Once upon a time, there was a little boy named Luke, who was as beautiful as a little boy could be — with thick, brown hair and a ceaseless, churning energy. Like every little boy, he grew up too fast. But unlike most little boys, he was born with a problem that grew even faster than he did.
By the time Luke celebrated his 10th birthday, his energy was gone. He felt tired pretty much all the time. He couldn’t play with his friends. Sometimes, he couldn’t muster the strength to leave his bed. He lost weight, till his bones showed through his skin, till he was just a fraction of himself.
Fortunately, in this time, there lived a doctor named Tony, who met Luke and his parents.
Dr. Tony spoke very quietly. He was gentle and patient. He had treated many boys and girls like Luke before, with spina bifida. He knew that part of Luke’s spinal cord had grown outside his spinal column. Kids like Luke often grow up with bladders that do not grow with them, or that allow urine to leak and back up into the kidney. This is one of the worst things that can happen to a spina bifida patient. Now it was happening to Luke.
Luke had already undergone 15 operations in his life, but Dr. Tony wanted to perform one more surgery — an operation to solve Luke’s problem. Because Luke had a broken bladder, Dr. Tony wanted to give him a new one. He described the procedure to Luke and his parents: He would take some healthy cells from Luke, urothelial cells that line the urinary tract and bladder. He would place these cells in a petri dish, feed them and wait for them to grow. These cells from Luke would grow and multiply, creating an extension of Luke. And as they grew, Dr. Tony would begin to build a new bladder.
He would use collagen, the same tissue that creates the cartilage of the nose, and shape it in such a way that any child would mistake it for a white balloon. Then he would take the cells he’d grown and paint them on the balloon, until its color changed. When he was finished, the white balloon would become a pink and healthy bladder. Dr. Tony would use this new bladder to replace the bladder that was — everyone knew, but never said — slowly killing Luke.
The procedure sounded crazy.
Who grows whole new organs for little boys?
But Luke and his parents believed in Dr. Tony and needed him to be right.
So in 2001, Luke Massella became one of seven boys and girls in the nation whom Dr. Tony supplied with a brand-new bladder, made from their own cells.
Seven years later, Luke captained his high school wrestling team.
Five years after that, he graduated from college.
The world changed, in some measurable way, for the better.
But the time had not yet arrived for happy ever-afters.
Regenerative Medicine's Long Road
There is some magic in the story of Anthony Atala, the scent of fairy tale and dream. Born one of many siblings, in Peru, Atala is one of the most celebrated research surgeons in the world, yet we know almost nothing about his background. Atala is so private that in 2006, when a reporter from The New York Times asked about his childhood, the only response he offered was a chuckle.
Asked the same question again many years later in his office in Winston-Salem, N.C., Atala smiles warmly. His face radiates real joy. Then the chuckle comes, low and light, as if he is reacting to an old joke that never fails to please him. The effect is magical — creating a public portrait of Atala as a man who appeared out of nowhere, on a quest to save many, many millions of lives. His work, however, is the most magical thing about him.
A short rundown of the achievements of Atala and his research team at the Wake Forest Institute for Regenerative Medicine strains credulity. They discovered a new class of stem cells in amniotic fluid, perfect for creating organs out of patients’ own cells without the risk of immunological rejection. They built blood vessels, skin, trachea, livers, kidneys, heart valves and bladders. Atala has successfully implanted lab-grown vaginas into four women. He hopes to conduct his first human trials of engineered penises for transplant within five years. The military is a major funder for his research.
And he has become a public figure, a famous face for science at its best and boldest, appearing on television shows and media outlets in segments tipping the end of chronic disease — a near-at-hand future in which any malfunctioning piece of us can be replaced with a whole new copy grown from our own living cells.
Atala has delivered two TED talks, subsequently seen by millions online. In both talks, he showed off the facet of his work that usually gets the most attention: his novel use of a desktop printer.
For the purposes of printing a kidney, Atala uses a printer cartridge loaded with human cells rather than ink, and a 3-D kidney-shaped substrate of collagen instead of paper. The printer, guided by computer imaging, drips cells, layer by layer, over the 3-D scaffold, and the inert mold comes to life. Over time, millions of cells begin to communicate and function as one organ. At one TED talk, Atala held out a pink, newly printed kidney in his gloved hands. The sense of wonder, awe, even mystification, was evident in the crowd’s feverish applause.
In these talks, Atala only hinted at the status of his creations — at how close or far we are from transplanting these solid organs into humans — once.
In person, he rejects a timetable entirely. Ten years? Fifteen? Twenty?
Atala won’t say. He can’t say. Because he doesn’t know. Consider: His bladder technology worked in seven children, including Luke Massella. Today, Massella coaches high school wrestling and has started a career in education. But 12 years after he saved Luke, the surgery still hasn’t been approved for general use.
The governmental approval process for new therapies is notoriously slow. But Atala also faces an even more vexing foe: What nature does so endlessly, technology might prove forever unable to mimic.
Regenerative medicine is a multibillion-dollar industry, with funding from venture capitalists, government entities and militaries. We stare agog at what’s been accomplished, like Atala’s printer demonstration, and burst into applause. But premature celebration is not unknown in science.
Remember the Vacanti mouse?
In 1997, Charles Vacanti of the University of Massachusetts Medical School published the results of an experiment: He and his colleagues used cow cartilage cells and an ear-shaped mold to grow an ear on the back of a mouse. The Vacanti ear appeared in media the world over, hailed as a massive breakthrough in regenerative medicine. But 18 years later, no one is walking around with a Vacanti ear on their head. A pair of research teams, using very different techniques, are still building toward a trial phase — meaning we are still a few years away from seeing the promise of the Vacanti ear become reality.
Joachim Kohn, a biomaterials scientist leading a staff of 30 at his Rutgers lab, says experience has rendered him skeptical about what regenerative medicine can achieve — and how the mainstream media tends to portray whatever advances come along. “When some story is published about our work,” he says, “we start getting phone calls from desperate people who need help, and it makes me very sad to have to tell them that what they read about is actually not available.”
At any given time, more than 1 million Americans await some form of tissue transplant. About 130,000 in the U.S. wait on organ transplant lists, hoping someone else’s death will give them life. Each year, the number of people added to the wait list exceeds those who actually receive transplants. About 20 people die every day awaiting an organ that never comes. In fairy tales, needed items appear through magic. In real life, the number of organ donors simply doesn’t meet the need.
Atala and Kohn are working to solve this problem through tissue engineering, by constructing whole new organs. But Kohn suggests the story of the Vacanti ear symbolizes regenerative medicine as a whole. “The ears kept breaking down,” says Kohn. “They could not hold their shape.”
The lesson, says Kohn, is that we are too eager to believe that nature can be mastered. Sometimes we even see what isn’t there. “Go back and look at those pictures of the Vacanti ear that appeared in the media,” he says. “Ask yourself: ‘Would you really want to wear that on your head?’”
I did look. And Kohn is right. The Vacanti ear was … kind of gross. “Everyone said it looked like a human ear,” says Kohn. “But it didn’t. Not to the extent that anyone would actually want to use it.”
And so the question is put to Atala: Is this real? Will we ever be putting entirely new livers and kidneys into ailing patients? “We may never get there,” he says. “I believe we will. We have prototypes for everything we’re working on. We’ve gotten that far.”
But Atala explains that doing it once isn’t enough.
“This is science,” he says, “and it needs to be reliable and reproducible. Doing it once is important because it proves it’s possible. But we need to be able to get this process down so it’s a success virtually every time.”
The printer enables Atala to scale up the technology, eliminating the time it takes to create new organs by hand and the possibility of human error. Yet the printer is nowhere near as important as the schematic it follows — the bank of knowledge built by research teams. Right now that bank still needs shoring up. “It could be,” he says, “that creating entire organs in a way that is reproducible may prove too difficult.”
For Atala, a scientist, this statement is less an admission, with its connotation of confession, and more a matter of fact. His happy ending, a world where we can swap out bad parts for working ones, remains only a goal. Atala feels the need for these therapies sharply, a constant presence, like a rock in his shoe. Like Kohn, Atala receives calls from people around the world, asking if one of these incredible new therapies they’ve seen in the papers or on TV is available. The answer is no. The result is that Atala remains an optimist, buoyed by his vision of the future, yet wholly dissatisfied with now. He is, in this sense, the perfect protagonist for the scientific version of a fairy tale: a story in which a man approaches nature with just the right measure of humility and ambition, a story in which sudden bursts of insight enable him to best the obstacles that face him, so he won’t need magic at all.
Searching for Solutions
Today, at 56, Atala oversees 300 researchers and support personnel, including chemists, biologists and engineers divided into different teams working on cell therapy, a technology for what he calls partial transplants and the creation of new organs. To overcome the rugged individualism he says often dominates research science, he houses all the teams in open lab spaces, so the problems and solutions found by one group can be quickly shared.
In person, Atala has a gentle demeanor. His office is large and immaculate, reflecting the orderly, administrative side of his job. The small table at which he sits with guests is placed so far from his desk, his bookshelf and personal pictures of his family that all these more intimate items seem to be in another room entirely. The effect is that asking to inspect these items seems invasive.
I mention to him that the driver who brought me in from the airport spoke enthusiastically about what the institute means to Winston-Salem, and that he was proud to be from the same state, West Virginia, as Atala’s wife. Atala blanches and changes the subject. Later, his press aide will tell me that Atala worries these sorts of biographical details are a distraction from his work. But at the moment, in his office, he regains his placid demeanor when the next question focuses strictly on his science.
For Atala, the story of his professional quest starts in 1990, as he finished a residency at a University of Louisville hospital and planned for life as a clinician. He looked into a one-year post at Harvard. But a supervisor suggested he would be a good candidate for a particular two-year program there. This other program would require him to serve one year in clinical practice and another conducting research.
“I don’t want to be a researcher,” Atala said.
At home, Atala told his wife about this other option. His own choice was clear. But his wife replied that, well, if she was going through all the trouble of moving to Boston, one year seemed like an awfully short time to stay. Two years, she said, would be nice. And that is how close Anthony Atala — one of the most accomplished researchers in modern medicine — came to disappearing into the bowels of a children’s hospital.
Once he got to Boston, his work as a clinician created a new interest in research. As a pediatric urologist, Atala learned that the “state-of-the-art” operation available to kids like Luke involved fashioning a new bladder from a section of existing intestine. The drawbacks were obvious: The bladder holds liquid prior to evacuation; the intestine absorbs fluid. Complications from the procedure included continued illness and a risk of tumors.
“The operation was the best thing available,” says Atala. In the meantime, the Harvard program required him to study the history of medical research. He found himself captivated by an animal that has inspired the fantasies of many doctors before him: the salamander. He came upon a peer-reviewed article that asked why a comparatively primitive lizard can regrow an entire limb, yet we can’t.
Most doctors bypass the salamander, but Atala chased the dream. He was entranced by the idea that we already are like the salamander. We replace our entire bodies as our cells die off and regenerate through the decades. Every time we cut ourselves, our body forms clots, carries off dead tissue and bacteria, and — like a salamander — regrows skin at the wound site.
The problem is that these processes are incredibly slow. Bone takes 10 years to regenerate. Illness and disease work much faster. Still, Atala wondered if he could harness the body’s own internal healing mechanism. He wondered if he might help the body produce better, faster results than it can achieve on its own. And ever since, he has tried to gin up human performance, to chase the salamander.
His work has focused on regenerating four major categories of human tissue.
First, at the simplest level, there are flat structures like muscle and skin. For these, Atala can work on a flat plane that he populates with cells.
Next up the scale are tubular structures, like blood vessels or the urethra, both of which have been successfully engineered and transplanted.
Third are the hollow, nontubular organs, like the crescent-shaped stomach or the balloonlike bladder. Such structures interact with the rest of the body in a more complicated way. The bladder connects to the kidney with a kind of valve, and to the urethra, requiring a muscle to contract and vacate urine. But in engineering terms, the bladder is just a flat sheet folded upon itself, like a balloon.
Atala’s biggest challenge is to create a solid organ, like the kidney.
Kidneys, bean-shaped organs about the size of a fist, act as a sophisticated filtration device, processing roughly 200 quarts of blood to remove 2 quarts of waste products and excess water. The waste removal function is carried out in each kidney by roughly 1 million nephrons, tiny vessels made up of even tinier urine-collecting structures called tubules. The kidneys also measure chemicals, including sodium and potassium, that are released back into the bloodstream in healthy amounts.
Even more daunting, solid organs are typified by a high level of blood flow — a network of blood vessels known as the vascular tree. These structures dwindle down to the size of the capillary, roughly 8 microns in diameter.
Estimates are tricky, but the human body likely holds about 60,000 miles of blood vessels, with many miles of them inside solid organs like the kidney. The kidney looms as a major goal for Atala. About 82 percent of the people on the U.S. organ transplant list are waiting for kidneys and are usually suffering on dialysis. “People do it because they have to,” he says, “but you don’t want to live for years on dialysis. The quality of life can be very poor.”
His entire career can be interpreted as an attempt to scale this ladder of regeneration all at once, rather than rung by rung. “It’s all interconnected,” he says. “Because when you solve one problem, like regrowing a cell, that brings you one step closer on every project.”
At this stage, he has won enough victories to be celebrated in the media, but he remains circumspect. “I’m happy when something works,” he says, “but I don’t really celebrate in the way you might think because there’s always more work to do until we’re actually done. We solve one challenge, and we move on to the next.”
Serving as the Scaffold
In the early 1990s, Atala was a young specialist in pediatric urology who had by this time made some progress in his thinking. He wanted to create three-dimensional scaffolds of various human organs out of safe, biodegradable material. He reasoned that the appropriate cells, grown outside the human body, could be reseeded onto the scaffold.
He was particularly interested in creating the simplest of solid organs, a phallus, which has just two different kinds of cells to manage. Injured adults, with genitals severely damaged or entirely destroyed in accidents or war, could only turn to cumbersome appliances for largely unsatisfactory solutions. Even worse, when babies born genetically male came into the world with penises too small to be functional, their parents were offered what Atala considered an insufficient, if not barbaric, “solution” — gender reassignment surgery.
Atala wasn’t sure how to create a 3-D, working model of the phallus, or any other solid organ. But he figured solving that problem would heal a lot of misery. And so it came to pass that he attended a medical conference in Washington, D.C., on some subject entirely unrelated to regenerative medicine, when the answer arrived, suddenly, forcefully, as if an unseen figure had hollered it in his ear.
He didn’t need to create a 3-D model at all.
Of anything.
3-D models already existed.
The penis itself.
The kidney.
The liver.
Atala had been experimenting with rabbits. But he couldn’t just take the phallus from one rabbit and attach it to another, like Frankenstein. Just as in a human, the rabbit’s immune suppression system would see this new organ as an invader and attack. But what came to Atala at the conference is that he might be able to decellularize the penis, to turn a cadaver phallus into the 3-D scaffold he needed. If he could wipe all the cells from the phallus, or any other organ, he could then reseed it with cells taken directly from the intended recipient, virtually eliminating the possibility of an immune rejection.
Back in his lab, Atala experimented. He plopped a phallus, livers and kidneys into still water with a mild detergent. He left them there for days, then viewed some tissue from each organ to see how many cells were removed. Unfortunately, he found, the organs were still virtually covered in cells.
Next, Atala placed the organs and detergent into the sort of shaker used to mix paint. The friction of the shaker afforded him better results, but there were still too many cadaver cells to risk transplant.
Finally, he tried a centrifuge, which whirled at speeds that forced detergents deep into the organ tissue. Again, he trimmed away some tissue, popped it under a microscope and looked.
Nothing.
The cadaver tissues, mostly composed of collagen, were essentially blank — empty canvases on which he could paint new cells.
He felt pleased, but like a hero on a quest, he knew the goblin at the door was merely a prelude to the dragon at the mountain’s heart. The next challenge he faced required him to gain even greater mastery over the most fundamental level of biology, the cell.
The human body has an estimated 37 trillion cells or more working at any given time, each with a specialty that together produces one living entity: us. Learning to grow cells outside the body, while retaining their functionality, was thought to be an insurmountable problem. The belief was borne from scientific history. In the past, researchers studied specific cells by isolating them, injecting them with ferrous iron and literally pulling cells away from each other with a magnet. Such cells persisted for a short time or quickly died. But Atala tried his hand first at these old experiments, as a place to start.
He isolated the cells he thought he needed, at least to replicate these old experiments, and fed them the same nutrients they got in the body. He placed them on the scaffold, where they grew and sometimes even formed the 3-D structures they build in nature. Then, usually in less than a month, they fell apart. His first attempts at reseeding a phallus ended in penises that quickly lost their shape and scarred.
Atala started thinking through the possible differences between the phallus he was creating and the phallus as it exists in nature. The penis, he reasoned, is highly vascularized, “like a great big sponge” of blood vessels. So he added endothelial cells, which line blood vessels, and observed them through a microscope as they began to build the same structures they form in the body. At first, this raised his hopes only a little. He had seen cells do this before, briefly, before collapsing. But “this time,” he says, a rare sense of satisfaction creeping into his voice, “they kept going.”
That step, of learning to grow the cells necessary to create a functional penis, took three years. “And it was a crucial step,” he says, “not just on this project, but in the way it helped on all our other projects.”
Atala would return, again and again, to what he learned: The idea, he says, “is to approximate, as closely as possible, the conditions found in the body in some controlled environment outside the body.”
By 2009, Atala announced that his lab had transplanted phalluses onto adult rabbits, which successfully used the manufactured organs to breed. He seems to see the victory in a different context than the rest of us — less as an end itself than “just another step” toward eradicating as much illness, disease and misery as nature will allow.
Set in Stone
On a summer weekend in the late ’90s, on the south shore of Boston, Atala stalked across the sand, enjoying some rare free time from his work at Harvard. He walked, head down, watching the sand pass under
his feet. The waves on Humarock Beach roared steady as an engine, and the sand rolled beneath him like a conveyer belt, carrying spit curls of sea foam, seaweed and broken shells.
Then, in a story he often tells, he saw the stone.
Atala was drawn in, initially, by its shape — its slight curl, like that of a perfect kidney. He reached down, his fingertips scraping the sand, and plucked the rock free. The day was brisk, and he held the rock aloft, fixated on its one blemish: Along the entire length of the stone ran a single ridge, almost like a biology teacher’s notation indicating what is known as the Brodel’s line of the kidney.
The Brodel’s line, in biology, denotes an avascular plane where the rich vascular tree of blood vessels and capillaries peters out. As Atala stood there, staring at the rock, what happened at the Washington, D.C., medical conference happened again: An idea, fully formed, arose in his mind with enough force to shift the entire world of medicine.
The media has focused on his most grandiose project — his attempt to grow whole organs. But what he realized there on the beach, all those years ago, is that he doesn’t actually need to grow an entire organ at all.
“I just need 10 percent,” he says.
Standing and staring at the line running along the stone, he knew he could part the delicate, dark-red tissue of the kidney along the avascular plane, across the organ’s whole length, causing little blood loss or damage, and pop a kind of cartridge into this incision — a wafer of healthy kidney tissue. The kidney, in its own salamander-like way, would grow and incorporate the new tissue, just as it extends itself into new skin that forms after we’re cut.
The logic that settled over him on the beach, however, went beyond the salamander to include a well-known truism in medicine: the human body’s remarkable 10-times reserve. “Usually, a patient doesn’t present with any serious symptoms till whatever organ is involved has lost 90 percent of its function,” he says.
The patient doesn’t collapse climbing the stairs, short of breath, until his lungs are functioning at 10 percent capacity. The heart patient doesn’t succumb to chest pain until her artery is 90 percent blocked. “It’s the same with the kidney or liver,” says Atala. “If I can insert healthy tissue, equal to 10 or 20 percent of the size of the organ, I can keep that patient functioning and alive at a high quality of life.”
Atala thinks of these serendipitous moments — when an answer to one problem arises suddenly, from some unlikely source — as a key aspect of his science. And in this instance, serendipity allowed him to envision a brand-new patient-treatment model, in which full organ transplants are rare and organ donor lists are eliminated. “Ideally, with this technology, you screen people and you augment the existing organ when they’ve only lost 40 or 50 percent of their function,” he says. The patient never even reaches an emergency stage.
Finding Success
The very next week, Atala isolated the kidney cells he needed, then seeded them onto a decellularized scaffold. The different types of cells made the structures as they do in nature — for example, distal cells made distal tubules, a segment of the nephron that filters urine — but they didn’t communicate. The frameworks they built were never connected. Atala, peering through a microscope, was like a pilot looking at an unfinished suburban development from an airplane. Structures dotted the landscape, but no roads ran between them.
Remembering what he learned from his work on the phallus, Atala tried another experiment. Seeking to approximate the conditions the cells experience in the body, he stopped isolating them in the first place. Like a chef making pesto with a mortar and pestle, Atala ground a section of healthy kidney tissue, extracting the various types of cells in a single pile.
“These cells already had a relationship, so to speak,” says Atala. “So with this technique, that relationship was never really severed. They were talking to each other, and this way they continued to talk.”
Looking through a microscope, Atala watched the ghostly, isolated structures he saw before connect — each to the other — healthy and alive.
“That one felt great,” he says. “It was just what we hoped to see.”
The words seem too small to encompass what he was really viewing — watching a kidney, in effect, regrow itself, the human body enacting its own salamander nature.
Atala continues to work on creating whole new organs. But he also has a team working on the model that occurred to him on the beach: Harvest and grow some healthy cells from a patient’s damaged kidneys. Concurrently, decellularize a pig kidney, leaving only the casing. Then repopulate the organ with the patient’s cells. Insert a section of that new kidney tissue, equal in weight to maybe 20 percent of the existing organ. With no cells from the pig, the recipient’s body should accept this new section of kidney.
Atala is also pursuing this “wafer” model of creating partial transplants for other organs.
Though Atala always remains circumspect about the status of his projects, he says this partial transplant model is different: That team is far along in the process, successfully placing kidney cartridges into animals for trials lasting several months. The major problems, he says, all appear to be solved. Relatively speaking, partial transplants are closer. The most practical solution may not be as dramatic, or garner as much publicity as creating a whole new organ. Yet millions of happy ever-afters beckon. Because he saw the answer when it washed in with the tide — the ocean rolling back in from the future, sounding like an echo of a mystified crowd’s applause.
[This article originally appeared in print as "The Doctor and the Salamander."]
