Elizabeth Nelson; Provided
Elizabeth Nelson; Provided

Left Turn Only: Exploring Gut Asymmetry

by Jackie Swift

Humans, like most vertebrates, are typically symmetric in appearance: we have a left and a right hand, a left and a right foot, our faces have a left and a right side that mirror each other. But inside our bodies, a different blueprint is in play. “The majority of our organs are strikingly asymmetric,” says Natasza A. Kurpios, Molecular Medicine. “There’s a fundamental reason for that. The form, the shape of the organ, reflects the function. The heart, for example, is intrinsically asymmetrical. That’s because one side pumps oxygenated blood through our bodies and the other side pumps unoxygenated blood into our lungs, and you don’t want the two to mix.”

Kurpios’ research revolves around left-right asymmetry. In particular, she focuses on the gut, or gastrointestinal (GI) tract, which is around 30 feet long in humans. In embryos, the gut tube at first forms symmetrically, then at a certain point in development begins to loop. “The gut tube not only elongates but it forms a leftward tilt that results in a counterclockwise rotation,” Kurpios explains. “It’s an ingenious process for correctly tacking this long garden hose of intestines into our abdominal cavity. But the question is, how did the cells know which way to turn? They must have signs that tell them to rotate the gut leftward.”

As a postdoctoral researcher at Harvard University, Kurpios discovered that the elusive signals that direct gut rotation in an embryo come not from the gut itself but from an adjacent connective tissue known as the dorsal mesentery (DM). “The left side of the DM becomes very short and narrow and compacted with cells,” she says. “While on the right side, the cells and cellular matrix (the microenvironment surrounding the cells) expand and become much longer. This displaces the gut tube to the left.”

The Drivers of Left-Right Asymmetry

Armed with the knowledge that the DM initiates the gut’s leftward tilt, Kurpios focused her lab at Cornell University on teasing out the biogenetic players behind this process of left-right asymmetric development. “We use the gut tube to understand how genes talk to each other in order to instruct an organ to form asymmetrically,” she says. Along with basic biological research to understand left-right asymmetry, the Kurpios lab is also contributing to the understanding of two birth defects—intestinal malrotation (where the intestines of a developing fetus do not turn properly) and volvulus (intestinal blockage connected to malrotation), both of which can be fatal unless treated in time.

Kurpios and her collaborators have focused on the gene Pitx2, a transcription factor that tells other genes what to do. Pitx2 is found only on the left side of an embryo, Kurpios explains. The researchers added the gene to the right side of chicken embryos, so it was expressed on both the left and the right. “That caused the DM to lose the normal bias,” she says. “Instead of the left side condensing and right side expanding, both sides condensed.” With no clear biomechanical mechanism to guide it, the elongating gut tube had a 50/50 chance of randomly coiling either leftward or rightward.

When Kurpios and her graduate student Aravind Sivakumar, PhD ’17 Biochemistry, Molecular and Cell Biology—now a postdoctoral researcher at Harvard—turned their attention to the right side of the DM, they made another unexpected discovery: The expansion on the right side happened at least eight hours before the condensation on the left side. “That suggested that the signals on the right are the first ones that break the initial symmetry,” Kurpios says. “We thought, there must be another driver in gut looping, something besides Pitx2.”

Through further experimentation, the researchers were surprised to find the hidden player wasn’t a gene but rather a sugar molecule called hyaluronan, which binds water molecules and expands the extracellular matrix. Hyaluronan is secreted by cells and is normally present in the cellular matrix throughout the body. However, the Kurpios lab found that in the DM of the embryo, hyaluronan accumulates on only the right side and is modified into a special form by the enzyme Tsg6 (tumor necrosis factor-inducible gene 6 protein). “The modification by Tsg6 gives hyaluronan an increased ability to hydrate its environment, which causes a massive expansion of the microenvironment on the right side of the DM, pushing the gut tube to the left,” Kurpios explains.

Vascular System Development Linked to Asymmetry

Kurpios and Aparna Mahadevan, PhD ’16 Genetics and Development—now at Harvard University—also discovered that the genes driving asymmetric rotation of the gut were the same ones that drove blood vascular development in the organ. “So the looping pattern must be coordinated with the early development of the blood system to avoid strangulation of the gut tube,” Kurpios says.

“I thought maybe I could learn what genes are driving those [DM] cell shape changes. Maybe those are the same genes that mutations act upon to transform a normal cell into a tumor cell.”

Exploration of the blood vascular system led Kurpios to branch off into the field of lymphatics, an area with broad clinical significance. “The lymphatic system is just like a blood vascular system only it transports interstitial fluid, which is anything left over from the blood,” she explains. “In the GI tract, the lymphatic system goes through the DM and is the major route of dietary fat transport. It also carries out the first immune surveillance function by absorbing things like germs, bacteria, or viruses that we eat along with food and transporting them to the lymph nodes. If you have defects in this system, you get diseases like inflammatory bowel disease and Crohn’s disease.”

The lymphatic system derives from veins during embryonic formation. Kurpios and her colleagues traced that formation in the GI tract but also discovered additional lymphatic cells. “We still don’t know where those cells come from,” she says. “But there must be some type of dual origin for lymphatics.” With further research, she hopes to pinpoint that origin.

Can Understanding Asymmetry Shed Light on Cancer?

Kurpios’ fascination with left-right asymmetry and gut tube formation is connected to her early work as a graduate student studying breast cancer. “When normal cells become mutated in cancer, they change shape,” she says. “When that happens, they do terrible things like migrate to other parts of the body. And I wondered about the starting point: How do cells change shape? What tells them to change?”

When she began studying the gut as a postdoctoral researcher, she noticed that the first thing that drives the leftward tilt is the change in shape of cells in the DM. “I thought maybe I could learn what genes are driving those cell shape changes,” she says. “Maybe those are the same genes that mutations act upon to transform a normal cell into a tumor cell.”

Kurpios enjoys extending her studies beyond dogma and established systems, and her eclectic research subjects—from the study of breast cancer to left-right asymmetry to the lymphatic system—reflect that passion. “In science, why feel constrained by the current paradigms?” she asks. “We go where the data takes us.”