This article appears in the August 2011 issue of LouisvilleMagazine. To subscribe, please visit loumag.com.
No alarm sounds, but Dr. Roberto Bolli is awake. Again.
He’d slept fitfully, waking often to fret about the coming day, the thousand things that could go wrong, every possible misstep. Now, at 6 a.m., there is no point staying in bed. By 8, the cardiologist is in the bone marrow transplant laboratory at the James Graham Brown Cancer Center watching his research team prepare precious stem cells. The cells, coddled and multiplied for four months, will now, with a bit of luck, save a life.
Across the street in Jewish Hospital, doctors prepare Mike Jones to receive those cells. Jones, 66, a painting and remodeling contractor, will be awake during the procedure.
It’s good to be awake when you’re making history.
Depending on how you look at it, Jones is either a first or a second. He will be the second patient in the world to receive stem cells grown from his own heart tissue. Three weeks ago, a research team at Cedar-Sinai Medical Center in Los Angeles beat the Louisville group to the “world’s first” title. But Jones can claim another first: He will be the first patient to receive a pure dose of this particular type of stem cell from heart tissue. The cell has a practical name: c-kit-positive cardiac stem cell. Although “c-kit” refers to a docking site on the cell surface designed to receive chemical communication, for Bolli, c-kit is simply a handle for grabbing cardiac stem cells, cells capable of growing every type of cell found in the heart.
Today’s procedure, on July 17, 2009, is about giving those cells back to Jones. They were collected during his open-heart surgery almost four months ago. If things work the way they’ve worked in experiments in mice, rats and pigs, within four months Mike Jones will be nearly as fit as any healthy man his age. His heart, now a wreck that can barely push his blood around, will return to life — not completely, maybe not even a lot, but still dramatically — and Roberto Bolli, the researcher and cardiologist who is orchestrating this Phase I clinical trial, will be much nearer to his goal in the race to repair broken hearts.
But Bolli isn’t the only runner. Not only have Cedar-Sinai researchers put another kind of cardiac stem cell into patients, but there also are researchers in the U.S. and Europe treating hearts with stem cells found in bone marrow. One team attaches stem cells to biodegradable threads that can be stitched through the dead parts of failing hearts. A few groups work on heart patches featuring stem cells. Other groups use cells from human embryos capable of making every cell in the body, including heart cells that rhythmically beat in a petri dish. And some work with cells called inducible pluripotent cells — adult cells coaxed to leave their mature ways behind and become primitive cells, like the embryonic cells.
It’s a big contest. For a big prize.
“Anything where the stakes are high, there’s going to be controversy, and here, the stakes are very high indeed, because this is such a bad illness, and it affects so many people, and the health implications are enormous, and the economic implications are enormous as well,” says Dr. Charles Murry of the University of Washington in Seattle.
Although some in the field are loathe to call this a competition, it often sounds like one. Maybe that’s not all bad, suggests Dr. Mark Slaughter, the surgeon who opened Mike Jones chest and collected the heart tissue that would yield stem cells. “These are exciting times,” Slaughter says. “It’s good to have five, six, seven programs going. It’s sort of like the race to the moon. That’s actually a good thing, competition, because everybody is learning more.”
Bolli’s office in the Ambulatory Care Building on the University of Louisville Health Science campus holds a prodigious number of chairs. There are desk chairs, and conference-table chairs, and a chair with the university seal on the back. There are enough chairs here for a dinner party, enough furniture for a high-end garage sale. It is a very crowded room.
He perches in one of those chairs in a glen plaid jacket, striped button-down Oxford shirt and a striped tie, and talks for two hours one afternoon in May 2011 about his research. The interview wraps up just as the Pegasus Parade begins its trek down Broadway. It won’t affect his drive home; he has several more hours to his day. He works until 8 every night. There is just too much to do. He runs the Institute of Molecular Cardiology, with a staff of 80, including 21 faculty members. He also has his own lab of 20 to lead. And he’s the editor of the journal Circulation Research.
He speaks accented English — he came to the States from Perugia, Italy, in 1978 after medical school there. Every day, sometimes twice a day, he talks on the phone with his friend — his collaborator in the stem cell trial — Harvard professor Dr. Piero Anversa. Anversa’s accent is heavier. He shares Bolli’s work ethic. His last vacation was four days in 1992. Otherwise, he’s in the office seven days a week.
It is Anversa’s research that got this started. He was the first to uncover stem cells in the heart — perhaps because no one else believed they were there. Then he worked out how to grow those few stem cells — no more than one in every 40,000 heart cells, he says — into populations of millions. And he’s been in the middle of a fight ever since he began overturning conventional wisdom about what the heart can do, starting with a New England Journal of Medicine paper he authored in 2002.
“We were crucified,” Anversa says.
At that time, nearly everyone believed that the adult heart was a one-and-done deal. If you lost heart cells in a heart attack, they were gone. Since heart tissue killed in a heart attack never recovered, the belief made sense. Still, Anversa wanted to consign that belief to history.
His was a minority view. So few people agreed with him, the New York Times called him the “lonely skeptic.”
Anversa’s 2002 paper was actually not his first attempt to pick away at the notion of the finished heart. A year earlier, also in the New England Journal of Medicine, he presented evidence of heart cells dividing. But the 2002 research caught the cells not just dividing, but also taking on new roles, as only stem cells can do. Anversa looked at hearts from men who received a woman’s heart in a transplant. After the men died, he wanted to see if all the heart cells remained female.
They didn’t. Scattered throughout the heart were cells with the XY chromosome all men carry. When Anversa looked more closely at these cells, he reckoned they came from a small bit of native male heart tissue that remains at the time of transplant. If he was right, then what people thought about the heart might be wrong. It seemed to indicate the heart had a population of cells waiting to become every cell type in the heart. This cell division wasn’t fast enough to undo the devastation of a heart attack, but it played some role in heart maintenance.
The opposition was immediate and sharp.
One letter to the journal disputing Anversa’s findings said the researcher used “inappropriate measures to reach an inappropriate conclusion.” Anversa’s remarks “added confusion to an emerging area of research already mired in controversy.”
A year later Anversa published another paper showing that c-kit-positive cells in the hearts of adult rats satisfied every definition of a stem cell: They were self-renewing, they could create clones of themselves and they were multipotent, meaning they could become many cardiac cell types. In September of that year, he demonstrated that the c-kit cells he found in rat hearts were also in adult human hearts. And he went on to show how these cells could be grown into cardiac myocytes — heart muscle cells.
Despite a flood of papers that followed, published in the most prestigious medical journals, controversy lingered. Nearly a decade after Anversa’s original discovery, some continue to believe that c-kit-positive cells lose their ability to become other cell types in the adult heart. Most notable in the group of c-kit skeptics is the University of Washington’s Murry. He cites research published last year in the journal Circulation by Loren Field of Indiana University that details a series of experiments in which c-kit-positive cells from the adult mouse heart failed to turn into other heart cells. Murry suggests that Anversa’s work cannot be reproduced.
“Virtuoso performance — science and medicine aren’t based on that kind of thing. The cornerstone of advances in medicine are things that can be reproduced,” Murry says. “Nobody else gets anything of this scope to happen. If you can’t do it in a controlled laboratory setting with genetically identical animals, there’s no way something is going to have a robust effect in the clinic.”
Field is more circumspect. “What’s important to keep in mind is that all these experiments are probably slightly different. When we get a negative result, that doesn’t mean the other guy is wrong,” he says. Even if the c-kit-positive cells are not stem cells, it’s not correct to say these cells won’t help patients like Mike Jones, he says. “It could be there is a benefit completely independent of any myogenic event.” In other words, it could mean the cells help, but without ever changing into heart muscle cells.
Anversa dismisses both Field’s research and Murry’s depiction of a “virtuoso performance.” He says a number of research groups have duplicated it. “They’ve been trying to challenge everything we do,” Anversa says, noting previous arguments with Murry and Field. “Loren Field and Chuck Murry, they’re making a career out of it. They’re saying the opposite of everything we say.”
In this new field of research, disagreement is the norm. What varies is the collegiality — or the vitriol — of the disputants.
For Mike Jones, the stem cell transplant procedure marks an already important occasion: the anniversary of his first date with his wife Shirley. For Dr. Sohail Ikram, the interventional cardiologist infusing the stem cells, it’s just a slightly different day at the office. For Roberto Bolli, it’s a nail-biter.
Ikram will thread a catheter through Jones’ femoral artery and maneuver it into the heart. He’ll take pictures of the coronary arteries. When the cells are ready, he’ll inflate a small balloon in an artery — actually, into the bypass artery Slaughter put in during Jones’ surgery four months ago. Up to that point, the procedure will be familiar. But this time, Ikram will leave the balloon inflated three minutes, blocking circulation. He’ll then release heart stem cells, a half million in one artery and, later, a half million in a second location, and hope the cells know where to go.
Bolli has worked four years to win approval to start this trial. Heaven forbid anything goes wrong; heaven forbid they cannot get the cells into Jones’ heart fast enough.
“These cells, once you take them out, they don’t like to stay at room temperature too long,” Bolli says.
Nearing 11 a.m., Bolli and his colleagues prepare to cross the street to Jewish. They pack the cells in a white polystyrene box. “I took the box myself because if somebody was going to be run over by a car carrying these cells, I would rather be the one. I will be remembered for something,” he says.
At Jewish, Bolli can’t help watching the clock. The arteries Ikram photographs are tortuous and difficult to get through. It’s slow going. The arteries spasm. Then the first balloon Ikram inflates is too small to block the artery. So is the next one. It takes a few tries to find one that is just right. In Bolli’s anxiety, the process seems like an eternity.
But it isn’t; it’s all over by two in the afternoon. Bolli is exhausted and happy. “We had done something that hopefully will benefit humankind. That doesn’t happen very often. It was a wonderful feeling,” he says. Now all anyone can do is wait to find out what the cells do in Mike Jones’ heart.
Time for a reality check. This is a phase 1 trial and it has one goal: to make sure the stem cells don’t harm Jones and the other trial participants. That’s it. If no one gets better, but no one gets sick from the stem cells, the trial will have been a success. In the next phase of testing, with many more patients, patient improvement will be the goal. But not now. Yet as often happens when the stakes are high, people forget this. If this therapy works, it will provide real hope for the five million Americans with heart failure, a quarter-million of whom die annually. Stakes don’t get much higher than this.
The amazing thing is, Mike Jones, patient No. 1, does get better. So does James Dearing, patient No. 2. Nearly all of the 15 patients assessed by May show improvement.
Bolli calls the results “striking, way above our most optimistic expectations.”
To track improvement, physicians use a heart measurement called “ejection fraction,” which assesses the heart’s pumping ability. The number represents the percentage of blood remaining in the left ventricle — the largest pumping chamber — after the ventricle squeezes blood out to the body. In a healthy heart, somewhere between 50 percent and 70 percent of the blood in the left ventricle pumps out with each beat. An ejection fraction of 40 percent or below usually means heart failure. People in the Louisville study must have ejection fractions below 40 percent to receive stem cells; their hearts are failing.
Among the 15 patients who’ve reached the four-month mark, ejection fraction improvements were unprecedented, averaging 8.5 points. And, more stunning, the improvement seemed to continue beyond the four-month mark. Ejection fraction gains for the eight patients who are one-year post-treatment averaged 13 points.
“That is huge,” Bolli says. “No other heart stem-cell trial has seen this kind of improvement in ejection fraction.” Previous stem-cell studies, most employing stem cells found in bone marrow, report improvements of 3 to 5 percent.
But ejection fraction would mean little if the patient were still struggling to walk across the room, so the researchers look at various quality-of-life measures. Here, too, improvement is dramatic. Bolli’s team also uses the Minnesota Living With Heart Failure Questionnaire, a proven quality-of-life measurement, which inquires about things such as ability to climb stairs without resting, shortness of breath, sleep difficulties and ease of pursuing hobbies or work. The higher someone scores on this measure, the worse his or her quality of life. Thus far, people who’ve received the c-kit-positive cells saw scores decrease from an average of 45 before the stem cell infusion to 25 one year later. He also looks at the New York Heart Association Functional Class for each patient, a standard measure of heart function in which 1 represents patients with normal heart function and 4 represents patients mostly bedridden and short of breath with minimal exertion. Louisville patients improved by more than one functional class, on average, Bolli says.
Before his procedure, Mike Jones tired tossing a football around with his granddaughter. “I couldn’t pass more than three or four times without it bothering me,” he says. After his stem cell infusion, “I got to the point where I was doing the treadmill for 30 minutes at 3 or 3.5 (miles per hour) with a 1 degree grade on it. It’s most definitely the stem cells. I can do about anything I want to do now.”
James Dearing, patient No. 2, says that when he went into the stem-cell trial, his ejection fraction was 37. Now it’s over 50. “I’m walking every day now,” he says. “I tell everyone I meet about this. Maybe someday it can rejuvenate many, many hearts.”
If these results hold up, Bolli says, “this will be the biggest revolution in cardiovascular medicine in my lifetime — bigger than heart transplants, bigger than the artificial heart.”
But other researchers in the field remain skeptics. They question whether ejection fraction really reveals much about the heart’s recovery. The real test, they posit, is to see if dead areas of the heart shrink. Limited testing on this issue among Louisville patients has been inconclusive. Others say that some portion of the dramatic increase in ejection fraction must be credited to the heart bypass operation each patient had first, a claim Bolli disputes.
And then there is the question of what the cells are actually doing in the heart. No one can say with any certainty. They don’t know where they go. They don’t know how they improve heart function. They don’t even know how many of them stay in the heart. In fact, it seems almost none do.
It’s May 2011, in a cool and bright surgical suite in Jewish Hospital. The blue-clad surgical team clusters over the anonymous man whose chest is laid open. Mark Slaughter prepares to shut down the patient’s heart in order to install new arteries, which will bypass severely blocked ones. But right now the heart beats, exposed and vulnerable, the best witness to its own troubled state.
The normal heart is about the size of a fist. This heart is the size of a football. This is what heart failure looks like.
When someone suffers a heart attack, the heart muscle is deprived of oxygen. The longer it takes to restore flow, the greater the risk that sections of the heart will die. When heart muscle dies, it weakens the heart’s ability to push blood through the body. The heart chambers try to compensate for this lost pressure, stretching to hold more blood. This eventually leads the heart to remodel itself. Heart walls grow thicker, and the heart grows larger and rounder. The muscle moves less with each beat. The lungs fill as blood backs up into them. The kidneys receive less blood than before and no longer fully fulfill their role of eliminating liquid waste. Fluids build up in the body; ankles, feet and legs swell. A walk across the room feels like mountain climbing.
As he prepares to bypass blocked arteries, Slaughter harvests tissue to provide stem cells for this man later. He cuts into the small, deep-red atria, a floppy pouch sitting atop the massive left ventricle, and puts aside a small crescent scrap of atrial tissue. Then, using the hole this created, he sutures a catheter into the heart, connecting it to the heart-lung machine. At 9 a.m., all lines on the heart monitor go flat. The big heart, no longer inflated, sinks into the chest cavity and disappears.
The eyes of Dr. John Loughren, who had entered the operating room just before the bypass began, shine above his surgical mask as he picks up the little gob of heart tissue Slaughter removed. It’s pink and wet looking, about one gram. In quick cuts of small black scissors, he minces the tissue until the pieces look like tiny bits of hamburger floating in a liquid. This way, the cell nutrient material, a cotton-candy-pink liquid, touches more tissue surface area, he says.
He divides the bits into one of 10 small vials, no wider than a finger, manufactured to withstand super-cold temperatures. The freezer where the cells will be stored will drop 1 degree Celsius every hour until it reaches minus-80 degrees Celsius, or minus-112 Fahrenheit. Once frozen, the vials are shipped to Boston, where Anversa’s team fishes out the stem cells and grows multiples of them.
Initially, researchers thought that stem cells, when injected into the heart, would turn into heart cells and replace the dead and dying tissue. Dr. Eduardo Marbán now calls that “a simple-minded idea.
“That was the rationale for our experiments. That’s what we started off thinking,” he says. “It doesn’t seem to work that way.”
Marbán leads the Cedar-Sinai cardiac stem-cell trial. In a way, he’s Bolli’s major competitor, the only other investigator using stem cells from the heart. Marbán will not release results from his work until November at the American Heart Association meeting.
But the cells in both trials — in fact, all the cells in heart trials eliciting some functional improvement — present an identical mystery once they are put into the heart. They vanish. “The transplanted cells go away,” Marbán says. “More than 99 percent disappear.” Most of them don’t last an hour.
“So if you deliver 10 million cells, only one million are actually there an hour later,” says researcher Glenn Gaudette of Worcester Polytechnic Institute in Massachusetts. The biomedical engineer is developing a way to “sew” stem cells into the heart to prevent their escape. But even with these high attrition rates, the cells seem to help. Gaudette notes a study that found a lot of stem cells injected into the heart ended up in the lungs, where they boosted lung function.
And that may provide a clue. The cells can, apparently, squirt chemical signals alerting any cells around them. They juice the fatigued heart to make its resident cells divide. When researchers look at animal hearts after stem-cell treatment, they do see new heart muscle cells, a lot of them, more than the number of cells injected into the heart, suggesting that something in the injected cells appears to tell the heart’s own stem cells to wake up and go to work. Injected stem cells, instead of acting like little building blocks for the sick heart, perform more like little doctors, administering some cellular medicine to which the heart can respond.
These kinds of surprising findings are what happens when you’re working out on the frontiers. “There are no global truths,” says Dr. Joshua Hare, a University of Miami physician/researcher who works with stem cells from bone marrow. “Actually, everybody disagrees.”
“Medical research is always — people may not realize this — we’re always in the dark a little bit,” Hare says.
Clinical trials are a lot like horse races. You can know all the horses on the track since their birth. You can know the jockeys every bit as well. You can know what both horse and jockey had for breakfast. Yet picking a winner remains, well, a gamble. The unknowable variables are legion, the complete picture always cast in shadow. You can confidently determine who ought to win, only to watch evidence outrace your wisest supposition.
In 1999, a drug called Enbrel, used to treat rheumatoid arthritis, looked like the next hope to cure heart failure. Phase 1 testing in 90 patients showed marked improvement in symptoms. Two years later, the drug was history, at least in terms of heart disease. The trial showed it was no better than a placebo — a sugar pill — and possibly worse than nothing.
This is a familiar story in drug development, the story of a hero turned mope. Early this year, iniparib, a drug breast cancer patients clamored for after its stellar performance in phase 2 trials, flopped in the larger follow-up test. Last year, dimebon, a drug referred to as a “potential blockbuster” in the treatment of Alzheimer’s, turned out to be another lying tease in Phase 3 research.
Positive results early on are encouraging, but not a promise.
“It’s the beginning of a revolution and we are in the very early stages,” Bolli says. “I think, realistically, we are still three, four years away from FDA approval of any cells, or more like five years when all is said and done.”
“I thought when I entered the field in 2001, we’d be repairing hearts in 2004 or 2005,” says Dr. Ira S. Cohen of Stony Brook University Medical Center, co-editor of a book on stem-cell research published this year. “Now I think we’ll be successfully repairing heart maybe by 2025.
“The more I know,” he says, “the more I realize there are very significant barriers with each of the approaches.”
Photo courtesy of: John Nation