Dr. Joseph Vacanti believes he can build a replacemnet liver. He says he's seen too many patients die waiting for a donor.

12:00 PM EDT on Sunday, April 11, 2004

BY G. WAYNE MILLER
Journal Staff Writer

Journal photo / Connie Grosch "I still believe completely that we can actually do this," Vacanti says.

BOSTON -- Dr. Joseph P. Vacanti steps to the operating table inside a small room at Massachusetts General Hospital. A large white rat lies asleep on its back, its legs spread-eagle with rubber bands anchored to pins. The rat's teeth are bared, its long whiskers still, its abdomen shaved.

Dr. Wing S. Cheung, Vacanti's chief assistant on this experiment, stands across from him at the table.

"Want me to open?" she says.

Vacanti nods.

Cheung cuts into the rat, down through skin and muscle until the animal's innards are exposed. No one speaks, but a man with a video camera zooms in. Someone else shoots a still. On the table next to the rat, a rectangle of plastic about the size of a stick of gum rests in a petri dish.

This prototypical "device" is the latest version of the man-made liver that Vacanti and his researchers have designed and built over a period of many years. No one else has ever built such a thing. Until today, no one has ever attempted to implant anything like it into a living creature.

It is a morning in the autumn of 2002.

Vacanti and Cheung free up the vessels to which they will connect the liver. It is meticulous work, time-consuming and allowing little margin of error.

"OK, it looks good," Vacanti says.

Vacanti and Cheung sew the liver to the vessels. But before they can loosen the clamps that would let blood through, the rat stops breathing.

"There's no flow in the portal vein," Vacanti says. "Oh, come on, rat! The operation was a success but the patient died! Crap! That sucks!"

Vacanti suspects the cause was shock caused by excessive bleeding or the wrong anesthetic.

"Someone go talk to the family," he jokes.

"They're all here," Cheung jokes back. Near the table, rats stir in their cages.

Grabbing the dead animal by the tail, Vacanti dumps it into a medical-waste bag. Cheung anesthetizes a second rat with a needle into its rump. It squeals and squirms, but soon falls still. She shaves it with electric clippers and brings it to the table.

"OK, rat, be more cooperative than your brother," Vacanti says.

But the animal dies. So do the next four.

Now, it is late afternoon, six rats up and six rats down, the sun setting outside the laboratory operating room. Vacanti has failed in his goal of establishing circulation through the liver device.

Click to see the entire graphic

"This is part of the learning experience," he says. "That's why we call it an experiment. Let's find the biggest, meanest son of a bitch in the cage!" He reasons that a larger rat might better tolerate the trauma of surgery.

"Take seven," Vacanti says, as a 475-gram rat, about the size of a grown guinea pig, is put under.

The surgeons open the rat, connect the liver, and unclamp the vessels. Blood fills the liver.

"Children, we've done it!" Vacanti says. "Here it comes! Come on baby! Good!"

Cheung fills a syringe with liver cells, which she grew in an incubator, and injects them, about 300 million in all, into the liver. Future versions will hold many more cells, in approximation of a natural organ -- a design that someday could save human lives.

Cheung sews up the rat's abdomen with the man-made liver inside. But the animal's lungs and heart are failing.

Hoping to revive the rodent, Vacanti massages its chest with his finger. Another of his assistants, an open-heart surgeon, performs mouth-to-mouth resuscitation with a tube.

"Come on animal!" Vacanti says.

But rat No. 7 seven is dead.

"He just didn't understand his pioneering role," Vacanti says.

The surgeon has made history: he is the first to build such a liver, and now to demonstrate that an animal's circulatory system can move blood through it.

Still, he isn't satisfied. He insists on two more tries.

Both end in failure.

Everyone but the boss seems discouraged. "Today was enormously productive," Vacanti says. "I don't think anyone should be disappointed."

"I wish we had a surviving rat," Cheung says.

"We will," Vacanti says.

SOME WHILE later, Vacanti takes the stage before an audience of doctors and technologists at a conference in Boston.

A man of average height and build with touches of gray in his brown hair and a face gently creased by laughter, Vacanti looks a decade younger than his 55 years. He wears a suit and loafers, his standard attire.

Journal photo / Connie Grosch Dr. Joseph Vacanti, meeting here with senior lab tech Katherine Kulig, says: "It's completely unacceptable to be the premier tissue-engineering group and not be able to get an NIH tissue-engineering grant."

He is introduced as a Harvard Medical School professor, the chief of pediatric surgery at Mass. General, and the director of the hospital's Laboratory of Tissue Engineering and Organ Fabrication. The latter position is what draws the crowds whenever he lectures.

After apologizing for being late -- a surprise ice storm delayed him -- Vacanti starts showing slides of a few of the nearly 140 children into whom he has transplanted livers from human donors, most of them brain-dead strangers.

One slide shows an infant boy ensnared in a tangle of wires and tubes.

"His heart, his lungs, his kidneys and his liver had failed," Vacanti tells his audience.

With treatment, including a liver transplant, the boy survived.

"Here he is some two years after that," Vacanti says. He projects a slide of a smiling kid in sneakers and a baseball cap.

Vacanti speaks of the sophistication of liver transplantation today -- and of the shortage of natural organs for people who need them. Because demand exceeds supply, thousands of patients die every year while waiting for transplants. And it is that cruel equation that many years ago inspired Vacanti's obsession with finding a better way.

In the beginning, he did not attempt to build livers and other organs.

Collaborating with Robert S. Langer, the renowned Massachusetts Institute of Technology scientist, Vacanti tried to grow cartilage, a relatively simple tissue found in ears, noses, elbows and knees.

Vacanti projects a slide showing cartilage he grew in the shapes of a cross, a square and a triangle. "In 1988," he says, "we learned that we could make precise shapes, add the cells, implant them, and produce living tissue."

With that success, Vacanti asked colleagues in plastic surgery for a bigger challenge. "They said the holy grail for reconstructive plastic surgery is the human ear," Vacanti tells the audience.

The surgeon shows Slide 21: a photograph of a hairless mouse climbing out of a petri dish.

A perfectly shaped, life-size human ear is growing off the animal's back. The ear is almost as large as the mouse.

It is a jarring image. It captures the promise -- and the potential dark side -- of a strange new technology.

"This occurred at about the time of the first Jurassic Park," Vacanti says. "When we presented this at the American College of Surgeons, this was affectionately called 'auriculosaurus.' "

The surgeons found the ear intriguing, if odd, but some lay people were horrified when the image was broadcast in a 1995 BBC documentary on Vacanti and his three younger doctor brothers, Chuck, Marty and Frank, who by then were collaborating with him. The Associated Press sent the photo world-wide.

"Obscene," said an animal-rights activist. What was next from Dr. Frankenstein -- an animal ear on a human?

VACANTI'S eleventh-story office is small and made smaller still by the papers and books that fill it. The view through the window is of roofs and a sliver of the Charles River near the Massachusetts Institute of Technology, a subway stop away. This is not the glistening corner domain of some successful entrepreneur. The most eye-catching object is the framed photograph of Sicily's Mount Etna that hangs behind Vacanti's desk. The volcano is erupting in a fury of orange and red.

"I took that picture," Vacanti says. "I took my kids to Sicily in the summer of 2001 so they could meet their relatives. Our families are from the southeast part of the island."

The Vacantis left Sicily in the late 1800s and settled in Omaha, Neb. The surgeon's paternal great-grandfather became a contractor and his paternal grandfather a courthouse clerk. His mother's family, the Francos, arrived in Omaha from Sicily early in the 20th century. Grandfather Filadelfo Franco took a job with the Union Pacific Railroad as a boiler repairman.

"I'm 100 percent Sicilian-American," Vacanti says. He was raised a Roman Catholic.

Vacanti shows a visitor a sepia-toned photograph of railroad workers, including the young Filadelfo, dated 1922. Decades later, he would sit his young grandson on his lap. "He'd be all greased up and dirty and gritty," Vacanti recalls, "and he'd say: 'JP, you learn to use your brain. I've had to use my back -- you learn to use your brain.' "

Vacanti's father became a professor of dentistry at Omaha's Creighton University, and his mother, a pre-medical student, left college in the 1940s to start a family of eight children. Vacanti, the second-oldest, wanted to be a doctor as a boy. From Creighton, he enrolled at the University of Nebraska College of Medicine. While there, he married and had two children, twin sons.

Vacanti decided to pursue pediatric surgery, which would combine his main interests in medicine. He did not expect to be offered an internship and residency at an Ivy League institution. "I thought coming from Nebraska I had a very low chance of getting into a good place."

During his last months at medical school, Vacanti, traveling with his wife and baby boys in a beat-up Volkswagen camper van, visited two dozen medical schools. He didn't plan to stop by Harvard until a University of Vermont professor put him in touch with Dr. Judah Folkman, the prominent cancer researcher and a mentor to generations of young doctors. Folkman took a liking to the Nebraskan, and Vacanti was invited to return for an entrance exam.

He wasn't sure he could get back.

"I had no money -- zero money. We had no jobs, I had two children, and I was living in Omaha, Nebraska, above the gym of my parish grade school because I was the guard and we got our rent [paid]. To get on an airplane to come to take this test was a huge big deal for me. But I committed to doing it because I didn't want to say 'what if?' ten years hence."

Vacanti passed the test. He moved east, and he and his wife had two more children. (All four are now grown). The couple later divorced. Vacanti remarried and lives with his wife, Susan, in the suburbs. Susan is the one who encouraged the surgeon to take time from his obsession for leisure.

"Find a hobby or you'll die," Susan says. Vacanti has two: photography and astronomy, the study of the heavens.

Journal photo / Connie Grosch Dr. Wing S. Cheung, Vacanti's chief assistant on the liver project, has an M.D. from Harvard and is working on an M.B.A. from Duke.

UNLIKE THE HEART, the liver is not romanticized.

Indeed, it is an unglamorous-looking thing: weighing about three pounds in a healthy adult, and located on the lower right-side abdomen, it is reddish brown, squishy to the touch, and shaped like a large apple turnover.

But what happens inside the liver's approximately 300 billion cells is unrivaled by any other organ. Among other functions, the liver makes bile to help digest fat, stores energy, processes nutrients, detoxifies poisons such as alcohol and drugs, produces clotting factors, and plays a vital role in the immune system. Compared to the heart, which is essentially a pump, the liver is princely.

In 1984, as now, livers for transplant were in short supply. The procurement network was primitive. And the University of Pittsburgh's Dr. Thomas E. Starzl, who had virtually single-handedly established the field, often got first dibs when an organ became available. He was, after all, the pioneer.

By 1984, Vacanti was head of the new transplant program at Boston Children's Hospital. One day, a dying baby was admitted to his hospital. The baby needed a new liver to survive.

The organ bank responsible for assigning livers, Vacanti recalls, had one available. According to Vacanti, it was in Nova Scotia.

It's going to Pittsburgh, an organ bank official told him over the phone.

What do you mean it's going to Pittsburgh? Vacanti said. He was stunned.

I'm sorry, the official said, but it's going to Pittsburgh.

But why?

Because that's the way the system works, Vacanti was told.

"I had this mental image of this organ flying directly over Boston and not coming to my patient for a reason that was not my fault or the baby's fault," the surgeon recalls. "I was enraged -- I was absolutely apoplectic. I thought I should have gotten that organ and I didn't, and that baby died. And so I said: 'This is a bad way to do things.' "

The dead baby haunted Vacanti. Increasing donor awareness would be unlikely to solve the organ shortage, he concluded, and he figured he had little to offer researchers seeking to use animal organs for transplants since he had no training in immunology, one of the key disciplines in that field, xenotransplantation. Stem cell therapies were still in the future.

"So I said, 'how is it that I could use my own abilities to figure out a way to do this?' " Vacanti says. "And I came to the conclusion that the way to do it was to build them."

ONE MORNING toward the end of last year, Vacanti gathers his researchers for his weekly lab meeting, in which everyone is updated on projects involving the creation of kidneys, lungs, marrow, bone, intestines, teeth, elastin, and more. Vacanti is nothing if not a man with many irons in the fire.

But the pressing topic this day is money. It costs some $30,000 a week to run this lab, and Vacanti himself must raise most of it.

The scientist has recently learned that the National Institutes of Health, a longtime sponsor of his research, has rejected his application for a five-year, $2.5-million grant for the liver project. The room falls silent when he announces the news. In the year since one of nine rats had made history, the liver team has made significant progress. They are not ready to try their device in a person yet, but they are much closer to trying it in a large animal, such as a pig -- just one step from human trials.

Vacanti praises everyone's efforts in helping write the grant application, then notes that the NIH's criticism had been harsh. " 'Missing critical information,' " was one comment from a grant reviewer. " 'Remarkable innovation overshadowed by problems,' " was another. The NIH was particularly displeased that not enough emphasis had been placed on the biology of an engineered device -- the biology of the hepatocytes, the human liver cells.

Craig Neville, a scientist on Vacanti's staff, says the NIH typically is leery of high-risk projects -- projects with no guarantee of success.

"They like slam-dunks," Neville says. That view is commonly held by researchers who work the frontier.

Vacanti is uncharacteristically upset.

"It's completely unacceptable to be the premier tissue-engineering group and not be able to get an NIH tissue-engineering grant," he says.

He suspects a bias against scientists like himself who hold M.D.s but not also PhDs, and as evidence, he cites a study showing that physicians with both degrees are nearly three times as likely to be awarded grants as those with M.D.s alone. "Transplant surgeons are considered dumb, even if you've been doing it for thirty years, as I have," he says.

But Vacanti does not remain glum for long.

"Clearly they like this whole concept," he says, "but we were weak."

So they will rewrite the application, emphasizing biology, perhaps with the input of a hepatologist. Other funds will allow the project to continue -- but not at the accelerated pace the grant would have permitted.

On another occasion, Vacanti talks about the burden of raising money from his three main sources: the government, industry and philanthropists. He laughs when asked if he ever fantasizes about Bill Gates writing him a check.

"If you've got his number," he said, "that would be great!"

But lightning rarely strikes like that, and barely a day passes that Vacanti and others in his position do not endeavor to find money. It takes time from the science, he says, "but you gotta do what you gotta do."

TWO WEEKS after Vacanti dropped his bomb, Cheung returns to the laboratory operating room for yet another experiment. Vacanti has other duties this day, but he has faith in Cheung.

Thirty-one years old and the first of three children, Cheung was born in Hong Kong, where her parents had relocated from their birthplace in China's Quandong province. Cheung was four when the family moved to Germany and opened a restaurant. After five years, the family went to California, where her parents remained in the hospitality business. She was in elementary school when she decided she wanted to be a doctor

"I think I respected my doctors and wanted to be just like them," she says.

Cheung graduated with honors from California Institute of Technology, then received her M.D. from a program run by Harvard Medical School and MIT. She was a surgical resident at Mass. General when Vacanti hired her as a research fellow and assigned her the lead role in his liver project. She works long hours in his lab, and every month spends a few days at Duke University, where she is pursuing a master's degree in business administration.

Although her quest for an MBA sets her apart, Cheung's ambition and intellect are representative of the caliber of people whom Vacanti now attracts. Some are established scientists, while others are fellows, graduate students, and even the occasional undergrad.

They come from China, Japan, Australia, France, Taiwan, Canada, the United States and elsewhere. Some are based at MIT, where the Iranian-born engineer Mohammad R. Kaazempur-Mofrad wrote the 60,000-line piece of software used in the liver device's internal design. Others work at Draper Laboratory in Cambridge, a technology center where guided-missile navigation systems are designed -- and where components of the devices are made. Some work for the Center for the Integration of Medicine and Innovative Technology, a collaborative of Draper, Harvard, Harvard hospitals, and MIT.

Some researchers stay weeks, some far longer. Cheung will be with Vacanti for two years, after which she will resume her surgical residency.

"Tissue engineering is really exciting and it's still very much pioneering work in a field people probably even five years ago didn't accept as science," Cheung says. "It's fun to be more in the beginning stages of a new paradigm than at the tail end of something well-established."

CHEUNG anesthetizes and shaves a rat and brings it to the table.

In the year since one of nine rats made history, nearly 200 more have visited this room. With the guidance and occasional hands-on involvement of her boss, the young doctor has resolved several problems.

She has corrected the anesthesia, and she has found a new position in the rat's abdomen that improves the flow of blood through the device. She has confirmed that larger rats tolerate surgery better than smaller ones, and since most breeders don't sell the rodents larger than about 400 to 500 grams, she has taken to buying what is available and fattening them up in the lab.

Meanwhile, new complications arose: rats survived the implantation of the liver device, but the blood clotted. Cheung hoped that heparin, a common anti-clotting agent, would solve the problem. First she injected it beneath the skin, without success. Infusion through a vein failed, too. Finally she infused heparin directly into the liver device itself.

That resolved the clotting issue, and the rats began routinely surviving -- for six to eight hours. Cheung observed that during that time, a whitish fluid accumulates in the device. Is it an infection releasing lethal toxins? Is it an inflammatory response to the device's synthetic materials killing the rats?

Journal photo / Connie Grosch Lauren Lukianov, 14, is one of Vacanti's inspirations. He's had to give her two liver transplants. "The research in my head never drifts from the patients," he says.

Paying special attention to sterile technique, which will reduce the risk of infection, Cheung opens the rat with the assistance of Dr. Michael Gross, 31, a new research fellow from Germany. Cheung has already given the animal a dose of steroids, which should prevent an inflammatory reaction.

After nearly 200 rat operations, Cheung moves confidently and quickly: a few minutes, and the latest version of Vacanti's liver is sewn in. She unclamps the artery, and blood begins to flow.

"That's fast -- very fast flow!" she says. "You can see the pulse."

Cheung and Gross observe for several minutes, then close the animal up. Cheung returns it to its cage and injects an anesthesia-reversing agent. Three minutes later, the rat begins to stir. A few minutes after that, it wobbles to its feet. Gross injects a pain killer.

IN FRAMINGHAM, Debbie Lukianov goes to the back door of her house and calls for her daughter Lauren to finish her homework. A rosy-cheeked, shy girl of 14 comes through the back door and stops at the dining room table, where her mother and father, Alex, are telling her story.

Born with a defective liver, infant Lauren survived when doctors performed two remedial procedures, but by the age of three the girl needed a replacement organ or she would die. Vacanti gave her one -- a piece cut from her father's liver that regenerated into her own. But it failed, slowly and painfully, and after years of rehospitalizations, only a second transplant could keep Lauren alive. Using a liver from a brain-dead stranger -- from some other family's tragedy -- Vacanti and his assistants performed it, in a 16-hour operation in October 2002 that nearly emptied the hospital's blood bank.

"A massive surgical undertaking," Vacanti called it. "Terrible."

Complications from that transplant, including kidney and lung failure, kept her in Mass. General until three days before Christmas 2002.

"It got annoying," Lauren says.

One of four children, Lauren has been in good health since: she has gained weight, and, with her doctors' approval, for a time considered trying out for a hockey team. Given her past, every day is a blessing.

Lauren disappears into her room while Alex, an operations manager for a chemical distributing company, remarks on Vacanti's obsession.

"There's such a shortage of donor livers," he says. "They go to the sickest people who have been on the list the longest. In some ways it defeats the purpose, because they have the lowest survival rates because they're already so sick. It's kind of behind the eight ball by the time you get an available organ.

"If there's any other alternative -- especially through manufacturing the liver and putting it in a kid or an adult when they're still in reasonable shape -- that would be tremendous."

CHEUNG PRESENTS the results at a lab meeting the week after the latest rat operation. Vacanti already knows. He monitored the experiment first-hand.

At twenty-four hours, the rat was alive and the device was functioning: no clotting, no whitish fluid. The same results were observed at 48 and 72 hours, and so Cheung decided to wait two days before opening the animal again. But sometime during that time, the animal's movements dislodged the catheter that was supplying heparin to the device, and it clotted.

Nonetheless, it is a significant achievement.

"This is the first long-term success," Vacanti says. "That's tremendous news!"

After the meeting, Vacanti elaborates on the importance of the experiment: "It's a huge milestone. In general, if you can do things once you ought to be able to do them again and again and again."

Vacanti notes other advances in the preceding year.

The team has made the layers of the device thinner, meaning more can be stacked together in imitation of a natural organ. They have improved the internal design, and the manufacturing and assembly -- the microfabrication. Vacanti envisions a liver that someday can be produced in bulk quantities, available on demand for anyone in need. It will be built of a biodegradable polymer, which will disappear over time, leaving an organ like what nature made.

But that day, if it comes, is still some while away -- how long exactly, the scientist cannot predict. More than a year ago, when one of nine rats made history, Vacanti had hoped to be conducting large-animal experiments in 2003; now, he hopes to get there by the end of 2004.

"I still believe completely that we can actually achieve this," Vacanti says.

And it is patients like Lauren, not the intricacies of microfabrication, that sustain him.

"The research in my head never drifts from the patients. Even when we were talking in that room -- polymer issues and microfabrication issues -- in my brain were all those patients. They never leave me."

DIGITAL EXTRA: Find Web site resources related to this story, and browse previous installments in G. Wayne Miller's occasional series on pioneering medical techniques, at:

http://projo.com/extra/2003/medical_pioneers/