“In many ways, you could say the field of transplantation plateaued for some time,” said Ali Zarrinpar, MD, PhD, a liver transplant surgeon and professor in the College of Medicine Department of Surgery. “I think the field has matured to a point where we know how to do a lot, and we’ve optimized many of those processes. Now many of us are looking toward what’s next — and deciding how we want to get there.”

What’s next for patients undergoing a transplant differs with respect to the organ in question. Lung transplantation, for example, carries idiosyncratic problems unique to an organ that is constantly exposed to outside elements and stimuli, hastening its rejection by the recipient’s immune system. Other solid organs commonly transplanted, like hearts, livers and kidneys, have an average life expectancy of 10 years — almost double those of lungs.

“Lung transplant has one of the worst outcomes of all the solid organ transplants,” said Ashish K. Sharma, MD, PhD, a vascular surgeon and associate professor in the Department of Surgery, whose lab is dedicated to improving primary graft dysfunction, organ preservation and ischemia-reperfusion injury across lung transplant recipients. “The truth of the matter is that almost 70% of lung transplant patients will die in 10 years, and half of them die at the five-year mark. Our lab’s goal is to delve into the problems behind why this area of transplantation has, historically, struggled so much.”

One piece of the puzzle is the donor shortage. For some organs, living donors are more of a readily available solution. Take the kidney, for instance: A person can donate one of their bean-shaped organs to a friend, family member or stranger and observe no changes to their day-to-day functioning after the donation.

But other organs, like the lungs, are in shorter supply. Thanks to the advent of ex vivo lung perfusion, the quantity has increased slightly. The therapy, applied to donor lungs outside of the body before transplantation, improves organ quality and makes lungs that were previously unsuitable safe for implantation.

However, Sharma’s chief focus is one the specialty has grappled with since the first lung transplant in 1963: the issue of primary graft dysfunction, or why lung transplants have such poor long-term results in the first place.

Typically, within the first three days following a lung transplant, graft dysfunction occurs because of a process called ischemia reperfusion injury, in which blood supply that returns to tissue after a period of deprivation results in damage due to a lack of oxygen. This event dictates the outcomes of whether the patient will develop chronic graft dysfunction or survive. The purpose of Sharma’s lab is to understand how researchers and clinicians can mitigate the chances of both primary graft dysfunction and ischemia perfusion injury early on — ideally within the first 72 hours.

“Our team is dedicated to the idea that one of the biggest obstacles we face is optimizing immunosuppression,” said Sergio Duarte, PhD, an assistant professor in the Department of Surgery whose research focuses on transplantation and hepatobiliary surgery. “These drugs have very narrow therapeutic ranges, and it can be difficult to determine the right dose or combination for any individual patient.”

Too much can lead to direct organ toxicity or to an immune system that cannot fight infections or malignancy — but too little can put a patient at risk of rejection and graft injury. In this case, researchers believe artificial intelligence can lend a helping hand in the form of platform phenotypic personalized medicine, or PPM. In theory the process will rely on nonlinear regression to mathematically relate each patient’s prescribed immunosuppressant dosing with quantitative measurements reflective of their phenotype — and their subsequent graft health.

“In other words, PPM will allow us to identify a functional relationship between a patient’s immunosuppressive treatment and response,” Duarte said. “Once we measure this relationship, we can optimize the phenotypic function to identify a combination of doses associated with the desired clinical outcome minimization of allograft injury.”

The real hope for PPM, however, is its ability to be tailored to each patient.

“When it comes to immunosuppression, this process is patient-specific and time-dependent on the clinical inputs we use,” Zarrinpar said.

In both modeling and optimization processes, research values are constantly updated, allowing the phenotypic response function to change and reflect fluctuations in a patient’s immunosuppressive needs over time. But ultimately, it has the potential to revolutionize the way clinicians and researchers approach the question of immunosuppression — and long-term patient health.

“I think every transplant researcher is invested in problemsolving these questions that arise as we get to know the science better year after year,” Sharma said. “And in many ways, it is how we show our commitment to our patients, who are at the heart of these questions we hope to continue to answer.”