WRITER: Michael Tanenbaum

Dr. Hesham Sadek is pioneering research that could change the face of medicine. If his work in cardiac regeneration proves successful, he could end heart disease altogether.

If you behold our anatomy from head to toe, within and without, few bodily structures will inspire greater wonder than the valiant, thumping heart. Far surpassing its circulatory function, factoring symbolically as homo sapiens’ expressive core, the heart is a notion infused with our most universally cherished qualities: love, courage, resilience, compassion and honour.

Demand that much of just about anything and even burdens that beautiful will levy a toll. It’s just that with the heart, that ‘toll’ is often fatal.

That’s why for cardiologist Hesham Sadek, a leading clinician and researcher at the University of Texas’ Southwestern Medical Centre in Dallas, mastering the genetic blueprint of the heart is both a calling and a public health necessity.

“Cardiovascular disease is, by far, the number one killer in the developed world,” the doctor tells me bluntly. “For me, as a medical student, the problem of heart failure was attractive, the idea that if you’re going to be asking questions, you should go after the biggest ones.”

With the World Health Organization estimating that 17 million cardiovascular-related deaths occur per year, this family of threatening conditions has come to define an alarming crisis in contemporary health. For cardiology specialists worldwide, it has initiated a quest to unlock the potential for both accelerated emergency response practices and innovative therapies for the treatment of heart failure.

Dr. Sadek and his UT Southwestern team have concentrated on the specific genetic factors regulating mammalian cardiac tissue formation. Once considered a terminal developmental process, Dr. Sadek’s findings are helping lay the groundwork for adult heart tissue regeneration, which would be a visionary breakthrough in cardiovascular medicine.

Sadek’s path to the lab in Dallas is unusual and covers considerable ground. Born in Manchester, his formal medical education began in Cairo, where he attended a six-year medical program at Ain Shams University, which included summer stints in the former Yugoslavia, Italy and the United States.

“In Egypt, research funding was insufficient,” Sadek says, explaining his eventual move to the United States. “That has improved, specifically in Aswan through the Magdi Yacoub Heart Foundation but I decided then that I had to pursue my career here so I could get more exposure to research.”

Between 1997 and 2005, Sadek completed his doctorate, residency and cardiology fellowship at Cleveland’s Case Western Reserve University, a preeminent institution for the study of cardiovascular disease and science in the U.S. His Ph.D. focused primarily on cardiomyocyte (heart cell) injury, in particular the complications of reperfusion, an injury sustained when blood returns after a period of oxygen deprivation, which can happen during heart attack operations. The more he refined his expertise in a clinical setting, the more Sadek observed the gap between this enormous demographic strain and the limitations of current medical intervention.

“When I went to do my postdoctoral fellowship, I had the opportunity to work in a lab that studies heart regeneration and stem cell biology,” he continues. “I entered the field of regeneration biology from a completely different angle than most, who tend to have been cell biologists or pathologists all their lives. Initially, I was a bit of an outcast.”

Efforts to induce organ-specific tissue regeneration are especially problematic in the mammalian heart, where cell proliferation ends quickly after birth. Sadek’s distinct view of this trait inspired him to train in vastly differing areas of medical science, empowering his lab to pinpoint complementary models of research. Over time, his interests have coalesced around the genetic and evolutionary bases of myocardial development.

In the last few years, he and his colleagues have introduced significant advances to the field with the publication of results from experimental studies. One of the lab’s pivotal experiments, published by Science in February 2011, challenged the basic premise that mammalian hearts lack capacity for regeneration after birth. Experiments with aquatic and amphibious species, like zebra fish and newts, have proven an ability to regenerate multiple organs throughout adult life. Sadek applied the same model to mammals, in this case, mice, in order to evaluate what occurs following injury at intervals after birth.

“As with the experiments on the other species, we cut off the apex of the heart in a one-day old mouse,” Sadek explains. “The site of injury grew back completely, within three weeks, even faster than it did with the zebra fish.”

With the aid of genetic fate mapping, a method for understanding the development of tissue by establishing a link between a cell in its embryonic and later adult form, Sadek’s experiment traced the source of cell re-growth in the day-old mouse directly to pre-existing cardiomyocytes, rather than stem cells. A parallel procedure determined that an identical injury inflicted on a week-old mouse yields only scar tissue patching, rather than myocardial regeneration, as is the case with the adult human heart. This suggested that effective heart cell regeneration might best be achieved through the use of endogenous tissue rather than stem cell treatment, which remains problematic because it can lead to more generalised, even unpredictable repair.

In such a contentious field, ruled by big ideas and microscopic progress, Sadek promotes the value of collaboration among different research agendas. “My mentors always told me the same thing,” he says. “Whenever you have the chance to retool and learn something new, do it. Our field is one of the most polarised areas of science. I am not against one camp or with another camp. We each play to our strengths as opposed to our weaknesses. I think we’re all trying to find an answer and if it works, everyone is going to run with it.”

Perhaps Sadek’s greatest strength is homing in on an original source to examine the basic science behind genetic phenomena. After determining cardiac regeneration could be effected by existing heart tissue – however ephemerally – the lab’s next goal was to investigate how and why the cell cycle of mammals becomes inhibited in the heart after birth.

With support from the American Heart Association, the National Institutes of Health and several other funding bodies, Sadek and his partners were able to isolate a specific gene transcription factor called Meis1, which is responsible for regulating the expression of regrowth. Their findings, published in the May 2013 edition of Nature, signal an exciting development in the search for alternatives to stem cell regeneration.

“We are getting closer to an answer,” Sadek says, adding that he is encouraged by his lab’s recent explorations into pharmacology. “The pathway that we discovered has great potential for repurposing existing drugs with other indications. We have run molecular screens over large data sets and we believe that we can direct current drugs to stimulate regeneration in the heart. This testing brings clinical applications much closer to reality than previously thought.”

If this proves to be the case, then Hesham Sadek and his team will go down in history. If already existing drugs could be repurposed to stimulate the regrowth of damaged heart tissue, millions of lives will be saved. Better yet, such success might encourage other specialists to explore whether other organs could also be induced to self-regenerate and that would open up the doors to a future that until now, has only existed in the pages of Science Fiction.

WHO Dr. Hesham Sadek
WHERE University of Texas Southwestern Medical Centre
WHAT Cardiac regeneration
WHY By reminding the heart how to regenerate, Sadek’s work offers the hope that one day soon we may be able to cure heart disease for good.