‘In regenerative medicine, the new organ is never rejected’

Peruvian surgeon, urologist and bioengineer, Anthony Atala, 65, has the perfect credentials for regenerative medicine research. Arriving in the U.S. from his native Peru aged 11, Atala now directs the Wake Forest Institute for Regenerative Medicine in North Carolina and is professor and head of the Urology Department at Wake Forest University. Sixteen technological applications developed in his laboratory have already been used on humans. Winner of numerous awards, he is one of the first organ bioprinters, something which involves reconstructing tissues and organs to implant in humans using the patient’s own cells. This is basically the definition of regenerative medicine. Atala visited Granada, Spain last week as a guest of Granada University’s Social Council and talked to EL PAÍS about his work.

Question. What is regenerative medicine and when did it establish itself as a line of research?

Answer. It has its origins in the first decades of the 20th century, with Alexis Carrel, a Frenchman who began to cultivate organs at the Rockefeller Institute in New York. He did it with Charles Lindbergh, the first aviator to cross the Atlantic. Lindbergh collaborated with him as a mechanical engineer. In 1935, the two of them built the first perfusion pump — an instrument to keep organs that had been removed from the body irrigated and functioning. This led to the possibility of extracting organs and keeping them alive outside the body. In 1954, the first successful organ transplant, involving a kidney transplanted from one twin to another, took place in Boston. It was performed by Joseph Murray, who would later be awarded the Nobel Prize. From there — and this is linked to cancer treatment — came the concept of cell transplantation. The treatment of skin cells in burns patients in the 1980s was another important development. The skin does not grow, but the cells do make the wounds better. This was the start of tissue engineering. But regenerative medicine did not kick off as such until this century. It brings all these elements together, transplanting cells, manufacturing support structures, growing tissue and making it possible to regenerate damaged organs or, better still, parts of them.

Q. Will regenerative medicine allow us to live longer and better?

A. Vital organs such as the uterus, heart, and kidney, do not have an expiry date. Theoretically, they are able to function for many years without failing us. If they do not give any problems, regenerative medicine will not prolong life. Instead, it will make it possible to replace tissues and organs if necessary. If this regeneration concerns organs that do not affect longevity, it will help you live better. If the regeneration affects vital organs, of course, we will live longer. One quality of regenerative medicine is that it restores organs to their original state and does so with its own cells, which avoids many problems. In fact, a report by several U.S. government agencies states that regenerative medicine will be the dominant direction for medicine’s future.

Q. Recently, in Barcelona, a woman with a transplanted uterus gave birth. Would it be possible to give birth with an artificial, bioprinted uterus, for example?

A. We have not tested this in humans yet, but our studies indicate that it will be possible. We have been working on this for almost 20 years and we know that, by using the patient’s own cells, all the organ’s natural functions can be reproduced. In short, it is an organ that is as much your own as the original.

Q. What percentage of a human being could be replaced by regenerative organs?

A. Theoretically, all the organs since they are the patient’s own cells. Prostheses can produce rejection and inflammation. Another person’s organs require immunosuppressive drugs for the rest of your life and there is always the risk of rejection because they are foreign cells. In regenerative medicine the new organ is never rejected. The body believes it is its own organ.

Q. What is the source of the cells?

A. They come from the same organ you want to build. If I want to make a kidney, I do a biopsy and extract cells from that kidney, keep them outside the body for four to six weeks. Then we build the support onto which we incorporate those cells, either by hand or printed, and the patient can then have the organ implanted. That is the technique.

Q. How do you know which cells are to become the kidney, bladder or skin?

A. Any cell has all the necessary information to replicate a person, as happened with “Dolly” the sheep. Then, depending on how they are made to grow, they become one type of tissue or another and are used for one organ or another.

Q. Who had the idea that those tissues that were made in a lab, outside the body, could be bioprinted?

A. The idea of printing DNA had been around for years, so printers have long been designed for use in the medical field. Injection 3D printers have also been around for a long time. Everything arose from that concept. The challenge was to get structures that were actually tissue. That required more technology than existed. So, we worked until we got what we have now.

Q. So what is bio-ink composed of?

A. It is just a liquid impregnated with human cells. To make that liquid we have up to 60 materials available. Then, depending on the case, we make a very liquid, gelatinous bio-ink, that’s like a jelly bean. This liquid is really just the support for the cells, and over time it disappears.

We are already making small brains. However, a full-size human brain has not yet been made

Q. How does it disappear — what happens to that support?

A. Either with the printer, or by hand, we make a structure with the shape of the organ we are regenerating to introduce the cells in their right place and with their shape. This support disintegrates with time, normally six months, though in the case of complicated organs with a lot of three-dimensional structure, it can take up to 18 months. The structure should not be permanent in order that the body has only its own cells. The mold, which, in any case, would not be rejected because it has no genetic content, must disappear because if it remains, we would be talking about a prosthesis, something foreign. The aim is that, when the support disappears and the cells note that their scaffolding is being lost, they behave naturally and rebuild their own support. This is regenerative medicine: the artificial support must disappear to eventually leave only the cells themselves.

Q. Can the brain be regenerated in this way?

A. Yes, we are already making small brains. However, a full-size human brain has not yet been made. There is a long way to go, but when it comes to science, you can never say never.

Q. Are some tissues or organs more difficult to regenerate than others?

A. They are all complicated, but flat tissues, such as skin, are easier. Then there are tubular tissues through which air or liquid passes. Next, there are non-tubular hollow tissues and, finally, the most complicated are the solid organs such as the liver, kidney, and heart, etc. The big challenge with these is they need nourished vascularly. This vascular network in solid organs is very complicated to reproduce. But now, we are able to reproduce all four types at different levels.

Q. In the U.S., there is 10 times more demand for organ transplants than there are organs available. Is this bioprinting and regeneration a solution? When will it be routinely available?

A. It is one of the solutions. In science, we never say never, but neither do we say when. In the U.S., different types of tissues, smooth, tubular and hollow, are already being regenerated in humans. With regard to organs, on the other hand, we are only making partial replacements. We do this because, in fact, the body has a reserve of about 10 times what it needs. This means that numerous organs only fail when they are 90% defunct. Only when the organ falls below 10% of its functioning capacity does it become noticeable, which is what happens, for example, with a heart attack, and kidney failure, etc. Therefore, we can make partial organ replacements and that is what we are doing with renal cells — restoring a percentage of the kidney, which is enough for the patient to live comfortably. We are now working on about 40 different tissues and we have performed 16 different types of treatments, but there is still a long way to go.

Q. What is more difficult, the research or adapting to the regulations?

A. One of the challenges of our research is ensuring the advances are safe for patients which is what the regulators also seek. It is true that, in some cases, as with any process carried out by humans, the regulations are stricter than in others. With regulations, as with other things, you have to be sure that the product is safe and that it works for the patient. The rest is adapting to the procedure and knowing how it works. It must be borne in mind that the average regulation of a technology takes 14 years and then another 14 years for doctors to become familiar with these new techniques. To be a researcher you also need to be very patient.

Q. Are EU and U.S. regulations very different in this area?

A. Actually, they are very similar. If we need a product from Europe in the U.S., it is accepted without any problem, and vice versa.

Q. The step after bioprinting is body-on-a-chip. What is this?

A. This has its origins in regenerative medicine technology. It involves printing different organs the size of the head of a pin using the technology we have talked about, support and cells. These different organs — up to 12 of them — are embedded in a microchip and using the appropriate sensors we reproduce the real behavior of the different organs and their relationship to each other. This means speeding up drug safety times, among other things. For example, 90% of the drugs that pass the first phase of clinical trials with humans never reach the market. To reach the market, it takes years, plus a lot of effort and money. We’re talking decades and maybe hundreds of millions of dollars. This is due to the fact that pharmaceutical companies use 2D tissue replica models when the human body is 3D, or they use animal models that are not exactly like humans. With these organs-on-a-chip, created in 3D from human cells, we can make an exact replica of the originals in shape, texture, behavior, etc. And we can test more accurately in a matter of weeks what takes traditional methods years — things like the safety of a drug, its influence on each organ and how the organs react together with the drug. All this accelerates the process of discovering the positive and negative impact of a drug. It is a mixture of regenerative medicine, microchips and biosensors.

Q. Is regenerative medicine used in hospitals?

A. It is slowly being adapted. Some hospitals are already working on skin tissue regeneration.

Q. Will it be possible, or necessary, for each hospital to have a regenerative medicine unit, or will there rather be production centers and distribution from there? Is thought being given to transportation and care?

A. This is, ultimately, an industrial process, with a specific protocol, and with manufacturing taking place according to the specific area. The hospital will take a biopsy, which will be sent to the production center where the tissue or organ will be manufactured and returned to the hospital. The good news is that the surgeon does not need to learn anything they do not already know in order to implant the new tissue. So another issue we are working on is transportation, and our clinical trials take this into account.

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