Myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS), is a mysterious disease that leaves victims with a debilitating lack of energy, as well as other symptoms such as pain, disrupted sleep, and brain fog. There is no definitive test for diagnosis and no cure. Approximately three million people in the United States, mostly women, are estimated to have ME/CFS, and at least 20 million people suffer from it worldwide.
“People with this disease are very ill,” says Maureen R. Hanson, Molecular Biology and Genetics. “Some are so sick they can’t get out of bed, can’t eat normally, and have to be tube fed. Yet it’s seriously underfunded and under researched.”
Hanson, who previously had worked on gene expression in plants, primarily, developed an interest in ME/CFS after her son was diagnosed with the disease. She began research on ME/CFS 11 years ago. “I attended scientific conferences on ME/CFS and noticed there was very little molecular biology being done on the disease,” she says. “I felt even though I worked on plant molecular biology, I could contribute to research on ME/CFS because plant gene expression is not very different from human gene expression.”
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Hanson founded the Cornell Center for Enervating NeuroImmune Disease, which is dedicated to promoting research on ME/CFS, and she is the center’s director. She is engaged in a number of research projects, looking at how ME/CFS affects the immune system. This research has a particular emphasis on extracellular vesicles (EVs)—particles carrying proteins, RNA, lipids, and metabolites that are naturally released by most cells in the body, including immune cells. “EVs have only recently been discovered,” Hanson says. “They seem to be a mechanism for signaling between cells. They contain proteins—especially cytokines, which are signaling proteins. One cell secretes a cytokine that goes to another cell that secretes a cytokine, and so on. It’s a cascading effect.”
“I felt even though I worked on plant molecular biology, I could contribute to research on ME/CFS because plant gene expression is not very different from human gene expression.”
Hanson and her colleagues are particularly interested in the role EVs may play in one of ME/CFS’s most debilitating aspects: post-exertional malaise, an increase in symptoms following physical or mental exertion. The researchers compared blood samples from ME/CFS patients with those from a healthy control group, looking for differences in cytokines.
“We found a problem with the cytokine communication process in ME/CFS,” Hanson says. “We now know there’s something going on with the immune system. There’s a dysregulation there as indicated by altered cytokine correlations in plasma and in EVs.”
The researchers are carrying out further studies seeking to identify how EV content, including cytokines, RNA, and other proteins, change during exercise and during post-exertional malaise. “We hope to find a signal in the immune response that is either causing or is a consequence of something that is causing post-exertional malaise,” Hanson says. “We’re also looking to see if a particular immune cell is driving the symptoms of ME/CFS.”
Genetically Engineering More Efficient Plant Photosynthesis
Before she became involved in ME/CFS research, Hanson built her career around plant biology, an area of study she still pursues. Among her many plant-related projects are two aimed at improving photosynthesis in plants. The research is timely because the world’s population is growing, but traditional plant breeding has run out of ways to increase crop yields.
“There’s been very little improvement because plants breeders are running out of natural variation,” Hanson says. “Better photosynthesis is something that could increase yields, but how do you select for photosynthesis if you’re a plant breeder? Previously you couldn’t go out in a field and say, ‘That plant is doing better photosynthesis.’ But maybe we can actually genetically engineer better photosynthesis.”
Toward that end, the Hanson group is working with Martin Parry, Lancaster University, and Michael Blatt, University of Glasgow, to optimize ribulose bisphosphate carboxylase/oxygenase (RuBisCO), one of the major enzymes that fixes carbon in photosynthesis. RuBisCO has a number of problems. To begin with, it is very slow. The enzyme only fixes three molecules of carbon dioxide per second while other enzymes engaged in other reactions might affect a thousand molecules a second. RuBisCO can also mistakenly react with oxygen, which results in a loss of energy. “When RuBisCO evolved eons ago, there was very little oxygen in the atmosphere,” Hanson says. “Now we have a lot, and the enzyme has problems discriminating between carbon dioxide and oxygen.”
The researchers were inspired by cyanobacteria, also known as blue-green algae, a microorganism which makes microcompartments called carboxysomes that concentrate carbon dioxide near RuBisCO to optimize the enzyme’s action. “In cyanobacteria the carboxysomes give RuBisCO less chance of reacting by mistake with oxygen,” Hanson says. “But carboxysomes don’t exist in plants. We want to introduce them into plant chloroplasts to make RuBisCO function more efficiently.”
Hanson and her colleagues put the cyanobacteria genes that create carboxysomes into tobacco plants, the preferred test plant for bioengineering experiments. “We expressed some of these genes, and we got little microcompartments,” Hanson says. “They’re not yet functional, but we’re working on it.”
Carbon Dioxide Specificity in Plants
The researchers are also looking at ways to mutagenize RuBisCO so that it has a higher specificity for carbon dioxide or becomes faster at fixing carbon, or both. Building on the work of other researchers who first expressed the RuBisCO enzyme in Escherichia coli (E coli), Hanson and her colleagues have tested all the genes that encode tobacco RuBisCO and its assembly factors in E coli, and have achieved production of active enzymes. Currently they are mutating tobacco RuBisCO in E coli, in an attempt to find enzymes with better properties than the original. “When we find one we like, we’ll take those mutagenized genes and put them back into tobacco to see if it improves carbon dioxide specificity or the enzyme’s speed,” Hanson says.
Hanson’s dual research interests in plant biology and the pathophysiology of ME/CFS may seem disparate, but both depend on modern methods for examining genome sequences and gene expression, she points out. Then, too, both Hanson’s graduate work in plant biology and her plant research at Cornell took place outside traditional plant departments.
“I’ve always been the odd person working on plants in the biology department,” she says. “As a result, I was exposed to a lot of nonplant work that made it easier to start working on biomedical questions. When it comes to ME/CFS, I intend to keep working on it until there is a breakthrough in the field that will give more direction as to where the research should go. I feel we’re on the cusp of that breakthrough. It’s getting closer.”