Hesham Sadek: “The traslational side of the medicine cannot exist in a vacum, there must be a solid foundation in basic science”

Hesham A Sadek is Professor in the in the Department of Internal Medicine at UT Southwestern Medical Center and Associate Director of the Center for Regenerative Science and Medicine. Sadek earned his medical degree at Ain Shams University School of Medicine in Cairo, Egypt, and his doctoral degree in physiology and biophysics at Case Western Reserve University. Dr. Sadek’s research focuses on cardiac regeneration. Specifically, he and his team are interested in identifying methods to activate endogenous mechanisms of cardiac regeneration in humans. Among many other awards, in 2015 he received the American Heart Association’s Established Investigator Award. Sadek has participated in the Visiting Researchers’ programme of the Catalana Occidente Group’s Fundación Jesús Serra.

Do you think you will see regeneration of the heart within your lifetime?

I have been working on it since I began in my independent laboratory 16 years ago. First, we have to bear in mind what the problem is with regeneration: if the skin has a lesion and the wound is not too deep, it will cure completely without leaving a scar. But mammals do not have that capacity in most of their tissues, except, for instance, the liver. In general, when they are cut most tissues and muscles don’t grow back, whereas in other organisms like the zebra fish or other vertebrates, a limb can be cut off and grow back. 

One of the first discoveries we made 12 years or so ago was that newborn mammals can regenerate their hearts completely without leaving scars, but only during the first days of life. We now know that under certain circumstances, regeneration is possible because there is a programme for it but, and we don’t know why, it stops. That is to say, we know there is a door that exists, but now it is closed. That’s why I say that it is easier now, because instead of asking: how I can regenerate something that has never regenerated? Now the question is: why does it activate but later stop?

At the moment, we are attempting to find the answer to that question. We have found certain aspects that are key in the loss of this capacity. When we modulate it, we can prolong this window of regeneration, we can reactivate it in an adult; we have discovered two drugs that are directed at the nodal points that detain the process.

Which is why I personally believe that I will see heart regeneration at some point in my life, since once we have identified the mechanism, we can try to attack it with gene therapy, with repurposed drugs, new drugs… There are many ways of doing it. I think that clinical trials will be conducted at different stages of cardiac regeneration. Maybe the first 20 or 30 will not be successful, but in the end, it will happen. The technology is there, and science is constantly advancing.

Is this the only way to renew the heart?

Most of the papers presented during the CNIC Conference focused on the cell cycle of cardiomyocytes.

Cardiomyocytes are the muscle cells that contract the heart and do not divide when we are adults. Our work, and that of many other laboratories, it to make these cells divide. We are basically working on two routes to regenerate cardiac muscle: one of these is the division of cardiac muscle cells and the other is the extrinsic administration of cardiomyocytes.

We know that there are cells that can make heart cells beat: induced pluripotent stem cells (iPS). Shinya Yamanaka, the Japanese scientist who won the 2012 Nobel Prize for Medicine, discovered the potential of these cells. For instance, embryonic cells can be obtained from reprogrammed skin cells.

Once it is discovered that it is possible to convert these embryonic cells into any type of cell, we have the possibility of making cardiomyocytes in the laboratory for their transfusion to the patient.

Following the same lines, the cells can be expanded, we can obtain cardiac cells that beat, and they can be returned to a patient who does not have any cardiac cells because they have died in a heart attack or a viral infection. In my opinion, these are the two main ways for cardiac regeneration: either real cardiac cells, cardiomyocytes, are obtained, probably from iPS cells or reprogrammed cells, or the endogenous cells of the heart are divided to repair the defect.

How is it that some animals maintain this capacity to regenerate throughout their lives?

When we published the first paper on the heart of a newborn mouse, we modelled it based on the zebra fish. The original zebra fish model was published in 2022, and it demonstrated that if a piece of the animal’s heart is cut off, the organ spontaneously regenerates. This is the basis of the regeneration model.

Clinical trials will be conducted at different stages of cardiac regeneration. Maybe the first 20 or 30 will not be successful, but in the end, it will happen. The technology is there, and science is constantly advancing

Do we know why this capacity does not deactivate in the same way as it does in mammals?

There are many theories. One of them is oxidation, and that is one of the things that we are working on with CNIC. The level of oxygen saturation of an unborn mammal in the uterus is half of what we are breathing now: the blood of the foetus has approximately 50% saturation compared to the 100% we are breathing now. But as soon as it is born, with the first breath, pulmonary breathing activates. This entails an oxygen shock to the system. We think that this oxygen shock is one of the reasons why mammals lose their capacity to regenerate tissues. For instance, if we look at the zebra fish, it only has one ventricle, which means it is always mixing its oxygen and the saturation is very low.

Another thing is the amount of mechanical load that has to be borne. We, and other groups, have shown that the higher the mechanical load, the more work you need to do. It’s a perfect storm, you have oxygen and then you have loads, so you need to use the oxygen to produce energy because you need to pump with strength. The zebra fish does not have much demand, it does not have much oxygen, which could be a reason why it can retain this capacity to regenerate.

Where does your scientific vocation come from?

I studied medicine in Egypt and spent some summer internships in Europe when I was a medical student. In the end, I went to the United States to research, and I was fascinated by the possibility of being able to discover something that affected the lives of patients. As a physician, it is very important to treat patients and attempt to solve their complaints. But I discovered that there was a previous stage, there were people researching so that the physicians had information about how to treat a disease or how to design a drug. I decided to form part of that stage, where something is discovered that can help patients and to develop therapies.

Do you think it is a key point for researchers to understand that what they are studying will benefit the population in general?

I think that a medical training is essential to have that mentality. Now, many of the drugs and the concepts that the therapy is based on were discovered in scientific studies that have nothing to do with humans. For instance, many of the genes we know about were discovered in the fruit fly, and those studies are pure basic science. The translational side of medicine is where someone like me comes in and attempts to discover a way of manipulating a gene to treat a disease, 

It cannot exist in a vacuum, there has to be a solid basis in very pure basic science that really has nothing to do with clinical medicine and translation.

The translational scientist is not going to find the gene that they have to manipulate to solve a disease unless another person has discovered it. So, the discovery of genes, the understanding of the communication mechanisms between cells and of cell division is pure biology. I mean that, without the first half of the story, someone like me would have nothing to study.

Basic science and applied science are essential. Institutes like the CNIC, for instance, with basic biology, cell biology, small animals, large animals and clinical medicine, are the most suitable centres because that is where the researchers that discover the bases coexist with others like me, who translate the bases to a drug, and the clinicians who apply the knowledge to a patient. It is difficult to find this continuum in a single place, obviously, but that would be the final objective.

The hope is to have this connection, like the one that exists in CNIC and other centres, but unfortunately, around the world everything is fragmented. I mean that each scientist studies what interests them. Fortunately, thanks to the exchange of ideas at conferences and congresses, and so on, we understand what other researchers are doing and we understand what can help us in our research. I can’t tell you how many times I have been to conferences whose title I didn’t understand but which, in the long term, have been of great use to me. I think that it is where science becomes very interesting, because you don’t know how the connection will be established or how it will be relevant for you.

What do you think about the Fundación Jesús Serra fellowship?

It allowed me to establish new relations in the field of research that I wouldn’t otherwise have been able to. I collaborate with two CNIC programmes: the regeneration programme and the heart failure programme. With the former, at CNIC we are developing a design line of drugs to identify new medicines that induce cardiac regeneration. And we already have a couple of candidates for testing in clinical trials.

As for the heart failure programme, we are studying the genetic mutations present in some children and families that weaken the heart or, for instance, what happens to athletes who die on the football pitch or basketball court. Usually, they have a genetic mutation in their heart that causes arrhythmias. The mutations are rare and, in general, there is no treatment for them.

We are trying to determine the magnitude of these mutations in Spain and Europe. We hope to develop a larger database. The idea is to develop a specific treatment for each mutation by repurposing already available drugs that are inexpensive. Sometimes the side effect of a drug is due to it attacking a target that it should not. The advantage of this is that the drugs are already available.