Transplant surgeon and clinician scientist Foad Rouhani says a better understanding of how our organs regenerate could usher in a new era of surgery.
Transplant surgeon and clinician scientist Foad Rouhani. Credit: Bethany Lavin.
Transplantation is a miracle of modern medicine. My early memories as a medical student – watching incredibly sick patients receive transplants then walk out of hospital a week later with a new organ, and a completely new lease of life – will always remain with me. Indeed, those memories were a major driver in shaping my choice of a career in surgery.
The stark reality, however, is that there’s a huge mismatch in the world of transplantation. Many more people urgently need a transplant than there are suitable organs available, and the number of people in the UK waiting for a transplant is the highest it has been for a decade.
Of course, the transplant community is working hard to reduce that gap, with some notable successes – for example, through increasing awareness of organ donation. But all too often, we find that a generously donated organ simply isn’t suitable for transplant since, for reasons we have yet to fully understand, its function has deteriorated such that it would not perform well in the patient receiving it.
In part, that’s because donors are frequently older, and more likely to have lifestyle‑related medical conditions due to things such as obesity and smoking.
But crucially we still don’t understand why, on a molecular level, organ function declines as we age, nor what drives organ repair following lifestyle‑related damage. And so, as my career progressed, I decided to embark on a pursuit to better understand how our tissues and organs regenerate.
And one organ, above all, is unique in this regard: the liver.
The liver has long been considered a remarkable organ. In Greek mythology, Zeus punished Prometheus for stealing fire by having his liver pecked out daily by an eagle, only for it to regrow, again and again, for eternity. Indeed, the ancient Greeks considered the liver to be the seat of the soul and emotions.
Prometheus Bound, Peter Paul Rubens. Credit: Philadelphia Art Museum.
In modern surgery, we routinely rely on the liver’s ability to regenerate. For example, in patients with liver cancer, we can safely remove large proportions of their liver. And in the case of liver transplants, a healthy person can safely donate up to two thirds of their liver, for example to give to a family member who has advanced liver disease. In these cases, their remaining liver will rapidly regrow back to its original size in a matter of months.
But this extraordinary ability to regenerate isn’t a given. It can decline, for example following chronic damage – such as from fatty liver disease or long‑term heavy drinking. The liver responds to this damage by triggering fibrosis and, over the long term, cirrhosis, for which the only effective treatment is a transplant. Across the world, rates of chronic liver diseases are rapidly increasing, in part due to obesity and diabetes. And while these issues are the focus of a range of public health and pharmacological approaches, a novel and complementary approach could be to find ways to boost the liver’s innate ability to regenerate.
To do this, we need a deeper understanding of the genetic and non‑genetic processes which cause liver damage in the first place, and how it repairs itself afterwards. This could open the door to new therapies to direct the regenerative response, which would have huge health impacts, both in the transplantation field, and beyond.
I started my lab at the Crick two years ago. My team comprises laboratory scientists, computational biologists and clinicians, using the latest genomics technologies to unravel the rapid and highly organised processes by which the liver recovers from damage – including mapping out the key cell types and genetic pathways that drive this process.
One avenue we’re pursuing is looking at the role played by DNA mutations – acquired through normal development, lifestyle and disease – in promoting or dampening biological processes inside liver cells. For this, we’re developing new AI and machine-learning approaches to analyse and integrate large and complex genomics datasets, using them to generate hypotheses, then testing them in laboratory‑based stem cell models. These powerful experimental systems allow us to study changes in liver cells, but then, in time, apply what we’ve learnt to non‑regenerative tissues such as the heart or brain.
We’re only at the start of this scientific journey, but already our research has shown us how complex these processes are. We’ve discovered new cell types, and new insights into the ingenious ways liver cells can adapt to survive in the hostile environment created by repeated and chronic damage.
We’ve been working very closely with different technical specialists in the Crick’s world‑class science technology platforms (STPs), whose expertise have been invaluable in getting these projects off the ground. They’ve also helped to shape some of our experimental approaches so, not only do we get data of the highest quality, but ultimately make more efficient use of our funding.
Alongside our stem cell work, we’re also developing complex human tissue models, inspired by a crucial technological advance in clinical transplantation that I now regularly use in the operating theatre: human organ perfusion machines.
Over the past decade, these extraordinary machines have allowed us to assess a donor liver by perfusing it with blood, under conditions which closely mimic those in the body, then run tests to ensure that it has good function before transporting it to the hospital for transplantation.
But as well as transforming clinical outcomes, these perfusion machines mean we can now study human organs in total isolation from the body. For the first time, we are able to better understand how an organ functions in health and how it responds to injury. By modelling these clinical processes in the lab, combined with what we’re learning from the stem cell work, we’re hoping we could open the door to transformative therapies.
The first stem cell derived cell therapies are already in clinical trials, meaning regenerative medicine may become a clinical reality in the next decade.
Much of the progress to date has been conceptually simple, relying on single functional cell types, such as insulin-producing pancreatic beta cells to treat diabetes. But more complex therapies are sure to follow, based on more complex structures with multiple cell types – for example, incorporating the supporting structural and immune cells – and eventually part or even whole organs. This is probably beyond what’s achievable with current technology, yet the rapid progress of 3D printing, together with ever increasing knowledge of the genetic networks which dictate cellular identity, mean it may one day be possible to generate complex multi cellular and functional structures for transplantation.
I also expect machine perfusion technologies to evolve beyond clinical assessments: eventually, we could use them to repair organs prior to transplantation. My ultimate ambition is to use these technologies, combined with my lab’s research at the Crick, to find ways to offer our patients entirely novel treatments.
Imagine if we could pre treat transplant organs to make them more resistant to disease, or modify them so they become ‘cloaked’ from the recipient’s immune system, thus avoiding rejection? This would herald a new dawn of precision medicine, in which we drive what is possible far beyond the current limitations, and tailor organs and therapies to individual patients.
This is the promise of regenerative medicine: quiet scientific advances towards restoring people’s futures.
