“A key question for the study of such different microbial strategies is how to define microbial ecological niches in the first place,” says Prof. Dr Bas E. Dutilh. Until now, this has mainly been done based on subjective environmental parameters, which hardly allow unbiased quantification of the niche. The bioinformatician from the Cluster of Excellence “Balance of the Microverse” at the University of Jena, together with researchers from Utrecht University, has therefore used a novel — data-driven — method to describe microbial niches, in which the species community itself is considered the decisive environmental factor instead of external habitat conditions. This works because microbial communities adapt rapidly to their environment, so their composition reflects the sum of all environmental factors.

Most microbial habitats dominated by generalists

For their study, the researchers analysed and quantified thousands of metagenomic data sets from different microbial samples from all over the world. “We found that in most habitats, generalists are dominant,” says Dutilh. The researchers were initially surprised by this finding, as they had assumed that in local niches, specialists might prevail because they are better adapted to the particular conditions. But they found that competing generalists could grow much faster and thus gain dominance in the niche. “For the generalists it’s hit-or-miss, though; either they make it or they don’t. This makes them quite variable in their presence. Specialists are more stable in their niche, albeit at low abundance.”

And there was another result that the researchers had not expected: The genomes of the generalists are not particularly large. “This was previously assumed because metabolic flexibility was thought to generally require a larger genome,” reports Dutilh. But as it turns out, the correlation between niche range and genome size is more complex. “We discovered two contrasting evolutionary strategies: In habitats with relatively low local biodiversity, such as animal-associated microbiomes, the specialists have a relatively small genome. In highly biodiverse habitats such as soils, the genome of the specialists is significantly larger.”

The genomes of generalists are more variable than those of specialists, with genes coming and going during evolution. This allows them to integrate genetic information from other organisms through horizontal gene transfer and thus to adapt rapidly to the local niche. “We also see specific functions that are associated with horizontal gene transfer in generalists’ genomes,” according to Dutilh. The functions associated with specialists are much more diverse, often related to very specific metabolic processes. The genomes of specialists are evolutionarily stable, unlike those of generalists.

“In conclusion, our analysis sheds new and unexpected light on microbial niche range strategies throughout the microbial tree of life,” Bas E. Dutilh is convinced.

A research team at TU Wien (Vienna) has now investigated the question: How can this law be reconciled with the rules of quantum physics? They succeeded in developing a “quantum version” of the third law of thermodynamics: Theoretically, absolute zero is attainable. But for any conceivable recipe for it, you need three ingredients: Energy, time and complexity. And only if you have an infinite amount of one of these ingredients can you reach absolute zero.

Information and thermodynamics: an apparent contradiction

When quantum particles reach absolute zero, their state is precisely known: They are guaranteed to be in the state with the lowest energy. The particles then no longer contain any information about what state they were in before. Everything that may have happened to the particle before is perfectly erased. From a quantum physics point of view, cooling and deleting information are thus closely related.

At this point, two important physical theories meet: Information theory and thermodynamics. But the two seem to contradict each other: “From information theory, we know the so-called Landauer principle. It says that a very specific minimum amount of energy is required to delete one bit of information,” explains Prof. Marcus Huber from the Atomic Institute of TU Wien. Thermodynamics, however, says that you need an infinite amount of energy to cool anything down exactly to absolute zero. But if deleting information and cooling to absolute zero are the same thing — how does that fit together?

Energy, time and complexity

The roots of the problem lie in the fact that thermodynamics was formulated in the 19th century for classical objects — for steam engines, refrigerators or glowing pieces of coal. At that time, people had no idea about quantum theory. If we want to understand the thermodynamics of individual particles, we first have to analyse how thermodynamics and quantum physics interact — and that is exactly what Marcus Huber and his team did.

“We quickly realised that you don’t necessarily have to use infinite energy to reach absolute zero,” says Marcus Huber. “It is also possible with finite energy — but then you need an infinitely long time to do it.” Up to this point, the considerations are still compatible with classical thermodynamics as we know it from textbooks. But then the team came across an additional detail of crucial importance:

“We found that quantum systems can be defined that allow the absolute ground state to be reached even at finite energy and in finite time — none of us had expected that,” says Marcus Huber. “But these special quantum systems have another important property: they are infinitely complex.” So you would need infinitely precise control over infinitely many details of the quantum system — then you could cool a quantum object to absolute zero in finite time with finite energy. In practice, of course, this is just as unattainable as infinitely high energy or infinitely long time.

Erasing data in the quantum computer

“So if you want to perfectly erase quantum information in a quantum computer, and in the process transfer a qubit to a perfectly pure ground state, then theoretically you would need an infinitely complex quantum computer that can perfectly control an infinite number of particles,” says Marcus Huber. In practice, however, perfection is not necessary — no machine is ever perfect. It is enough for a quantum computer to do its job fairly well. So the new results are not an obstacle in principle to the development of quantum computers.

In practical applications of quantum technologies, temperature plays a key role today — the higher the temperature, the easier it is for quantum states to break and become unusable for any technical use. “This is precisely why it is so important to better understand the connection between quantum theory and thermodynamics,” says Marcus Huber. “There is a lot of interesting progress in this area at the moment. It is slowly becoming possible to see how these two important parts of physics intertwine.”

Accordingly, permafrost has not only been viewed as a solid platform for buildings and infrastructure. “Traditionally, it’s also been considered a natural barrier that prevents the spread of pollutants,” explains Moritz Langer from the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI). “Consequently, industrial waste from defunct or active facilities was often simply left on-site, instead of investing the considerable effort and expense needed to remove it.” As a result of the industrial expansion during the cold war, over the decades this led to micro-dumps full of toxic sludge from oil and gas exploration, stockpiles of mining debris, abandoned military installations, and lakes in which pollutants were intentionally poured. “In many cases, the assumption was that the permafrost would reliably and permanently seal off these toxic substances, which meant there was no need for costly disposal efforts,” says Guido Grosse, who heads the AWI’s Permafrost Research Section. “Today, this industrial legacy still lies buried in the permafrost or on its surface. The substances involved range from toxic diesel fuel to heavy metals and even radioactive waste.”

But as climate change progresses, this “sleeping giant” could soon become an acute threat: since the permafrost regions are warming between twice as fast and four times as fast as the rest of the world, the frozen soil is increasingly thawing. When this happens, it changes the hydrology of the region in question, and the permafrost no longer provides an effective barrier. As a result, contaminants that have accumulated in the Arctic over decades can be released, spreading across larger regions.

In addition, thawing permafrost becomes more and more unstable, which can lead to further contamination. When the ground collapses, it can damage pipelines, chemical stockpiles and depots. Just how real this risk already is can be seen in a major incident from May 2020 near the industrial city Norilsk in northern Siberia: a destabilized storage tank released 17,000 metric tons of diesel, which polluted the surrounding rivers, lakes and tundra. According to Langer: “Incidents like this could easily become more frequent in the future.”

In order to more accurately assess such risks, he and an international team of experts from Germany, the Netherlands and Norway took a closer look at industrial activities in the High North. To do so, they first analysed freely available data from the portal OpenStreetMap and from the Atlas of Population, Society and Economy in the Arctic. According to these sources, the Arctic permafrost regions contain ca. 4,500 industrial sites that either store or use potentially hazardous substances.

“But this alone didn’t tell us what types of facilities they were, or how badly they could potentially pollute the environment,” says Langer. More detailed information on contaminated sites is currently only available for North America, where roughly 40 percent of the global permafrost lies. The data from Canada and Alaska showed that, using the location and type of facility, it should be possible to accurately estimate where hazardous substances were most likely to be found.

For Alaska, the Contaminated Sites Program also offers insights into the respective types of contaminants. For example, roughly half of the contaminations listed can be attributed to fuels like diesel, kerosene and petrol. Mercury, lead and arsenic are also in the top 20 documented environmental pollutants. And the problem isn’t limited to the legacy of past decades: although the number of newly registered contaminated sites in the northernmost state of the USA declined from ca. 90 in 1992 to 38 in 2019, the number of affected sites continues to rise.

There are no comparable databases for Siberia’s extensive permafrost regions. “As such, our only option there was to analyse reports on environmental problems that were published in the Russian media or other freely accessible sources between 2000 and 2020,” says Langer. “But the somewhat sparse information available indicates that industrial facilities and contaminated sites are also closely linked in Russia’s permafrost regions.”

Using computer models, the team calculated the occurrence of contaminated sites for the Arctic as a whole. According to the results, the 4,500 industrial facilities in the permafrost regions have most likely produced between 13,000 and 20,000 contaminated sites. 3,500 to 5,200 of them are located in regions where the permafrost is still stable, but will start to thaw before the end of the century. “But without more extensive data, these findings should be considered a rather conservative estimate,” Langer emphasises. “The true scale of the problem could be even greater.”

Making matters worse, the interest in pursuing commercial activities in the Arctic continues to grow. As a result, more and more industrial facilities are being constructed, which could also release toxic substances into nearby ecosystems. Further, this is happening at a time when removing such environmental hazards is getting harder and harder — after all, doing so often requires vehicles and heavy gear, which can hardly be used on vulnerable tundra soils that are increasingly affected by thaw.

“In a nutshell, what we’re seeing here is a serious environmental problem that is sure to get worse,” summarises Guido Grosse. What is urgently called for, according to the experts: more data, and a monitoring system for hazardous substances in connection with industrial activities in the Arctic. “These pollutants can, via rivers and the ocean, ultimately find their way back to people living in the Arctic, or to us.” Other important aspects are intensified efforts to prevent the release of pollutants and undo the damage in those areas that are already contaminated. And lastly, the experts no longer consider it appropriate to leave industrial waste behind in the Arctic without secure disposal options. After all, the permafrost can no longer be relied upon to counter the associated risks.

“This is a huge problem in the treatment of chronic disease,” said Kevin McHugh, corresponding author of a study about the technology published online in Advanced Materials. “It’s estimated that 50% of people don’t take their medications correctly. With this, you’d give them one shot, and they’d be all set for the next couple of months.”

When patients fail to take prescription medicine or take it incorrectly, the costs can be staggering. The annual toll in the United States alone has been estimated at more than 100,000 deaths, up to 25% of hospitalizations and more than $100 billion in healthcare costs.

Encapsulating medicine in microparticles that dissolve and release drugs over time isn’t a new idea. But McHugh and graduate student Tyler Graf used 21st-century methods to develop next-level encapsulation technology that is far more versatile than its forerunners.

Dubbed PULSED (short for Particles Uniformly Liquified and Sealed to Encapsulate Drugs), the technology employs high-resolution 3D printing and soft lithography to produce arrays of more than 300 nontoxic, biodegradable cylinders that are small enough to be injected with standard hypodermic needles.

The cylinders are made of a polymer called PLGA that’s widely used in clinical medical treatment. McHugh and Graf demonstrated four methods of loading the microcylinders with drugs, and showed they could tweak the PLGA recipe to vary how quickly the particles dissolved and released the drugs — from as little as 10 days to almost five weeks. They also developed a fast and easy method for sealing the cylinders, a critical step to demonstrate the technology is both scalable and capable of addressing a major hurdle in time-release drug delivery.

“The thing we’re trying to overcome is ‘first-order release,'” McHugh said, referring to the uneven dosing that’s characteristic with current methods of drug encapsulation. “The common pattern is for a lot of the drug to be released early, on day one. And then on day 10, you might get 10 times less than you got on day one.

“If there’s a huge therapeutic window, then releasing 10 times less on day 10 might still be OK, but that’s rarely the case,” McHugh said. “Most of the time it’s really problematic, either because the day-one dose brings you close to toxicity or because getting 10 times less — or even four or five times less — at later time points isn’t enough to be effective.”

In many cases, it would be ideal for patients to have the same amount of a drug in their systems throughout treatment. McHugh said PULSED can be tailored for that kind of release profile, and it also could be used in other ways.

“Our motivation for this particular project actually came from the vaccine space,” he said. “In vaccination, you often need multiple doses spread out over the course of months. That’s really difficult to do in low- and middle-income countries because of health care accessibility issues. The idea was, ‘What if we made particles that exhibit pulsatile release?’ And we hypothesized that this core-shell structure — where you’d have the vaccine in a pocket inside a biodegradable polymer shell — could both produce that kind of all-or-nothing release event and provide a reliable way to set the delayed timing of the release.”

Though PULSED hasn’t yet been tested for months-long release delays, McHugh said previous studies from other labs have shown PLGA capsules can be formulated to release drugs as much as six months after injection.

In their study, Graf and McHugh showed they could make and load particles with diameters ranging from 400 microns to 100 microns. McHugh said this size enables particles to stay where they are injected until they dissolve, which could be useful for delivering large or continuous doses of one or more drugs at a specific location, like a cancerous tumor.

“For toxic cancer chemotherapies, you’d love to have the poison concentrated in the tumor and not in the rest of the body,” he said. “People have done that experimentally, injecting soluble drugs into tumors. But then the question is how long is it going to take for that to diffuse out.

“Our microparticles will stay where you put them,” McHugh said. “The idea is to make chemotherapy more effective and reduce its side effects by delivering a prolonged, concentrated dose of the drugs exactly where they’re needed.”

The crucial discovery of the contactless sealing method happened partly by chance. McHugh said previous studies had explored the use of PLGA microparticles for time-released drug encapsulation, but sealing large numbers of particles had proven so difficult that the cost of production was considered impractical for many applications.

While exploring alternative sealing methods, Graf noticed that trying to seal the microparticles by dipping them into different melted polymers was not giving the desired outcome. “Eventually, I questioned whether dipping the microparticles into a liquid polymer was even necessary,” said Graf, who proceeded to suspend the PLGA microparticles above a hot plate, enabling the top of the particles to melt and to self-seal while the bottom of the particles remained intact, “Those first particle batches barely sealed, but seeing the process was possible was very exciting.”Further optimization and experimentation resulted in consistent and robust sealing of the cylinders, which eventually proved to be one of the easier steps in making the time-released drug capsules. Each 22×14 array of cylinders was about the size of a postage stamp, and Graf made them atop glass microscope slides.

After loading an array with drugs, Graf said he would suspend it about a millimeter or so above the hot plate for a short time. “I’d just flip it over and rest it on two other glass slides, one on either end, and set a timer for however long it would take to seal. It just takes a few seconds.”

This work was supported by the Cancer Prevention and Research Institute of Texas (RR190056), the National Institutes of Health (EB031495, EB023833) and the National Science Foundation (1842494, 2236422).