Inside a warren of rooms buried in the basement of Gregorio Marañón hospital here, Dr. Francisco Fernandez-Aviles and his team are at the sharpest edge of the bioengineering revolution that has turned the science-fiction dream of building replacement parts for the human body into a reality.
Since a laboratory in North Carolina made a bladder in 1996, scientists have built increasingly more complex organs. There have been five windpipe replacements so far. A London researcher, Alex Seifalian, has transplanted lab-grown tear ducts and an artery into patients. He has made an artificial nose he expects to transplant later this year in a man who lost his nose to skin cancer.
"The work has been extraordinarily pioneering," said Sir Roy Calne, an 82-year-old British surgeon who figured out in the 1950s how to use drugs to prevent the body from rejecting transplanted organs.
Now, with the quest to build a heart, researchers are tackling the most complex organ yet. The payoff could be huge, both medically and financially, because so many people around the world are afflicted with heart disease. Researchers see a multi-billion-dollar market developing for heart parts that could repair diseased hearts and clogged arteries.
In additional to the artificial nose, Dr. Seifalian is making cardiovascular body parts. He sees a time when scientists would grow the structures needed for artery bypass procedures instead of taking a vein from another part the body. As part of a clinical trial, Dr. Seifalian plans to transplant a bioengineered coronary artery into a person later this year. His employer, University College London, has designated a person to oversee any future commercialization of it and other man-made organs.
The development of lab-built body parts is being spurred by a shortage of organ donors amid rising demand for transplants. Also, unlike patients getting transplants, recipients of lab-built organs won't have to take powerful anti-rejection drugs for the rest of their lives. That's because the bioengineered organs are built with the patients' own cells.
Until the late 1980s, few scientists believed it would be possible to make human organs because it was a struggle to grow human cells in the laboratory. The task became easier once scientists figured out the chemicals—known as growth factors—that the body itself uses to promote cellular growth.
Scientists started out growing simple organs. In 1999, Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine in Winston-Salem, N.C., implanted lab-grown bladders into the first of several children with severely dysfunctional bladders. The organs have continued to function well for several years. Dr. Atala's team now is trying to grow a whole range of bioengineered parts, from simple blood vessels to human livers.
"You can see the acceleration in the field," Dr. Atala said.
Some of the most complex work is under way at Dr. Seifalian's laboratory at the Royal Free Hospital in London. A 56-year-old native of Iran, Dr. Seifalian started out as a nuclear physicist, and became interested in medical uses of nuclear technology. That ultimately led him to bioengineering.
In 2011, Dr. Seifalian made a windpipe from a patient's cells. It was used to replace the cancerous windpipe of the patient, saving his life, his surgeon has said.
Dr. Seifalian and 30 scientists now seek to build a larynx, ears, noses, urethras and bile ducts.
Most human organs get their form from an internal scaffolding of collagen and other proteins. Scientists struggled for years to find a replacement material that was strong and flexible and yet wouldn't be rejected by the body.
Eventually, they homed in on a couple of high-tech materials made from plant fibers, resins and other substances. Dr. Seifalian said he uses a material that is modeled on the honeycomb structure of a butterfly's wing. The material, a so-called nanocomposite, is resistant to infectious bacteria and has pores that are the right size to hold cells.
"The material has to be accepted by the body, but it also has to be easy to manipulate into different shapes, different strengths," said Dr. Seifalian.
The researchers poured the material into the artist's mold. They added salt and sugar. That created holes in the material and gave it a spongy, porous feel, just like the real thing.
The key to all the lab-built organs are stem cells, found in human bone marrow, fat and elsewhere. Stem cells can be transformed into other tissues of the body, making them the basic building blocks for any organ.
In the case of the nose, stem cells extracted from the patient's fat tissue were added to the artist's mold, along with chemicals that control cell development. The stem cells sat inside the pores of the lab-made organ and gradually differentiated into cells that make cartilage.
However, the nose was missing a crucial piece: skin.
This posed a substantial hurdle. No one has made natural human skin from scratch. Dr. Seifalian's idea: to implant the nose under the skin of the patient's forehead in the hope that skin tissue there would automatically sheath the nose.
But the patient objected, and for good reason: The implanted nose would have to sit inside his forehead for weeks or even months. In the end, Dr. Seifalian chose a less obtrusive approach. The bioengineered nose was implanted under the patient's forearm.
The team now is using imaging equipment to keep tabs on whether the necessary blood vessels, skin and cartilage are forming in the right way. "We'll have to also make sure there's no infection," Dr. Seifalian said in late November, on the day of the patient's surgery.
If the skin graft works, surgeons will remove the nose from the arm and attach it to the patient's face. Dr. Seifalian will then apply the right chemicals to convert the man's stem cells into epithelial cells, a common type of tissue found in the nose and in the lining of other organs. The epithelial cells will be inserted into the nose.
As a final step, surgeons will connect blood vessels from the face to the site of the new nose to provide a steady flow of nourishment for the growing cells. "The whole process could take six months," said Dr. Seifalian. He estimates the cost of making the nose in the lab is about $40,000, but the patient isn't being charged because the doctors and scientists are either donating their time or working on this as part of their research.
Regenerating a nose would be a striking achievement; creating a complex organ like the heart would be historic. A team led by Spain's Dr. Aviles is trying to get there first.
Dr. Aviles trained as a cardiologist but became frustrated with the difficulty of treating patients with advanced heart disease. The only option for the worst cases was a heart transplant, and there was a shortage of hearts. Spain has the highest donor rate in the world, yet Dr. Aviles said that only about 10% of patients who need a heart transplant get one.
He was approached in 2009 by a U.S. scientist, Doris Taylor, who had already grown a beating rat heart in the lab while at the University of Minnesota. Instead of using a man-made scaffold, Dr. Taylor had used the scaffolding from an actual rat heart as the starting point. She believed the same technique was crucial for making a working human heart. She was attracted to Spain because the higher donor rate meant that more hearts unsuitable for transplant could be used for experiments.
Dr. Aviles and about 10 colleagues began their human-heart experiments crammed into a small storage room at the hospital. In 2010, a sparkling new lab opened. It has two large freezers with human cells and human hearts, and a dozen stainless steel sinks containing pig hearts immersed in a colorless liquid.
Growing a heart is much harder than, say, growing a windpipe, because the heart is so big and has several types of cells, including those that beat, those that form blood vessels, and those that help conduct electrical signals. For a long time, scientists didn't know how to make all the cells grow in the right place and in the right order.
The problem had been cracked by Dr. Taylor. She said that when human stem cells were put into a heart scaffold in 2010, they seemed to know just where to go. "They organized themselves in a way I didn't believe," said Dr. Taylor, who now works at the Texas Heart Institute but makes regular visits to Madrid to help with the experiments. "It's amazing that the [scaffold] can be as instructional as it is. Maybe we don't need to micromanage every aspect of this."
A person's heart grows in the womb where its cells receive the right mixtures of oxygen and nutrients and chemicals to grow into a working organ. To duplicate that process in a laboratory, scientists uses a device called a bioreactor, which has various tubes ferrying materials to the heart and whisking away waste products. The lab's bioreactor—a cylindrical device nearly a foot in diameter—is being designed by Harvard Bioscience Inc., a maker of medical devices in Holliston, Mass. The machine will be ready for experiments in April, according to Dr. Aviles.
Mimicking the heart isn't easy. For example, more than a gallon of blood courses through the human heart each minute. The bioreactor will have to be set up so that a similar volume is pumped through it, but gently—to avoid killing the cells.
In addition, the heart cells must be given the right electrical connections.
To model these connections, the Spanish team built a vest with 70 electrical points. Team members wore the vest, which record their hearts' electrical activity. That pattern of signals will have to be replicated for the lab-made heart.
When Dr. Taylor built a rat heart in a lab dish five years ago, she used a pacemaker to make it beat. "Electrical activity doesn't spontaneously emerge," said Dr. Aviles. "We'll use a pacemaker, too."
Dr. Aviles said he hopes to have a working, lab-made version ready in five or six years, but the regulatory and safety hurdles for putting such an organ in a patient will be high. The most realistic scenario, he said, is that "in about 10 years" his lab will be transplanting heart parts.
He and his team already have grown early-stage valves and patches that could be used some day to repair tissue damaged by heart attack.
The Madrid lab has made only baby steps toward its grand plan to grow a human heart using the same techniques that Dr. Taylor pioneered with a rat heart.
"We opened the door and showed it was possible," she said. "This is no longer science-fiction. It's becoming science."