Severe and persistent disability often undermines the life-saving benefits of cancer treatment. Pain and fatigue — together with sensory, motor, and cognitive disorders — are chief among the constellation of side effects that occur with the platinum-based agents used widely in chemotherapy treatments worldwide.

A new study by Georgia Tech researchers in the lab of Timothy C. Cope has found a novel pathway for understanding why these debilitating conditions happen for cancer patients and why scientists should focus on all of the possible neural processes that deliver sensory or motor problems to a patient’s brain — including the central nervous system — and not just the “peripheral degeneration of sensory neurons” that occurs away from the center of the body.

The new findings “Neural circuit mechanisms of sensorimotor disability in cancer treatment” are published in the Proceedings of the National Academy of Sciences (PNAS) and could impact development of effective treatments that are not yet available for restoring a patient’s normal abilities to receive and process sensory input as part of post cancer treatment, in particular.

Stephen N. (Nick) Housley, a postdoctoral researcher in the School of Biological Sciences, the Integrated Cancer Research Center, and the Parker H. Petit Institute for Bioengineering and Bioscience at Georgia Tech, is the study’s lead author. Co-authors include Paul Nardelli, research scientist and Travis Rotterman, postdoctoral fellow (both of the School of Biological Sciences), along with Timothy Cope, who serves as a professor with joint appointments in the School of Biological Sciences at Georgia Tech and in the Coulter Department of Biomedical Engineering at Emory University and Georgia Tech.

Neurologic consequences

“Chemotherapy undoubtedly negatively influences the peripheral nervous system, which is often viewed as the main culprit of neurologic disorders during cancer treatment,” shares Housley. However, he says, for the nervous system to operate normally, both the peripheral and central nervous system must cooperate.

“This occurs through synaptic communication between neurons. Through an elegant series of studies, we show that those hubs of communication in the central nervous system are also vulnerable to cancer treatment’s adverse effects,” Housley shares, adding that the findings force “recognition of the numerous places throughout the nervous system that we have to treat if we ever want to fix the neurological consequences of cancer treatment — because correcting any one may not be enough to improve human function and quality of life.”

“These disabilities remain clinically unmitigated and empirically unexplained as research concentrates on peripheral degeneration of sensory neurons,” the research team explains in the study, “while understating the possible involvement of neural processes within the central nervous system. The present findings demonstrate functional defects in the fundamental properties of information processing localized within the central nervous system,” concluding that “long-lasting sensorimotor and possibly other disabilities induced by cancer treatment result from independent neural defects compounded across both peripheral and central nervous systems.”

Sensorimotor disabilities and ‘cOIN’

The research team notes that cancer survivors “rank sensorimotor disability among the most distressing, long-term consequences of chemotherapy. Disorders in gait, balance, and skilled movements are commonly assigned to chemotoxic damage of peripheral sensory neurons without consideration of the deterministic role played by the neural circuits that translate sensory information into movement,” adding that this oversight “precludes sufficient, mechanistic understanding and contributes to the absence of effective treatment for reversing chemotherapy-induced disability.”

Cope says the team resolved this omission “through the use of a combination of electrophysiology, behavior, and modeling to study the operation of a spinal sensorimotor circuit in vivo” in a rodent model of “chronic, oxaliplatin (chemotherapy)–induced neuropathy: cOIN.”

Key sequential events were studied in the encoding of “propriosensory” information (think kinesthesia: the body's ability to sense its location, movements, and actions) and its circuit translation into the synaptic potentials produced in motoneurons.

In the “cOIN” rats, the team noted multiple classes of propriosensory neurons expressed defective firing that reduced accurate sensory representation of muscle mechanical responses to stretch, adding that accuracy “degraded further in the translation of propriosensory signals into synaptic potentials as a result of defective mechanisms residing inside the spinal cord.”

Joint expression, independent defects

“These sequential, peripheral, and central defects compounded to drive the sensorimotor circuit into a functional collapse that was consequential in predicting the significant errors in propriosensory-guided movement behaviors demonstrated here in our rat model and reported for people with cOIN,” Cope and Housley report. “We conclude that sensorimotor disability induced by cancer treatment emerges from the joint expression of independent defects occurring in both peripheral and central elements of sensorimotor circuits.”

“These findings have broad impact on the scientific field and on clinical management of neurologic consequences of cancer treatment,” Housley says. “As both a clinician and scientist, I can envision the urgent need to jointly develop quantitative clinical tests that have the capacity to identify which parts of a patient nervous system are impacted by their cancer treatment.”

Housley also says that having the capacity to monitor neural function across various sites during the course of treatment “will provide a biomarker on which we can optimize treatment — e.g. maximize anti-neoplastic effects while minimizing the adverse effects,” adding that, as we move into the next generation cancer treatments, “clinical tests that can objectively monitor specific aspects of the nervous system will be exceptionally important to test for the presence off-target effect.”

***

FUNDING: This work is supported by NIH Grants R01CA221363 and R01HD090642 and the Northside Hospital Foundation, Inc.

DOI: doi.org/10.1073/pnas.2100428118

ACKNOWLEDGMENTS: The researchers thank Marc Binder (Department of Physiology & Biophysics at University of Washington) and Todd Streelman (School of Biological Sciences at Georgia Tech) for providing useful discussions and comments on a preliminary version of the manuscript. Lead author Housley also serves as chief scientific officer for Motus Nova, a healthcare robotics and technology company.

***

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.

James Stringfellow, an employment specialist with a history of helping Atlanta-based veterans and entertainment industry staff in the workforce, has been named the first career educator for the College of Sciences.

“I am thrilled to have James join the Georgia Tech Career Center,” says Laura Garcia, director of Career Education Programs. “I hope everyone gives him a warm welcome to the Georgia Tech community.” 

Stringfellow, who began his duties on January 4, leads the following initiatives:

• Assisting students with career mapping, co-op and internships, and workforce preparedness.
• Supporting College of Sciences programs by facilitating career education events.
• Supporting College instructors with employer updates and industry trends.
• Developing employer partnerships to cultivate employment opportunities. 
• Assisting the Career Center team in meeting its community goals.

Stringfellow will be available for remote meetings from 8 a.m. to 5 p.m. on Mondays and Tuesdays. He will work out of Room 2-90 in the Boggs Building from 8 a.m. to 5 p.m. Wednesdays and Thursdays, and at the Georgia Tech Career Center (located on the first floor of the Bill Moore Student Success Center) from 8 p.m. to 5 p.m. on Fridays.

Stringfellow previously worked for the Veterans Empowerment Organization (VEO) as their employment specialist responsible for assisting veterans with re-entry into the civilian workforce. Prior to the VEO, he served as an award-winning career services manager at SAE Institute where he oversaw employer outreach and graduate employment for audio, film, and entertainment business programs. Stringfellow also worked for DeVry University in both career services and admissions in support of its College of Health Sciences.  

Stringfellow earned a bachelor’s degree in Marketing from Tuskegee University, and received his MBA in International Business from Keller Graduate School of Management at DeVry. A member of Phi Beta Sigma Fraternity, Stringfellow shares that he stays connected to the entertainment industry by coaching creatives on how to protect their musical brand, speaking at related conferences, and serving as a disc jockey at various events throughout Atlanta.

“I am thrilled to have James join the College of Sciences,” shares Cameron Tyson, assistant dean for Academic Programs in the College of Sciences. 

Tyson and Garcia also extend a special thanks to the new role’s search committee for their “hard work and finding a great addition to our team.” Committee members included:

• Alonzo Whyte (search chair), academic professional, Undergraduate Neuroscience Program
• Andrew Newman, professor and undergraduate coordinator, School of Earth and Atmospheric Sciences
• Enid Steinbart, principal academic professional and director of Undergraduate Advising and Assessment, School of Mathematics
• Mariah Liggins, advisor for Pre-Health, Pre-Graduate and Pre-Professional Advising
• Mackenzie Pierce, undergraduate student, School of Psychology

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.