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.
3-D models already existed.
The penis itself.
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.
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 underhis 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.
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."]
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