Symbiosis and cancer are totally different fields in biology – or so we used to believe. But our recent discoveries on the symbiosis between spittlebug insects and their bacteria changed our minds. Our lab studies symbiotic interactions between insects and certain bacteria that they have relied on for more than one hundred million years to produce nutrients that are in short supply in the insect’s diet. These insects feed on plant sap that flows in the plant xylem and phloem vessels. Both xylem and phloem sap are poor food sources, especially deficient in certain amino acids, and predicted to be unable to support the growth of any animal. We wanted to understand exactly how certain insects and bacteria work together to produce high-quality amino acids from the low-quality food the insects feed on. We recently discovered that one of the insects we work with, the dogwood spittlebug, uses a metabolic “trick” known as the Warburg effect to facilitate the production of amino acids by the insect’s bacterial partners. The Warburg effect is a hallmark of cancer cells, enabling them to grow fast and overcome the constraints that keep normal cells of the body in check. In the Warburg effect, also known as aerobic glycolysis, cells consume large amounts of the sugar glucose but do not oxidize the glucose completely, even though there is plenty of oxygen. The partial breakdown of glucose (glycolysis) yields valuable building blocks for amino acid synthesis and cell growth.
But let us start at the beginning which – for us – was the spittlebugs.
How common and widespread are spittlebugs in nature?
Spittlebugs can be found almost everywhere in the world. You can even find them in your backyard on almost any plant! In temperate climates, they are easy to identify in the spring months because they cover themselves in a spittle made from their xylem sap food and this spittle is very obvious on the underside of leaves and on branches of shrubs and plants. The spittle bubbles protect spittlebugs from predators and drying out from exposure to the elements.
How does the dogwood spittlebug use the Warburg effect in amino acid production?
The dogwood spittlebug has two intracellular bacterial partners Sulcia and Zinderia housed inside separate spittlebug organs called bacteriomes, and provide complementary sets of amino acids that the spittlebug needs to grow. The two bacteriomes exhibit high rates of aerobic glycolysis to generate precursors for amino acid synthesis, and these products are handed over to the bacteria. In addition, certain glycolytic products, pyruvic acid and lactic acid, are also exchanged between the bacteriomes, enabling the insect cells to produce energy more efficiently. This is very important because their diet of xylem sap is exceptionally nutrient-poor.
How did we discover this similarity with cancer metabolism?
It is a long story. We needed lots of spittlebugs, and we were lucky to find large populations of these insects in the vegetation around Beebe Lake on the Cornell University campus. Then we had to design our experiments, and a bagel shop in Ithaca hosted some key discussions with our chemistry collaborators. And, most of all, we are grateful to lab members who helped the authors to collect the spittlebugs and set up the organ cultures for experiments, to Jason Dombroskie in the Cornell University Insect Collection for help with insect identification, and to our colleagues in the Aristotle Cloud Federation and Cornell Center for Advanced Computing who facilitated the computer resources we needed for our metabolic modeling. Our great colleagues who helped us are mentioned in the Acknowledgements of our paper.
How widespread is the Warburg effect among insect symbioses?
We don’t know the answer to this question! To our knowledge, our article the first demonstration of aerobic glycolysis as a strategy to facilitate amino acid production in symbioses, although other insects that don’t have these symbiotic bacteria are known to use Warburg metabolism for fast growth. We are currently conducting additional studies in other insect symbioses to investigate whether the symbiotic Warburg effect is general in plant sap feeding insects.