparatus equipped with high-speed cameras and a novel particle injection mechanism. Using a 3D-printer, they created particles of different shapes resembling discs of thickness as low as 50 micrometer and rods of length as high as 880 micrometers. Thanks to this setup, they could observe that particles tend to oscillate as they settle in quiescent air.

“So far, most studies on the behavior of such small particles were done with models in liquids since experiments in air are extremely challenging,” Mohsen Bagheri, group leader at MPI-DS, describes previous approaches. “However, the true settling dynamics could not be explored this way. They were now revealed in our experimental setting, directly measuring the motion of real-size particles, which are much heavier than the surrounding environment,” he continues.

The observed oscillation could impact the collision of individual particles, their travelling distance in the atmosphere and their interaction with the solar radiation.

Predicting the dynamics of particles

Typically, atmospheric particles are not perfectly spherical, but rather flattened or elongated structures. The scientists developed and tested a model to describe and predict the movement of such particles, which very accurately captures the experimental results. The new model can be used to study the dynamics and formation of particles clusters and the resulting effects in everyday life. “In particular, our results can help to better predict how long pollutants reside in the atmosphere or how precipitation is initiated in clouds,” summarizes Alain Pumir. The CNRS researcher developed the model together with his colleagues Bernhard Mehlig and Kristian Gustavsson.

In total, these new insights contribute to a more accurate understanding of atmospheric particles, and how they affect our environment and climate.

For the first time, researchers have identified the long-term health burden of bacterial meningitis. The bacterial infection can currently be cured with antibiotics, but it often leads to permanent neurological impairment. And since children are often affected, the consequences are significant.

“When children are affected, the whole family is affected. If a three-year-old child has impaired cognition, a motor disability, impaired or lost vision or hearing, it has a major impact. These are lifelong disabilities that become a major burden for both the individual and society, as those affected need health care support for the rest of their lives,” says Federico Iovino, associate professor in Medical Microbiology at the Department of Neuroscience, Karolinska Institutet, and one of the authors of the current study.

By analyzing data from the Swedish quality register on bacterial meningitis between 1987 and 2021, the researchers have been able to compare just over 3,500 people who contracted bacterial meningitis as children with just over 32,000 matched controls from the general population. The average follow-up time is over 23 years.

The results show that those diagnosed with bacterial meningitis consistently have a higher prevalence of neurological disabilities such as cognitive impairment, seizures, visual or hearing impairment, motor impairment, behavioral disorders, or structural damage to the head.

The risk was highest for structural head injuries — 26 times the risk, hearing impairment — almost eight times the risk, and motor impairment — almost five times the risk.

About one in three people affected by bacterial meningitis had at least one neurological impairment compared to one in ten among controls.

“This shows that even if the bacterial infection is cured, many people suffer from neurological impairment afterwards,” says Federico Iovino.

With the long-term effects of bacterial meningitis identified, Federico Iovino and his colleagues will now move forward with their research.

“We are trying to develop treatments that can protect neurons in the brain during the window of a few days it takes for antibiotics to take full effect. We now have very promising data from human neurons and are just entering a preclinical phase with animal models. Eventually, we hope to present this in the clinic within the next few years,” says Federico Iovino.

The research was funded by Merck & Co (in Sweden MSD).

Facts:

Bacterial meningitis is a rare but very serious infection that can affect people of all ages, but is most common in newborns, children and adolescents, and the elderly. It is often caused by pneumococcus (Streptococcus pneumoniae) which is also a major cause of bacterial respiratory infections such as pneumonia, otitis and sinusitis, which also mainly affect the youngest and oldest members of society.

Untreated, bacterial meningitis is fatal, but the infection can now be cured with antibiotics. However, antibiotics have difficulty penetrating the blood-brain barrier, which means that it takes time to fight the infection. During this time, nerve cells can be damaged and result in various permanent neurological damage. Furthermore, there is the constant threat of antibiotic-resistance to face in the clinics.

Source: Federico Iovino, Public Health Agency and Centers for Disease Control and Prevention.