The new research, which will appear Jan. 6 in the journal Science Advances, is the latest to probe the lives of what may be nature’s hardest working microbes: cyanobacteria.

These single-celled, photosynthetic organisms, also known as “blue-green algae,” can be found in almost any large body of water today. But more than 2 billion years ago, they took on an extra important role in the history of life on Earth: During a period known as the “Great Oxygenation Event,” ancient cyanobacteria produced a sudden, and dramatic, surge in oxygen gas.

“We see this total shift in the chemistry of the oceans and the atmosphere, which changed the evolution of life, as well,” said study lead author Sarah Hurley, a postdoctoral research associate in the departments of Geological Sciences and Biochemistry. “Today, all higher animals need oxygen to survive.”

To date, scientists still don’t know what these foundational microbes might have looked like, where they lived or what triggered their transformation of the globe.

But Hurley and her colleagues think they might have gotten closer to an answer by drawing on studies of naturally-occurring and genetically-engineered cyanobacteria. The team reports that these ancient microbes may have floated freely in an open ocean and resembled a modern form of life called beta-cyanobacteria.

Studying them, the researchers said, offers a window into a time when single-celled organisms ruled the Earth.

“This research gave us the unique opportunity to form and test hypotheses of what the ancient Earth might have looked like, and what these ancient organisms could have been,” said co-author Jeffrey Cameron, an assistant professor of biochemistry.

Take a breath

You can still make the case that cyanobacteria rule the planet. Hurley noted that these organisms currently produce about a quarter of the oxygen that comes from the world’s oceans.

One secret to their success may lie in carboxysomes — or tiny, protein-lined compartments that float inside all living cyanobacteria. These pockets are critical to the lives of these organisms, allowing them to concentrate molecules of carbon dioxide within their cells.

“Being able to concentrate carbon allows cyanobacteria to live at what are, in the context of Earth’s history, really low carbon dioxide concentrations,” Hurley said.

Before the Great Oxidation Event, it was a different story. Carbon dioxide levels in the atmosphere may have been as much as 100 times what they are today, and oxygen was almost nonexistent. For that reason, many scientists long assumed that ancient microorganisms didn’t need carboxysomes for concentrating carbon dioxide.

“Cyanobacteria have persisted in some form over two billion years of Earth’s history,” she said. “They could have been really different than today’s cyanobacteria.”

To find out how similar they were, the researchers cultured jars filled with bright-green cyanobacteria under conditions resembling those on Earth 2 billion years ago.

Hurley explained that different types of cyanobacteria prefer to digest different forms, or “isotopes,” of carbon atoms. As a result, when they grow, die and decompose, the organisms leave behind varying chemical signatures in ancient sedimentary rocks.

“We think that cyanobacteria were around billions of years ago,” she said. “Now, we can get at what they were doing and where they were living at that time because we have a record of their metabolism.”

Resurrecting zombie microbes

In particular, the team studied two different types of cyanobacteria. They included beta-cyanobacteria, which are common in the oceans today. But the researchers also added a new twist to the study. They attempted to bring an ancient cyanobacterium back from the dead. Hurley and her colleagues used genetic engineering to design a special type of microorganism that didn’t have any carboxysomes. Think of it like a zombie cyanobacterium.

“We had the ability to do what was essentially a physiological resurrection in the lab,” said Boswell Wing, a study coauthor and associate professor of geological sciences.

But when the researchers studied the metabolism of their cultures, they found something surprising: Their zombie cyanobacterium didn’t seem to produce a chemical signature that aligned with the carbon isotope signatures that scientists had previously seen in the rock record. In fact, the best fit for those ancient signals were likely beta-cyanobacteria — still very much alive today.

The team, in other words, appears to have stumbled on a living fossil that was hiding in plain sight. And, they said, it’s clear that cyanobacteria living around the time of the Great Oxygenation Event did have a structure akin to a carboxysome. This structure may have helped cells to protect themselves from growing concentrations of oxygen in the air.

“That modern organisms could resemble these ancient cyanobacteria — that was really counterintuitive,” Wing said.

Scientists, they note, now have a much better idea of what ancient cyanobacteria looked like and where they lived. And that means that they can begin running experiments to dig deeper into what life was like in the 2 billion-year-old ocean.

“Here is hard evidence from the geological record and a model organism that can shed new light on life on ancient Earth,” Cameron said.

Other coauthors on the new paper included CU Boulder undergraduate student Claire Jasper and graduate student Nicholas Hill.

Medina, an assistant professor of biomedical engineering, led the team who published its results Jan. 4 in Nature Biomedical Engineering.

“One of the best protective mechanisms we have to prevent infection are beneficial bacteria that inhabit our bodies, known as commensals,” Medina said. “For example, we often avoid food poisoning because our guts are already populated by helpful bacteria. There’s no room for the pathogen to take hold and colonize. If you wipe out the good bacteria, opportunistic pathogens can take advantage and cause infections.”

Antibiotics can knock out an infection, but they can also kill off good bacteria, creating an opportunity for a potentially fatal secondary infection. Repeated exposure to antibiotics can also breed bacteria resistant to drugs. The potential for secondary infection and drug-resistant bacteria holds true for infections elsewhere in the body, too, according to Medina.

Led by biomedical engineering doctoral student Andrew W. Simonson, first author on the paper, the team set out to develop a peptide that could eradicate the pathogen that causes tuberculosis (TB), one of the top 10 causes of death worldwide, without harming surrounding good bacteria.

“There are great control strategies and treatments in place for tuberculosis, making it largely preventable and treatable, but drug-resistant TB is an emerging threat that is on track to becoming a serious global health problem,” Medina said. “It’s a scary prospect.”

To develop a pathogen-specific antibacterial against TB, the researchers looked to the pathogen itself. The TB pathogen is wrapped in a thick envelope that is difficult to penetrate, especially compared to other bacteria.

“The envelope has pores, though — channels through which the pathogen takes in nutrients and metabolites,” Medina said. “We asked if we could mimic these channels to design antibacterials that would create holes in the bacterial envelope, and ultimately kill the pathogen.”

The researchers made a peptide that seems to disrupt the protective outer coating of the pathogen, making the TB bacteria susceptible to antibiotics and die, but it does not interact with the good bacteria. Medina said they are currently studying the exact mechanism by which the peptide attacks the TB pathogen, but they suspect it has something to do with a fatty acid that lives on the pathogen’s surface.

“There aren’t many biochemical differences between the targeted pathogen and good bacteria, except for this surface lipid,” Medina said. “We think the interaction of our peptide with this fatty acid is one of the things driving this preferential interaction.”

He also pointed to the bacteria’s thin carbohydrate region. In other types of bacteria, the carbohydrates form a thick defensive barrier that appears to insulate the bacteria against the peptide.

“It’s not entirely clear why this works, but it’s working on TB,” Medina said. “There’s a 10-fold improvement on the effectiveness of antibiotics on this pathogen relative to the other good bacteria.”

Next, the researchers plan to investigate how to administer the peptide to treat TB in a full model system. Peptides tend to break down when injected, Medina said, so his team is working to develop an aerosol that would allow a person to inhale the peptides directly to the infected lung tissue.

“Once we understand why this peptide targets TB, and how to administer the peptide as a viable therapeutic, we can use this platform to design antibacterials toward other lung pathogens,” Medina said.

The National Institutes of Health supported this work.

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Materials provided by Penn State. Original written by Ashley J. WennersHerron. Note: Content may be edited for style and length.

The research sought to understand how P. gingivalis colonizes the mouth. The pathogen is unable to produce its own growth molecules until it achieves a large population in the oral microbiome (the community of microorganisms that live on and inside the body).

The answer: It borrows growth molecules from V. parvula, a common yet harmless bacteria in the mouth whose growth is not population dependent.

In a healthy mouth, P. gingivalis makes up a miniscule amount of the bacteria in the oral microbiome and cannot replicate. But if dental plaque is allowed to grow unchecked due to poor oral hygiene, V. parvula will multiply and eventually produce enough growth molecules to also spur the reproduction of P. gingivalis.

More than 47% of adults 30 and older have some form of periodontitis (also known as gum disease), according to the Centers for Disease Control and Prevention. Understanding the relationship between P. gingivalis and V. parvula will help researchers create targeted therapies for periodontitis, says Patricia Diaz, DDS, PhD, lead investigator on the study and Professor of Empire Innovation in the UB School of Dental Medicine.

“Having worked with P. gingivalis for nearly two decades, we knew it needed a large population size to grow, but the specific processes that drive this phenomenon were not completely understood,” says Diaz, also director of the UB Microbiome Center. “Successfully targeting the accessory pathogen V. parvula should prevent P. gingivalis from expanding within the oral microbial community to pathogenic levels.”

The study, which was published on Dec. 28 in the ISME Journal, tested the effects of growth molecules exuded by microorganisms in the mouth on P. gingivalis, including molecules from five species of bacteria that are prevalent in gingivitis, a condition that precedes periodontitis.

Of the bacteria examined, only growth molecules secreted by V. parvula enabled the replication of P. gingivalis, regardless of the strain of either microbe. When V. parvula was removed from the microbiome, growth of P. gingivalis halted. However, the mere presence of any V. parvula was not enough to stimulate P. gingivalis, as the pathogen was only incited by a large population of V. parvula.

Data suggest that the relationship is one-directional as V. parvula received no obvious benefit from sharing its growth molecules, says Diaz.

“P. gingivalis and V. parvula interact at many levels, but the beneficiary is P. gingivalis,” says Diaz, noting that V. parvula also produces heme, which is the preferred iron source for P. gingivalis.

“This relationship that allows growth of P. gingivalis was not only confirmed in a preclinical model of periodontitis, but also, in the presence of V. parvula, P. gingivalis could amplify periodontal bone loss, which is the hallmark of the disease,” says George Hajishengallis, DDS, PhD, co-investigator on the study and Thomas W. Evans Centennial Professor in the University of Pennsylvania School of Dental Medicine.

“It is not clear whether the growth-promoting cues produced by P. gingivalis and V. parvula are chemically identical,” says Diaz. “Far more work is needed to uncover the identity of these molecules.”

Additional investigators include Anilei Hoare, PhD, assistant professor, University of Chile; Hui Wang, PhD, postdoctoral researcher, University of Pennsylvania; Archana Meethil, resident, University of Connecticut; Loreto Abusleme, PhD, assistant professor, University of Chile; Bo-Young Hong, PhD, associate research scientist, Jackson Laboratory for Genomic Medicine; Niki Moutsopoulos, DDS, PhD, senior investigator, National Institute of Dental and Craniofacial Research; and Philip Marsh, PhD, professor, University of Leeds.

The research was funded by the National Institute of Dental and Craniofacial Research of the National Institutes of Health.

But how much pressure can they stand? The 2014-2016 North Pacific marine heatwave, known as the Blob, led to a harmful algal bloom of unprecedented scale. It necessitated substantial delays in the opening of the 2015-16 U.S. West Coast Dungeness crab fishery. The fishery is vital to West Coast communities. It produces around 26 percent of all annual fishing revenue and supports more than 30 percent of all commercial fishing vessels.

Understanding Impacts from Climate Shocks

Previous studies have documented the devastating economic impacts from the 2015-16 event on Dungeness crab fishermen. Members of affected coastal communities attest that these socioeconomic effects rippled through associated industries and coastal communities. But can changes in fishing practices in response to this significant climate shock be quantified?

“We wanted to examine the extent to which the Dungeness crab fishery delays affected participation in other fisheries, and the duration of those changes,” said Mary Fisher, a doctoral student at the University of Washington. Fisher did the work as a National Science Foundation Graduate Research Internship Program Fellow at NOAA’s Northwest Fisheries Science Center.

Fisher and her colleagues at NOAA Fisheries, University of Washington, and Oregon State University studied the impacts on more than 2,500 vessels across seven California fishing communities. The researchers wanted to see how a climate-related shock (like the heatwave and associated harmful algal bloom) can impact communities’ use of ocean resources.

The researchers used 10 years of fishery landings data to map resource use networks for seven California port groups where Dungeness crab is an important revenue source. The networks visualize the portfolio of fisheries that a community harvests and how vessels move between fisheries. The network visualization is similar to a food web, except that the connections represent harvest by fishing vessels rather than predator-prey relationships.

Resilient Fishing Communities

Researchers found that 71 percent of California Dungeness crab fishing vessels temporarily left the industry and stopped fishing altogether during the delays. The two other strategies that fishermen used to cope with the disruption were:

• Participating in other fisheries that were not affected by the harmful algal bloom.
• Moving out of delayed areas to fish in other more favorable locations.

These strategies significantly changed communities’ resource use patterns, but some communities were more affected by the climate shock than others. Researchers could predict which communities would be least sensitive to the shock by looking at their resource use patterns before the 2015-16 season.

These communities, located in central California, were less dependent on Dungeness crab and had shorter fishery delays. In these communities, fishermen had access to more open fisheries during the winter months and were more flexible in how they fished previously. These characteristics provided more options, buffering fishermen from the disruption to the Dungeness crab fishing season.

No matter how central Dungeness crab was to a community’s fisheries portfolio, the researchers didn’t observe any significant, lasting changes in how vessels participated in fisheries after the closures lifted. This suggests fishing communities may mostly return to “normal” fishing practices relatively quickly after short-term disturbances like climate shocks, provided those changes don’t pile up one after the other.

Access to Other Fisheries and Ports Important

The results highlight the importance of nearshore groundfish fisheries like sablefish, rockfish, and lingcod as alternatives to the Dungeness crab fishery. “Most of the crab vessels that stayed out on the water were using pot or hook-and-line gear to fish groundfish,” says Fisher. “I think we can expect access to these fisheries to continue to be important during crab season delays.”

Fishermen with larger vessels also landed their catch at different ports, a strategy less common among smaller vessels. This was possible in part because regulations only restricted fishing in delayed areas at the district level. In 2018, the California Department of Fish and Wildlife amended these rules, called the Fair Start Provisions. The amendments provide more protection to fishermen at a finer scale than districts in the event of future delays.

These results may open up a relatively easy method for early detection of cognitive decline in this population, providing better ways to understand, diagnose and ultimately treat the decline, said George L. King, MD, Joslin’s Chief Scientific Officer and senior author on a paper about the study in the Journal of Clinical Endocrinology & Metabolism.

Previous research had demonstrated an association between proliferative diabetic retinopathy (PDR, a complication of diabetes that can severely damage eyesight) and cognitive impairment in people with type 1 diabetes. “Since we knew that there were cellular changes in the retina that might reflect changes in the brain, we were interested to see whether imaging techniques that visualize those changes in the retina might be reflective of changes in cognitive functions,” said Ward Fickweiler, MD, a Joslin postdoctoral fellow and first author on the paper.

The scientists drew on eye scans routinely gathered from patients as part of normal vision care at Joslin’s Beetham Eye Institute. One set of scans was based on optical coherence tomography (OCT, a technique employing light to provide cross-sections of the retina). A second set of scans employed OCT angiography (OCTA, an extension of OCT technology that examines blood vessels in the retina). Both types of scans are non-invasive and widely available in eye clinics in the United States, and can be performed within minutes.

The study enlisted 129 participants in the Joslin Medalist Study, which examines outcomes among people who have had type 1 diabetes for 50 years or longer. These volunteers took a series of cognitive tests that included tasks probing memory function as well as psychomotor speed (assessing the time it took to arrange objects by hand).

Strikingly, the researchers found very strong associations between performance on memory tasks and structural changes in deep blood vessel networks in the retina. “Memory is the main cognitive task that is affected in Alzheimer’s disease and cognitive decline, so that was exciting,” Fickweiler said.

The Joslin team also discovered strong associations between PDR and psychomotor speed. This finding reinforced earlier outcomes that had been identified among a smaller group of Joslin Medalists, and provided details about related changes in retinal structure. Additionally, the researchers saw that PDR was associated with memory performance among the larger group of Medalists.

While these results need to be confirmed in larger clinical investigations, the routine eye exams do seem to detect the cognitive changes happening in people with diabetes, said Fickweiler.

Currently, other ways to detect conditions such as Alzheimer’s disease such as MRI scans are difficult and expensive. People typically are tested only when they’re showing symptoms of cognitive decline and treatments at that stage generally don’t offer much help.

“If you can detect the condition at an earlier stage, when they’re still asymptomatic, that may benefit patients,” Fickweiler said. Earlier detection also could aid the quest to develop better therapies for neurocognitive diseases.

The Joslin team plans to launch a larger prospective study to confirm the potential of eye imaging to pick up signs of cognitive decline over time. This research will include people with type 1 diabetes who are younger and haven’t had the disease for as long as the Medalists. The scientists also will analyze MRI brain images and postmortem brain samples donated by Medalists.

Additionally, the investigators will look for common mechanisms that may inflict damage on brain and retina tissues, which share much of their early embryonic development pathways. Likely suspects in people with diabetes include impaired blood vessels and high or low levels of blood glucose. The autoimmunity that drives type 1 diabetes also might inflict other forms of harm, King said.

Notably, Joslin Medalists often display relatively low levels of the complications that can afflict those with long-term type 1 diabetes. For instance, almost half of Medalists don’t develop advanced eye disease, and only one of the 129 Medalists in the eye-scan study may have Alzheimer’s disease. “It is possible that in the Medalists, a shared mechanism alters the progression of the early stages of retinal and brain neurodegeneration, and provides protection against both PDR and Alzheimer’s disease,” Fickweiler speculated.

In addition to follow-up work in type 1 diabetes, King and his team plan to perform a similar study for people with type 2 diabetes. PDR also is associated with cognitive decline in this much larger group of patients, who also get OCT and OCTA eye scans as part of their regular vision care.

The paper’s co-authors include Joslin’s Emily Wolfson, Samantha Paniagua, Atif Adam, Vanessa Bahnam, Konstantina Sampani, I-Hsien Wu, Gail Musen, Lloyd Aiello, Hetal Shah and Jennifer Sun. Marc Yu of Harvard Medical School also contributed.

Funding came from the Dianne Nunnally Hoppes Fund; the Beatson Pledge Fund; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Eye Institute; the National Institutes of Health; JDRF; and the American Diabetes Association.