The Impossible Heart

They said it couldn’t be done, they being just about everybody in science, from the lowliest lab tech—excluding the ones working at Doris Taylor’s research laboratory at the University of Minnesota—to the honchos at the National Institutes of Health who refused to fund the initial work to create the world’s first transplantable bio-artificial heart.

Photo by Mark Luinenberg

One of the Taylor team’s bio-artificial hearts in a jar.

The first step—finding just the right mix of detergents that would strip a dead rat heart of all its cells while leaving the three-dimensional matrix they grew on intact—turned out to be the hardest. It took about a year. Getting the inert gelatinous structure ready to accept new stem cells from a live rat, injecting those cells into the matrix, and coaxing the heart to pump required less than a month. The now-famous “heart in a jar” had begun beating in the spring of 2005. Taylor would spend the next two years trying to get someone in science to believe it.

“Impossible,” the skeptics said. “Preposterous.” They should have known better than to use that kind of talk around Taylor, whose beating rat heart finally made the national news this past winter. “The last thing you want to tell Doris is you can’t go there,” says her sister, Juliana.

“I call ’em like I see ’em,” says Doris Taylor, several times a day. Taylor has an abiding love of the hackneyed phrase—as long as it gets her point across. Trust your crazy ideas. Think outside the box. Go for the home run. Make a difference. Trite maybe, but consider this: Practicing the truths she holds self-evident has made her one of the most original thinkers in science today.

Some compare her bio-artificial heart breakthrough to the discovery of penicillin, though such hyperbolic statements make her cringe. First, she says, it’s way too early to make such judgments. Moreover, she knows how they grate on scientists who are just as smart and dedicated as she is, but maybe haven’t been as lucky. “A million things could’ve gone wrong with that heart,” she says in her Mississippi accent.

On the other hand, few scientists follow the Taylor corollary to her observation about luck: Give nature the tools and get out of the way. The usual route to success in cell therapy research begins and ends in a petri dish, not with something as crude as a recycled rat heart cleansed of its cells and reseeded with new ones. Before coming to the U of M to occupy the prestigious Medtronic–Bakken Chair in Integrative Biology and Physiology, she hit her first home run at Duke University, training stem cells to turn into muscle cells. (Since hearts are mostly muscle, this is a critical step in creating a beating heart.)

In some respects, Taylor is true to type: a bit absentminded and not too concerned about her appearance until the media come calling—when she combs her hair, tucks in her blouse, takes off her glasses, and puts on some red lipstick. In other ways, she’s very much her own person, true to her roots. She’s given, for instance, to starting her sentences with the word so, which is usually followed by you know, long and drawn out and tilting toward a question mark, as if she’s thinking out loud, buying time, and also making sure her listener hasn’t futzed out after one too many fibroblasts and perfusable scaffolds.

Whether she’s explaining what endothelial cells do (line blood vessels) or why her all-time favorite book is The Secret Garden (“I’m a sap for stories full of feelings”), she doesn’t rest until she connects. She was painfully shy growing up, she says, and indecisive. She thought she wanted to be a physician when she majored in biology at Mississippi University for Women. Its president took an interest in her and pushed her hard. “I was lazy,” she says.

Self-awareness doesn’t necessarily give you a crystal-clear picture of yourself as others see you, especially if you’re a perfectionist. Juliana Taylor remembers her sister as a gregarious and highly industrious straight-A student who won a National Science Foundation trip to New York City for a high school project involving antibacterial substances secreted by red ants. It may have taken her awhile to decide between medical practice and research, but for as long as Juliana can remember, Doris has wanted to make a difference in people’s lives.

The lives of sick people, first and foremost.

Born in Germany to a career soldier and his wife, Doris Taylor grew up in the South in the sixties. After her dad died unexpectedly of cancer, her mother, Julia Taylor, brought six-year-old Doris and her twin brother, Dan, and one-year-old Juliana home so family could help raise them. Doris describes her mother as a strong woman who encouraged Doris and Juliana, who is a lawyer, to be whatever they wanted to be. “Mama had the brains but not the opportunities we had,” Doris says. “When I look back at her life”—she stops in midsentence and slowly shakes her head as if it’s just now beginning to sink in.

Julia Taylor had wanted to be a chemist like her father, but he couldn’t accept the notion of a woman scientist, so she majored in home economics and ended up in Japan. She was going to see the world one way or the other, Doris says. “Here’s this single woman in Japan, running service clubs for military guys, which is how she met my dad.”

If it was her mother who, as Taylor puts it, “planted the seed” of her ambition to be a scientist, family tragedy nurtured the seed into germinating. “My dad went from being sick to dying in two months,” she explains. Dan got the worst of it when the twins were born prematurely. (“We weren’t supposed to live,” Doris says.) Dan has cerebral palsy, and his care has always been a top priority in the Taylor family. “It brought us together like nothing else could have,” Doris says. “Mama made Dan the focal point of everything we did. She was a remarkable woman.”

Doris acknowledges that all that unfairness had its effect—not only the medical unfairness (Why did her dad have to die so young? Why was she born healthy and Dan wasn’t?), but the gender bias that kept her mother from having the career she’d wanted and the racial inequality of that place and time that came as a rude shock when the family moved home after Benton Taylor’s death. “Mama always told us, ‘Just do the right thing,’ ” Doris recalls. “She didn’t need to say any more.”

As a graduate student at the University of Texas Health Science Center in Dallas, Taylor thought she might end up in brain research, partly because of her brother. But she was told that the kind of real-world results that are the energizing force behind her sometimes unorthodox methods—in this case, seeing someone like Dan able to understand numbers, tell time, walk unassisted, and quell the demons that were eventually diagnosed as schizophrenia—could not be achieved in her lifetime or his. That’s when she decided, in the interest of making a difference, to concentrate on the heart.

In 2004 she’d been in Minnesota for three years. She was building a team, raising funds, experimenting with cells, and following up on her work at Duke to strengthen muscle tissue after heart attacks when one day she got this crazy idea. (She would prefer the sentence to read “her team got this crazy idea.” She may be team leader, but she is, most emphatically, a team player, who says she owes a particular debt to Harald Ott, a young Austrian PhD student. “Harald drove the heart project,” she says of Ott, who left the lab before the story broke to do his surgery residency at Massachusetts General Hospital in Boston.)

As Taylor remembers the scenario, she and Ott were brainstorming as usual one day, mulling over how to take stem cell research “from bench to bedside,” she says, when one of them, possibly Taylor but maybe Ott, said, What if we give the cells something to grow on that they might recognize as their own heart even though it isn’t—some sort of organic structure that the recipient would be less likely to reject than, say, a plastic or metal scaffold? And the other one said, Why not?

At the time, Taylor had been thinking about pig valves, which are routinely used in humans for replacement valves—their cells removed in order for transplantation to succeed. The idea of growing new cells on a whole-organ scaffold emerged from that thought process. Taylor sought, in effect, to skip over the tissue-engineering research that was progressing at a snail’s pace and build a heart from scratch. So they started riffing on this superbly crazy idea—Taylor in her drawl and Ott with his clipped accent—marveling at the sheer audacity of it. If the lab could strip a dead heart of its cells, reseed it with new cells, attach a pacemaker, and get it to beat—well, they’d have something amazing.

“Harald tried all sorts of things [to remove the old cells] and one day he tried something like ordinary shampoo,” Taylor says, “and, lo and behold, it worked!”

In the Newsmaking article she later published in Nature Medicine, Taylor describes the decellularized hearts this way: “The fiber composition (waves, struts, and coils) and orientation of the myocardial/ECM [extracellular matrix] were preserved, whereas cardiac cells were removed in compressed constructs. Within the retained ventricular ECM we saw intact vascular basal membranes without endothelia or smooth muscle cells.” In plain language, the “new” heart retained the architecture required to pump blood. It appeared to be perfusable. Even the aortic valve was in good working order.

“So the next thing we did was inject cells into the wall of the heart,” she says, while seated at a round table in her office, talking to one of the many journalists she’s explained this to since the story became public in January. “Cardiac muscle cells, smooth muscle cells, a mixture of endothelial cells, fibroblasts, heart stem cells, and everything that makes up a heart. That those cells living in the wall of the heart would connect to each other and would move to the blood vessel areas and do the right thing—we had no idea would happen. This was all new information for us. Every piece of it was new, and again every piece of it is where it could’ve gone wrong . . . . We did everything we could to bias it in our favor. We took cells we thought would work, cells we could isolate in the lab and that were resistant to ischemia [the effects of too little blood flow to the heart], you know, to increase the odds. But, still, there were plenty of ways we could’ve messed it up.”

The reseeded scaffold was placed in a bioreactor that simulates the cardiac environment. The team attached a Medtronic pacemaker that had come to Minnesota from Duke with Taylor. It took only four days for a semblance of a heart contraction to appear, and another four days for the hearts to pump hard enough to equal the function of a neonatal heart at sixteen weeks (about 2 percent of adult heart function). The breakthrough was dramatic.

One night, Ott and lab tech Thomas Matthiesen were babysitting the heart in the lab. It was hanging like a piece of meat in a butcher’s shop window—a very small piece of meat, smaller than a golf ball. The heart was inside a glass jar connected to more glass jars, tubes, cylinders, and the electrical leads that would be needed to jump-start the heart from lifeless protein to pulsating organ. The heart had started out looking like a hunk of gristle, but in recent days had gone from ghostly white to flesh-colored to pink to pink shot through with streaks of crimson.

The deepening in color had been greeted with slaps on the back and high fives. It showed that, in Taylor’s words, “both the larger cardiac vessels and the smaller third- and fourth-level branches were patent.” The scientists figured they might as well enjoy the progress while it lasted because they were sure it wouldn’t—couldn’t possibly—last much longer. But tonight was different. The red dollop of cell-infused collagen was no longer inert but moving—expanding and contracting. In, out. In, out.

Ott couldn’t believe his eyes. Sure, they’d hoped for this, but, like contestants on a game show, they knew that with every step forward the stakes grew higher, the statistical odds stacking more formidably against them. Ott grabbed a video camera and e-mailed his “movies” to Taylor at her condo so she wouldn’t accuse him of pulling her leg when he told her why he was calling at 3 a.m.

The hearts were next transplanted into live rat abdomens to test their viability (they weren’t strong enough yet to keep the animal alive). “The recellularized construct was contracting and drug-responsive after eight days of culture,” Taylor wrote later. Given time to mature, the heart could “be transplanted either in part (for example, as a ventricle for congenital heart disease . . . ) or as an entire donor heart in end-stage heart failure . . . . This approach holds promise for virtually any solid organ.”

The team hung more rat hearts. And soon they were decellularizing a pig’s heart, which is as close as an animal heart gets to a human’s. Someone was assigned the task of coming up with a pancreas scaffold. Livers, kidneys, valves, and blood vessels were added to the inventory for future reseeding with stem cells.

Using a human cadaver heart may be the likeliest long-term scenario if this technique becomes common, but Taylor doesn’t rule out building a human heart on a pig heart scaffold. Either way, she says, the challenge is one of scale, not cell biology. And scale, according to tissue engineers who have been trying to build organs for years, is a whole lot easier to solve. Taylor’s core ambition is to show that stem cells that are moved from one organ to another, even from a heart to a kidney, will adapt to the new environment and change their characteristics to support the new organ. For human subjects, the stem cells will likely come from the recipient’s bone marrow or heart tissue.

As for the rejection issues that have long bedeviled transplant efforts, removing the original cells and reseeding the heart with those of the recipient will, theoretically, eliminate problems associated with mechanical hearts. There’s no reason, Taylor says, why someone with a bio-artificial heart should need anti-immune drug therapy.

Making the bio-heart stronger is the U of M lab’s near-term priority. This involves coaxing cells to put on mass, through density and numbers, to build muscle. By the time the process has advanced to the point where a transplant can be performed in humans, there may be better approaches to solving life-threatening cardiovascular problems than transplanting an entire reseeded organ. That is why the lab is also researching, for instance, how to use new cells to reverse atherosclerosis, a leading cause of heart attacks and strokes.

Taylor keeps a pig’s decellularized heart in a jar in her office. Sometimes she picks up the jar and turns it in her hand. The heart floats, in limbo, waiting to meet its destiny. Could this ghostly white organ one day end up in a human? For all her optimism, Taylor doesn’t want to raise false hopes for the 30,000 Americans currently awaiting a donor heart. Yet, when asked if her breakthrough should accelerate the process, she smiles broadly and says, “Absolutely!” She says she can’t wait to enlarge her already wide circle of fellow problem-solvers and to bring skeptics, especially the tissue engineers over whose work she’s effectively leapfrogged, into the tent. “I’m a collaborator, and that’s what science is all about,” she says. “I’m also a very idealistic person.”

Taylor insists she has no illusions about who really deserves the credit for the world’s first perfusable bio-artificial heart. In her mind, the credit belongs to Mother Nature. “For a while, we were calling the heart our smart heart because we figured it could tell the cells what to do, and in many ways it did,” she says. “When we saw the heart beating, that was the eureka. That was fascinating and fabulous.”

Once the team had the bio-heart up and running, Taylor was faced with a quandary. To whom to tell the story—and how to best tell it? Determined as always to “swing for the fences,” Taylor devised a two-pronged scheme. They’d sell Tissue Engineering an article about the decellularization; Nature Medicine would be the lucky recipient of the sexier story about how the team reseeded the scaffold with new cells to create a beating heart.

But both publications wanted all or nothing. So Taylor opted to focus on Nature Medicine, where she had already been published. The editorial process is byzantine, and peer review in such a prestigious journal can be daunting. At Nature Medicine, three individuals—each an expert in a relevant field—have the power to accept or reject a submission.

It took Taylor two years and countless revisions before Nature Medicine accepted her paper. The team felt thoroughly beaten up by the process in which they’d all participated, throwing in additional facts and comments until it was looking to them more like a tuna hot dish (Taylor is still working up the courage to try this Minnesota delicacy) than a scientific journal article. After two rejections, Taylor had to make a choice. Should she appeal? Ask the U of M to cough up more funding for additional experiments to prove perfusability? Try to get a biotech company interested? Give up? She decided to appeal.

Christmas 2006 was an especially trying time. The group needed a lift, so Taylor went shopping at Target and bought a wind-up toy heart for everyone in the lab. Someday, she told the team, we’ll have an “off-the-shelf organ” on sale at Target too.

They sent off a revision on May 31. More waiting. Then, on a day like any other October-in-Minnesota day, they received an acceptance letter. Three months later, Nature Medicine led its January 13 online edition with the bio-heart story, including videos of the beating organ that triggered a cascade of attention. One media outlet would see the heart beating in another outlet’s video and give Taylor a call. She was getting so many calls she thought about disconnecting her phone. She’s still not answering media e-mails.

Of the scientists interviewed for this article, it was clinical heart doctors such as surgeons Jay Traverse at the U of M and Abbott Northwestern Hospital in Minneapolis and Francis Pagani at the University of Michigan who seem to most appreciate Taylor’s accomplishment. Like Taylor, they focus on the human patient whose heart isn’t working right. While each is well aware of the obstacles remaining between the slippery little blob hanging in a jar in a university research lab and the full-sized organ their patient must have to stay alive, both Pagani and Traverse can’t wait for the clinical trials to begin. And they say they’re confident there will be clinical trials—maybe not next year or the year after, but soon.

While she officially puts the time frame at ten years, Taylor the self-described enthusiastic idealist believes she can have a heart up and ticking and transplanted in a human even sooner, depending on how willing other labs are to share their data as scientists elsewhere attempt to replicate her experiment and take it one step further. Still, first things first. “We need to prove to ourselves that the heart truly is perfusable, that it can support a blood supply,” she says. “That’s what keeps me awake at night. Figuring out ways to test that.”

An important test of perfusability involves the transplantation of the heart into a rat’s abdomen. The bio-heart isn’t strong enough yet to keep the rat alive, so its own heart stays put, while scientists monitor blood flow and the animal’s reaction to the new heart in the abdomen. There may be other issues Taylor hasn’t foreseen, she says, emphasizing that she and her team are exploring new territory—which is precisely why she finds it such a thrilling adventure, like her mother’s long-ago adventure overseas when there wasn’t a job in her own country that would satisfy her curiosity about the world.

“It really did break in a big way,” Taylor says of the headlines the bio-heart story drew worldwide early this year. “That speaks to three things: the need out there, that it’s a story that makes sense to people, and that it’s a platform and not just bacteria in a dish.” Twenty-two million Americans are living with heart failure, and that number will grow as baby boomers move into their sixties and seventies. It’s impossible to estimate how many millions of people around the world need not just new hearts but new valves or vessels and how many need other organs.

Heart researchers in competing labs immediately expressed their astonishment at both Taylor’s achievement and their own thickheadedness. It’s so simple, one tissue engineer said to The New York Times; so obvious. This reminded Taylor of another Times reporter, one who, in 1998, covering her breakthrough at Duke, had asked, If it’s so simple, why hasn’t it been done already? To which she replied with her now stock spiel about out-of-the-box thinking. As devoted as she is to her rules to live by, when it comes to science, “Break the rules” is rule number one.

She was disappointed when some people questioned her methods, looked for flaws, kibitzed about the team’s initial failure to garner NIH funding, or complained that certain members of Taylor’s team hadn’t received enough credit. “The team is always the first thing I talk about,” she says. She frets about Ott’s departure. She misses him and hopes that one day he’ll again be part of her lab, this time with clinical surgery credentials to add to his PhD.

Ott, for his part, says he would love to work with Taylor again: “It would not have been possible to achieve these milestones in a lab where out-of-the-box approaches and a creative, sometimes unconventional way of looking at things were less welcome than in hers. I remember the countless afternoons and evenings we spent brainstorming and discussing scientific questions. And, in the end, we made tremendous progress in the fields of cardiac regeneration and cardiac tissue engineering. We had a good mix of translational researchers, allowing us to generate new data, always keeping the human application in perspective.

“When Thomas and I saw the first heartbeats and called her right away—it is hard to put these feelings into words . . . .”

Stefan Kren, who joined Taylor’s team after Ott left, thinks that, for Taylor, being a woman in the male bastion that is Big Science has been a challenge, one she doesn’t like to talk about. “Doris doesn’t mince words,” Kren says. “When a famous male scientist tells you in no uncertain terms you’ve messed up, you automatically cower and say he’s brilliant, but if a woman does, she’s the b-word.”

But it isn’t her gender per se that’s made her an inviting target in her male-dominated field. It’s how she thinks. Women are expected to be meek and accommodating, to perform certain “biologically appropriate” roles, to be followers, to be the meticulous data collectors. Whereas a man might be permitted to take risks and break rules, a woman is suspect unless she follows the conventional protocol, which, in science, means the incremental reductionist method that keeps researchers inside the box until every question is answered.

Taylor respectfully disagrees with those who regard reductionism as sacrosanct. It’s fine as far as it goes, she says, but for her it doesn’t go far enough. “What is a hypothesis? It’s a hunch, and then you go find all the data you can to back up that hunch—or not.” Hypothesis is also defined as the process of attempting to falsify a hunch through experimentation, and Taylor’s approach, if not heretical, is regarded as reckless by some.

While it’s tempting to attribute to that extra Y chromosome Taylor’s passion and openness, treatment of her team as family, willingness to collaborate, and faith in intuition, she will have none of it. What makes her a good teacher, for instance, is a sense of values, priorities, conscious decision-making, and intent, not some quirk of biology. “I’m good at articulating in a fairly straightforward way what we do, bringing together absolutely disparate thoughts and ideas.” To which she might add “without fear of consequences.”

“Like that New York Times guy said in ’98, if it was simple or easy somebody else would’ve done it,” she says. “It’s true we want to make a difference. So we want to go for the things that are likely to work. There are so many things we could’ve done. We could’ve said, ‘Let’s transplant cells and then slice the heart and look at them’ or ‘Let’s transplant cells and see if they make a difference in the ability of the heart to function. If they do, we can figure out how. If they don’t, we stop or we go back and figure out if we did the experiment wrong.’

“We’re never going to understand every detail. That’s where my mantra, ‘Give nature the tools and get out of the way,’ comes in for me. That’s what the whole cell therapy piece taught me [at Duke]—that we can wait the rest of our lives and understand exactly what every one of those cells does or we can start trying to understand it enough to make it safe and effective. And then we can go ahead and try to make a difference in somebody’s life. Tell ’em the truth. Tell ’em what we know and when we think it’s safe. ‘It’s an experiment, but here’s what we know. If you’re on board, you’re on board.’ ”

Her assignment when she was given her state-of-the-art lab and plush corner office on the seventh floor of the Mayo Building on the Minneapolis campus was to help make the U of M one of the world’s top research institutions, whatever that took. Minnesota’s weather terrified her at first, and its chilly social customs seemed a far cry from southern hospitality. But she was given a taste of something sweeter than a mint julep when she took the decell idea that had been rejected by the National Institutes of Health to the university’s Academic Health Center and was handed $250,000—though it was a pittance by NIH standards.

She has since shown the world what can be done on a relative shoestring, and now the NIH wants to fund her research to the tune of millions. What she and her team can do with that kind of money should make every Minnesotan’s heart beat a little faster.

“Ask My sister about the ants,” Taylor says toward the end of a recent conversation. If you were to focus on the species that put Doris on the road to science stardom, it wouldn’t be rats, pigs, or even people. Remember that National Science Foundation project? It would be ants.

Juliana Taylor hesitates a few seconds before telling the story. “Yeah, it’s true,” she says. “Doris and Dan made me drink red ant poison. They didn’t think it would do anything. They were just curious, I guess.” The twins were ten, Juliana only four. She nearly died. “You know those chemistry sets kids used to get?” Juliana asks. “Doris wanted that chemistry set so bad, and when she finally got it for Christmas—oh, the stuff she came up with! The vile sulfur smells! Something was always exploding at our house. They shouldn’t put stuff like that in the hands of children. I’ve always said, though, ‘Someday Doris is going to win the Nobel Prize.’ ”

People still claim center stage in Taylor’s life. She and her sister talk on the phone every day, and usually the topic is Juliana’s eighteen-year-old son, Taylor Forrest, who spent a month working in his aunt’s lab last year. Doris concedes she treated him as if he were her own son. While she misses the South, especially her family and her colleagues at Duke, Taylor says she’s made “wonderful” friends in Minnesota, including her partner, who brought to the relationship three teenaged children. It’s taken time and emotional energy, but Doris “is a Minnesotan now,” Juliana says. “Except when it’s minus-15 and she’ll call me and say, ‘They’re wearing Bermuda shorts!’ ”

Taylor hopes that with the NIH now apparently eager to fund her research (“We’ll believe it when we see it,” she hastens to say, because she hasn’t written the proposal yet), she’ll be able to attract more young scientists to her adopted state to work by her side, trusting their crazy ideas, thinking outside the box, and making a difference the way she was taught by her mother.

Julia Taylor died two years ago. She lived long enough to see pictures of her daughter’s beating bio-artificial heart, though not the headlines when the story finally broke on January 13. “But do you want to know the coolest thing?” Doris Taylor says. “January 13 is Mama’s birthday.”

Bonnie Blodgett is a St. Paul freelance writer whose book on smell will be published by Houghton Mifflin in 2009.