Because humans and animals breathe and metabolize oxygen, they generate a variety of reactive oxygen species (ROS), or cell-damaging oxidants, as byproducts. Our bodies usually make enough antioxidants to counter that damage, but when that balance starts to favor oxidants, they can attack important biomolecules like proteins, nucleic acids, and lipids. That can lead to cancer, neurodegenerative disorders, and cardiovascular diseases.

Fortunately, our bodies evolved to produce antioxidant enzymes such as Cu/Zn (copper/zinc) superoxide dismutase, or SOD1, which detoxifies certain harmful oxidants. In a weird twist, SOD1 is the only antioxidant enzyme that can take on one specific oxidant, superoxide, only to produce another ROS: hydrogen peroxide.

A team of Georgia Tech researchers have published a study that found an even stranger twist to this oxidant-antioxidant tale: SOD1 (good for cells) produces hydrogen peroxide (bad for cells) which stimulates the production of another important cellular antioxidant known as NADPH (also good for cells; more on this in a moment.)

“Yes, you heard that right,” says Amit Reddi, associate professor in the School of Chemistry and Biochemistry. “SOD1, an antioxidant enzyme, produces an oxidant, hydrogen peroxide, which in turn stimulates the production of another (good) antioxidant.”

Reddi is a co-author of this research along with Matthew Torres, associate professor in the School of Biological Sciences; Claudia Montllor-Albalate, former Reddi Lab member who received her Ph.D. in 2020 from the School of Chemistry and Biochemistry; Hyojung Kim, School of Chemistry and Biochemistry Ph.D. candidate; Annalise Thompson, a third-year graduate student in Reddi’s lab; and Alex Jonke, research scientist with the School of Biological Sciences. 

Their study, “SOD1 Integrates Oxygen Availability to Redox Regulate NADPH Production and the Thiol Redoxome” is published in the Proceedings of the Natural Academy of Sciences (PNAS).

The NADPH/GAPDH connection

NADPH (nicotinamide adenine dinucleotide phosphate) is an important metabolite that is produced in cells. It provides a source of electrons that can act as an antioxidant and for the biosynthesis of numerous biomolecules, including fatty acids, amino acids, nucleotides, and cholesterol. 

“NADPH is not only used as an antioxidant, but also to build new biomolecules to sustain cell proliferation,” Reddi says. “How do cells know to make enough NADPH to support aerobic life?  We discovered that SOD1 senses oxygen availability via superoxide, and then converts this to hydrogen peroxide, which in turn inactivates an enzyme responsible for the breakdown of glucose, glyceraldehyde phosphate dehydrogenase (GAPDH).” That inactivation causes the build-up of metabolites that are re-routed to a pathway that synthesizes NADPH.

The story behind the SOD1 revelation

The PNAS research study began with a casual conversation in 2014 between Reddi and Torres at the former café in the Parker H. Petit Institute for Bioengineering and Biosciences (IBB). 

“Given the very collaborative and collegial nature of faculty across the College of Sciences, and the Institute as a whole, it was easy to grab a coffee and discuss these ideas,” Reddi says. Work in the Reddi lab includes potential signaling roles for SOD1 and the hydrogen peroxide it produces; but understanding the extent to which these factors regulate signaling required a systems-level understanding of how widespread targets of SOD1 are in a cell. 

Torres focuses on mass spectrometry-based proteomics (the study of all proteins produced and modified by an organism or system) to probe cell-wide signaling networks, so it seemed to Reddi like a perfect fit.

Then, Reddi says, Montllor-Albalate made the discovery that SOD1-derived hydrogen peroxide can regulate NADPH production and adaptation to aerobic life.  Meanwhile, Kim, a joint student of the Reddi and Torres labs, drove the work to identify proteome-wide targets of SOD1-derived hydrogen peroxide. 

The conversation in IBB led to a 2016 grant from the National Institutes of Health to study the topic further. The resulting paper “we feel will make a strong impact in the field of redox biology and signaling,” Reddi adds. 

SOD1’s potential in future cancer therapy

SOD1 is often thought of as an appealing anti-cancer therapeutic because of its ability to scavenge superoxides. The theory is that if SOD1 is inactivated, cancer cells will be at a disadvantage. 

Reddi says his team’s results “suggest this very simple approach may need to be reconsidered, because the hydrogen peroxide that is produced by SOD1 plays broader roles in metabolism — and regulates many other enzymes and pathways. For instance, many cancer cells are addicted to glucose (sugars) and have an increased reliance on it for energy and metabolism, with GAPDH being a key enzyme in the process. Our findings that SOD1-derived hydrogen peroxide inactivates GAPDH would suggest that inhibiting SOD1 in certain cancers could actually result in elevated GAPDH activity, and increased metabolism of glucose, which may be detrimental in fighting cancer.”

Torres and Reddi are continuing their collaboration to investigate other aspects of SOD1 and hydrogen peroxide signaling in cancer metabolism and its implications for disease progression.

doi.org/10.1073/pnas.2023328119

This work was supported by GM118744 to Reddi and Torres, and Blanchard Fellowship to Reddi. 

Jenny McGuire plans to use the late Cenozoic fossil record in Africa — a span of 7.5 million years — to study the long-term relationships between animals, their traits, and how they respond to changes in their environments. The goal is to use the data to forecast future changes and help inform conservation biology decisions for the continent.

McGuire, an assistant professor with joint appointments in the School of Earth and Atmospheric Sciences and School of Biological Sciences at Georgia Tech, and her Spatial Ecology & Paleontology Lab are teaming up with an international cohort of researchers for the effort, which includes scientists from Texas A&M University, University of Cambridge, and the National Museums of Kenya. The work is jointly funded by the National Science Foundation (US NSF) and the National Environment Research Council (NERC), part of UK Research & Innovation (UKRI), a new body which works in partnership with universities, research organizations, businesses, charities and government “to create the best possible environment for research and innovation to flourish.”

McGuire says the team hopes to learn more about which functional traits vertebrates (animals with backbones) have that closely relate to shifting factors at a given location like temperature, rain and other precipitation, and their natural environment — and how those changes have occurred as environments and humans evolved.

“Community-level trait calculations correlate with specific environmental conditions,” McGuire says. “For example, in places or times when there is less precipitation, mammal communities overall will have more robust, rugged, resistant teeth. And the ankle gear ratios of mammals living in open versus more enclosed habitats reflect this condition, since animals living in more open habitats typically need to run faster.”

McGuire says Africa offers a crucial natural laboratory for these types of conservation paleobiological studies, noting a rich, well-sampled fossil record. The continent is also home to a diverse range of vertebrate ecosystems, including the most complete natural community of remaining terrestrial megafauna: large animals that include the “big five” of Africa — elephants, giraffes, hippopotamuses, rhinoceroses, and large bovines like wildebeests, antelopes, and water buffaloes.

“Critically, these megafauna are facing increasing pressures from global economic demands leading to habitat loss, as well as from changing climates,” McGuire shares.

Michelle Lawing, an associate professor in Texas A&M’s Department of Ecology and Conservation Biology, is the lead institution principal investigator for the project, and McGuire is the collaborating institution’s principal investigator. Fredrick Kyalo Manthi, co-principal investigator, is director of Antiquities, Sites, and Monuments and a senior research scientist in the Department of Earth Sciences at the National Museums of Kenya in Nairobi. Jason Head, NERC principal investigator, is a professor in the Department of Zoology at the University of Cambridge.

Responding to changing climates and environments

Related research into how communities have evolved over time, and how they’ve been impacted by terrain, animal migration, and climate change, has taken McGuire to Wyoming’s Natural Trap Cave for five of the past seven summers. There, the so-called “pit” or sinkhole cave trapped animals for millennia, leaving only their bones and other fossils remaining to tell their stories to McGuire and fellow researchers about life there more than 35,000 years ago.

“What we’re really looking at is how communities shift across the landscape,” McGuire shared in an earlier interview about the work. “So, if we have glaciers that are coming really far south in North America, how does that drive the distributions of species on the landscape and where they’re living, and whether or not there’s new communities or total remixing of communities, or if communities just shift in a uniform way?

“We’re really trying to understand how animals respond to changing climate and changing environments, so that we can get a better sense of how they’ll respond to increased warming and climate change that’s occurring today.”

Positive trait to environment relationships — and a negative one

When it comes to an example of a good trait-environment relationship involving animals, McGuire cites the role that elephants play in Africa — something mastodons also did in North America before their extinction.

“Elephants help maintain savanna habitats,” McGuire says, referring to the giants’ relationships with Africa’s grassland regions. “They control trees along the perimeters of forests, preventing them from expanding into, and taking over, savanna habitats.”

Similarly, in ancient North American ecosystems, the loss of the mammoth, along with climate change, is thought to have resulted in the loss of the mammoth steppe ecosystem, “a no-analog, widespread Arctic shrubland that went extinct as a biome (a community of plants and animals) around the time of North American megafauna extinction,” McGuire says.

The new project’s outreach efforts

The US NSF and UK NERC funding for the project also includes student outreach and mentoring for early career academics. The project’s broader impact goals include measures to support inclusivity and diversity in science, high-impact training experiences for students and postdoctoral researchers, application of the researcher’s modeling framework for applied conservation, and meaningful engagement with the public.

“This international collaborative project will also help train both Kenyan and American (and) European students, thus establishing another generation of researchers,” National Museums of Kenya’s Fredrick Kyalo Manthi says.

“We plan to pair travel and research objectives with workshops so that workshop students get to directly participate in research, and serve as co-authors on projects as appropriate,” McGuire adds.

***

Funding: NSFDEB-NERC Award #2124770; NSF CAREER Award #1945013; International Union of Biological Sciences: Conservation Paleobiology in Africa Program.

***

The Georgia Institute of Technology, or Georgia Tech, is a top 10 public research university developing leaders who advance technology and improve the human condition. The Institute offers business, computing, design, engineering, liberal arts, and sciences degrees. Its nearly 44,000 students representing 50 states and 149 countries, study at the main campus in Atlanta, at campuses in France and China, and through distance and online learning. As a leading technological university, Georgia Tech is an engine of economic development for Georgia, the Southeast, and the nation, conducting more than $1 billion in research annually for government, industry, and society.

As of this week, the omicron variant makes up the majority of new coronavirus cases in the U.S. Omicron is more contagious than previous variants and has caused a spike in cases across the nation, including locally.

The same prevention measures that have been put in place previously can still help slow the spread of this variant — vaccination, wearing a face covering, physical distancing, and regular surveillance testing. A well-fitting mask with good filtration is a strong defense for when you are out in public, even if you are fully vaccinated.

As the campus community looks toward winter break, Georgia Tech encourages all students, faculty, and staff to get fully vaccinated, including a booster shot. Campus vaccination clinics will resume in January; to find a vaccination site before that, visit vaccines.gov. Vaccines help reduce the risk of severe illness and hospitalization.

Anyone with Covid-19 symptoms — even mild ones — should get tested and wait for a negative result before interacting with others. Testing on campus is closed through winter break and will resume Tuesday, Jan. 4, 2022. Until then, you can find an alternate testing site.

We recommend all students, faculty, and staff plan to get tested off-campus before returning for the spring semester, and we recommend each person test again on campus upon their return. Campus testing sites will reopen at full capacity on Jan. 4th to accommodate those returning to campus.

Black soldier fly larvae devour food waste and other organic matter and are made of 60% protein, making them an attractive sustainable food source in agriculture. But increasingly, black soldier larvae are dying before they reach livestock facilities as animal feed. 

Georgia Tech researchers, recognizing the culprit is the collective heat generated when the maggots eat in crowded conditions, have found that delivering the right amount of airflow could help solve the overheating issue. Their findings were published this month in Frontiers in Physics as part of a special issue on the “Physics of Social Interactions.”

“Black soldier fly larvae are widely used in an emerging food-recycling industry. The idea is to feed the larvae with food waste and then turn them into chicken feed,” explained first author Hungtang Ko, a Ph.D. student in the George W. Woodruff School of Mechanical Engineering.  “These larvae make a great candidate for this process because they eat just about everything.”

Each year humans waste more than one billion tons of food, or a third of all food production, and many countries are running out of options for disposing of this waste.

The larvae thrive in and around compost piles, where their larvae help break down organic material, from rotten produce to animal remains and manure. Black soldier fly larvae commonly grow to about 1,000 times their size, noted David Hu, professor in the School of Mechanical Engineering.

“It’s like going from the size of a person to the size of a big truck,” he said of the larvae’s growth from eggs to adults.

Hu has appeared on Science Friday graphically showing the voracious appetite of black soldier fly larvae, which can eat twice their body mass in food per day. But when these maggots feed while tightly packed in container bins, they generate metabolic heat that collectively can turn lethal for them.

Air Flow Matters

Ko and Hu collaborated with Daniel Goldman, Dunn Family Professor in the School of Physics, to set up the experiments. Goldman uses fluidized beds —widely used in industrial applications like oil refining ― to control properties of granular media in animal and robot locomotion studies. Fluidized beds operate by forcing a vertical flow of fluid through a collection of particulate matter; above a certain flow rate, the grains transition from a solid pile to a fluid-like arrangement, where they collide and jostle.  

The researchers placed the larvae in a container subjected to regular air flow at a consistent temperature. They then attached a leaf blower to supply air flow into the chamber, manually ramping up and down the air speed in five-minute trials.

Because of the larvae’s constant activity, the collectives’ behavior under air fluidization differs from what is observed in traditional fluidized beds: larvae were un-jammable when air flow became low. Instead, they behave like a fluid that adapted and adjusted to external forces.

“An interesting aspect of this work is that it probes a regime of ‘active matter,’ which has received less attention from physicists: Instead of 3D swarms composed of widely separated, non-colliding flying birds and insects, our `swarm’ exists in another regime, where animals are packed tightly together,” Goldman said.

In a second experiment, the team used x-ray imaging and constant air speed to see how fast larvae eat. Specifically, Ko measured the average velocity and pressure of the larvae, as well as how much food they ate under various airflow speeds.

“As you continue to increase the flow, you’ll reach a point where all the larvae are flying [through the air]. The airflow is too fast, and they won’t eat well,” he said.   

Optimal air velocity will ensure the larvae are cooled off properly and can still feed effectively. “Probing optimal flow velocity will be a good next step. Also, from an engineering perspective, we need to consider other ways that we can cool the larvae down, including using heat transfer,” he added. 

The results indicated that as larvae are agitated by rapid flows, the insects are more likely to be suspended in mid-air without contacting the food, suggesting that a moderate flow rate would be optimal for feeding dense groups of larvae.

The researchers also hope this work will enable black soldier fly larvae to be more readily available as recyclers of food waste, which totals 1.3 billion tons per year, according to the Food and Agriculture Organization of the United Nations. But just as important is the potential of these protein-rich insects to reduce the carbon effects of feeding animals. Global food production contributes more than 17 billion metric tons of human-made greenhouse gas emissions every year, according to a study published in September in Nature Food. Animal-based foods produce more than twice the emissions of plant-based food, the study found. 

“There's no sustainable protein source for the animals that we eat,” noted Ko. “The black soldier fly larvae could play a role in reducing the environmental impact of feeding these animals.”

CITATION: H. Ko, et. all, “Air-Fluidized Aggregates of Black Soldier Fly Larvae,” (Frontiers in Physics, 2021) https://doi.org/10.3389/fphy.2021.734447

Cancer chemotherapy has undergone a paradigm shift in recent years with traditional treatments like broad-spectrum cytotoxic agents being complemented or replaced by drugs that target specific genes believed to drive the onset and progression of the disease.

This more personalized approach to chemotherapy became possible when genomic profiling of individual patient tumors led researchers to identify specific "cancer driver genes" that, when mutated or abnormally expressed, led to the onset and development of cancer.

Different types of cancer — like lung cancer versus breast cancer — and, to some extent, different patients diagnosed with the same cancer type — show variations in the cancer driver genes believed to be responsible for disease onset and progression. “For example, the therapeutic drug Herceptin is commonly used to treat breast cancer patients when its target gene, HER-2, is found to be over-expressed,” says John F. McDonald, professor in the School of Biological Sciences.

McDonald explains that, currently, the identification of potential targets for gene therapy relies almost exclusively on genomic analyses of tumors that identify cancer driver genes that are significantly over-expressed.

But in their latest study, McDonald and Bioinformatics Ph.D. student Zainab Arshad have found that another important class of genetic changes may be happening in places where scientists don’t normally look: the network of gene-gene interactions associated with cancer onset and progression.

“Genes and the proteins they encode do not operate in isolation from one another,” McDonald says. “Rather, they communicate with one another in a highly integrated network of interactions.”

“What I think is most remarkable about our findings is that the vast majority of changes — more than 90% — in the network of interactions accompanying cancer are not associated with genes displaying changes in their expression,” adds Arshad, co-author of the paper. “What this means is that genes playing a central role in bringing about changes in network structure associated with cancer — the ‘hub genes’ — may be important new targets for gene therapy that can go undetected by gene expression analyses.”

Their research paper “Changes in gene-gene interactions associated with cancer onset and progression are largely independent of changes in gene expression” is published in the journal iScience.

Mutations, expression — and changes in network structure

In the study, Arshad and McDonald worked with samples of brain, thyroid, breast, lung adenocarcinoma, lung squamous cell carcinoma, skin, kidney, ovarian, and acute myeloid leukemia cancers — and they noticed differences in cell network structure for each of these cancers as they progressed from early to later stages.

When early-stage cancers develop, and stayed confined to their body tissue of origin, they noted a reduction in network complexity relative to normal pre-cursor cells. Normal, healthy cells are highly differentiated, but as they transition to cancer, “[T]hey go through a process of de-differentiation to a more primitive or stem cell-like state. It’s known from developmental biology that as cells transition from early embryonic stem cells to highly specialized fully differentiated cells, network complexity increases. What we see in the transition from normal to early-stage cancers is a reversal of this process,” McDonald explains.

McDonald says as the cancers progress to advanced stages, when they can spread or metastasize to other parts of the body, “[W]e observe re-establishment of high levels of network complexity, but the genes comprising the complex networks associated with advanced cancers are quite different from those comprising the complex networks associated with the precursor normal tissues.”

“As cancers evolve in function, they are typically associated with changes in DNA structure, and/or with changes in the RNA expression of cancer driver genes. Our results indicate that there’s an important third class of changes going on — changes in gene interactions — and many of these changes are not detectable if all you’re looking for are changes in gene expression.”

DOI: https://doi.org/10.1016/j.isci.2021.103522

Acknowledgments: This research was supported by the Mark Light Integrated Cancer Research Center Student Fellowship , the Deborah Nash Endowment Fund , and the Ovarian Cancer Institute (Atlanta), where John F. McDonald serves as chief research officer. The results shown here are based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/.

About Georgia Institute of Technology

The Georgia Institute of Technology, or Georgia Tech, is a top 10 public research university developing leaders who advance technology and improve the human condition. The Institute offers business, computing, design, engineering, liberal arts, and sciences degrees. Its nearly 40,000 students representing 50 states and 149 countries, study at the main campus in Atlanta, at campuses in France and China, and through distance and online learning. As a leading technological university, Georgia Tech is an engine of economic development for Georgia, the Southeast, and the nation, conducting more than $1 billion in research annually for government, industry, and society.