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an online version of the magazine Fall 2005
Irrepressible Dr. De
  Basic science is crucial, Josh Hare says. But should we really withhold a potential new treatment from desperate people while we study how it works in animals?

JOSH HARE WISHES HE COULD DO MORE FOR THIS PATIENT. The man before him is a graying gentle giant, a tall and good-natured divorced father of two grown daughters who's been battling heart failure since shortly after he hit 50. With aggressive applications of all the best therapies that conventional medicine has to offer, the man is now doing fine. But he's still only 58. A man that age should have the strength to go out for a run if he feels like it.

Hare wishes he could give Ronald Mueller new heart muscle, as he's starting to attempt with two new trial patients. The trouble is, Mueller's heart damage is too old for the trial's eligibility requirements.

“Heart rate's a little fast,” says Hare, shifting his stethoscope in a pattern across Mueller's chest and onto an enlarged belly.

“I was excited about seeing you,” Mueller chuckles a little nervously.

Hare and Mueller met six years ago, when Mueller ended up in a Hopkins Hospital bed gasping for breath, in serious need of a heart transplant—or some other medical marvel. Hare brought him back from the edge, but the recovery was interrupted by an aortic valve blockage two years ago. The returning shortness of breath so alarmed Mueller that he instantly called Hare, who sent him to surgery to implant a mechanical heart valve. Today Hare finds everything “in good working order,” given his patient's history.

“So you're going to renew my warranty for another year?” Mueller jokes, as he outlines plans to move from Maryland with one of his daughters to San Diego , where he can operate his home office tax-consulting business in between walks on the beach. He chats congenially with Hare about the latest cardiac developments, and Hare mentions his ongoing bid to apply stem cells to repairing injured hearts. “So that's what's next on the horizon for body parts,” Mueller quips.




A Damaged Heart Grows Back
With fellow dean (of education) David Nichols.
The heart of an untreated animal shows a thinned and scarred chamber wall after heart attack. The heart of an animal treated with stem cells shows the growth of new tissue over the region of scar in the chamber wall.

To keep it in the vernacular, the horizon is bursting with new ideas for body parts, and Josh Hare is in the vanguard. On the day of Mueller's visit to the Johns Hopkins Outpatient Center , Hare is three months into a bold new therapy tried only a handful of times before. He has enrolled the first of 48 patients with recent heart attack damage into a stem cell trial aimed at regenerating the dead tissue. At 43, Hare has set his sights on one of medicine's ultimate grails—to make weakened hearts nearly new again.

It's an exciting place to be, and, in its own way, also a supreme test of juggling ability. Just this morning, Hare participated in an exchange with the bioethics committee here. Hare and the ethicists discussed issues related to the future of this therapy, especially focusing on the question of whether it would be available to the masses. The carefully cultivated stem cells Hare is using are the commercial product of a private biotech firm. If the product ever wins federal approval for widespread use, will poor people have access to it?

But the bioethics discussion is just one more pressing detail in the intense juggle that has become Hare's everyday life. He must comply with a separate institutional review panel that checks his ongoing trial's design at every turn and holds the ever-present authority to stop him in midstream if it thinks patient safety could be compromised. He must adjudicate the urgent calls of anxious patients and their loved ones hoping for cures. He must preside over the routine turnover of ambitious post-docs and other associates in his research lab. He must maintain a $12 million NIH research grant. He must meet with a small parade of visiting U.S. senators, one pro-life, two others pro-choice, looking for his thoughts on the use of embryonic stem cells. He must also field the inevitable flow of media calls, all keyed to the heady notion coursing through medicine that certain very knowledgeable cardiologists know how to repair injured heart tissue, creating the expectation that heart attack victims waiting at death's door might one day be made vital again.

Other cardiologists at a handful of medical centers around the world are racing into the same niche, of course, and the advances are mounting. But Hare's own major paper has just been published, and it demonstrates for the first time the actual growth of a layer of new cardiac muscle atop the dead tissue, in laboratory pigs. The paper has become one of the linchpins upon which Hare will try the therapy with humans. But in moving to this stage now, he has entered into an arena fraught with heated debate over the way studies like his should proceed. Some scientists are conditioned to keep human patients at bay until they can understand how the new idea is actually working—at a molecular level—under the relentless gaze of unblinking microscopes.

Such exhaustive study can slow down breakthrough research for years, but the credo for many scientists is better safe than sorry. By not bringing potential new treatments to the market too soon, they believe, their process creates a valuable safeguard against injuring people. Hare sympathizes with these impulses, but he remains focused on the untold numbers of lives that will be gone by the time science can authoritatively explain why a new therapy works.




“I'm not afraid to challenge paradigms,” Hare says over a quick coffee in the Ross Building 's third floor café. His generous shock of rich black hair and intense gaze make him look perpetually awake, but today he looks especially on edge. This may have something to do with his mid-morning arrival from his Fells Point townhouse, where he and his wife are still adjusting to the spring birth of their second boy. Add to that the fact that Hare and his lab-mates are about to move from the older Ross Building into the brand new Broadway Research Building that adjoins it. The new space is very primo, and Hare will have a magnificent view out across the medical campus and beyond to the silhouette of the city's downtown district to the west. His new domain is part of the Institute for Cell Engineering, the sparkling banner behind one of Hopkins ' most promising portals into the brave new world.

Patients. People waiting for cures. As a true believer in the bench-to-bedside ethos, Hare thinks his routine interactions with patients sharpen his sense of purpose; the abstract ideas he studies in the lab take on the consequences of a human face. But he also cites a compelling voice that encouraged his current course.

In 2003, Hare started reading about Christopher Reeve's campaign to change the way medical researchers work. The “Superman” actor who'd become a quadriplegic had lost his cool, and was admonishing scientists. Reeve said too many researchers lacked a moral sense of urgency. He accused scientists of placing careerism ahead of the more immediate needs of people. He urged them to leapfrog past the glacial pace of molecular biology and focus on the agonized waiting of people stuck in wheelchairs. Reeve's chiding irritated many meticulous scientists, but Josh Hare took it to heart. And then he decided to take it to the human hearts all around him.




Joel Parran is a 61-year-old dentist from Columbia. He looks like a retired racing jockey, with a lean physique that testifies to his regular weekday Stairmaster and weight workouts. His appearance only accentuates the level of insult he feels over the heart attack he suffered the previous weekend. It happened during his regular workout in a Columbia health club. At first he thought the symptoms just couldn't be in the cards for a man so fit. Then he found himself lying flat on his back as people gathered. His first stop was Howard County General. His next, Hopkins, where cardiologist Steven Schulman told him of a revolutionary new study.

Schulman, one of Josh Hare's partners in the trial, was very low-key with Parran, even though he was inviting the dentist to become the first human in history to enter the stem cell study. Schulman carefully outlined the trial: Parran would receive a simple infusion, possibly containing adult stem cells, which had been derived from the bone marrow of an anonymous donor. Over the next six-month period, his health would be monitored carefully. Schulman described the potential promise, the potential risks, even the unknowns. And since this would be a blind study in which some participants would receive stem cells and others placebos, Parran might receive no benefit at all from this new approach.

Parran lay awake all night. On the merits, he actually had little to gain. The cardiologists had told him he'd only lost 20 percent of his heart muscle, which meant he'd had the “lucky” sort of heart attack from which healthy people can recover with only the mildest lasting effect. But by morning, Parran decided to act more out of altruism than self-interest. “The people here are good people,” he thought. They'd given him outstanding care. Helping them to get their study launched was the least he could do.

When Parran and Hare met the next day, they found that the common ground of their professions made the conversation easy. Hare asked Parran if there was anything he wanted to know about the treatment that was not covered in the consent forms.

“How do you know that the stem cells are going to go where you want them to go?” Parran asked, looking up at Hare from his hospital bed in the regular patient room where the cells would be infused.

These particular cells, Hare explained, have the ability to seek out injured cardiac tissue. Since Parran's heart damage was still new, the stem cells would find it.

“How do you know they won't form malignancies?” Parran asked.

“You don't,” Hare responded, acknowledging the unknowns. But none had manifested during repeated studies with healthy animals, he assured Parran.

Parran opted to stay in the trial.

And so at about 1:30 in the afternoon of March 25, 2005 , study coordinator Elayne Breton began preparing Parran's infusion. Her patient lay in bed, looking pale but relaxed, as cardiac leads were attached to key locations on his chest. The historical import of the moment became obvious as the room filled with a number of senior cardiologists. Hare was there, but so were trial partners Schulman and Gary Gerstenblith; even co-investigator Eduardo Marbán, head of the cardiology division, stopped in. Parran joked that it “felt like a ribbon-cutting,” and then he signaled to his infusers that they could proceed without further ado. “Let's do what has to be done,” he said.




When he was growing up outside Johannesburg , South Africa , young Joshua Michael Hare displayed an unbridled quality of initiative that sometimes overflowed. The Hare family was well-situated, with Philip Hare working as an attorney specializing in civil rights while his wife Isadora served on the faculty of the premier university, Witswatersrand, as a professor of social work. But they set their sights on departing the country in the wake of the infamous “Sharpeville Incident,” in which police opened fire on a crowd of civil rights protesters.

The Hares' ensuing departure plans encountered a vast web of bureaucratic obstacles, delaying their move until 1974, when Josh was 12. Then, the family packed up its belongings in two shipping containers bound for the United States . During the voyage over, the ship became wrecked in a storm, losing one of the two containers, including family heirlooms and all the photographs, adding to the strain of moving into a modest rental home in the Maryland suburbs just outside Washington . But Josh, the oldest of four, quickly excelled academically at the local high school.

Hare spent four years at the University of Pennsylvania as an undergrad, attended Hopkins medical school and then did a residency and a quick series of fellowships at Hopkins, Harvard and Brigham & Women's in Boston. In 1995, he was back at Hopkins , drafted by former head of cardiology Kenneth Baughman to help ramp up the heart failure service. Baughman had mentored Hare back in med school, and the two had maintained close contact in the intervening years. Baughman says he wanted Hare for his drive, but recalls how the institution placed nothing on a silver platter. For lab space, Hare was forced to rely on the kindness of fellow cardiologist Bob Weiss, who let him homestead on part of a bench. Even after he got an NIH grant, Hare toiled without his own lab space. Only when one of the lab researchers died, making a lab bench available, did Hare finally speak up and ask for the space. Hare had to “look out for himself,” Baughman says, but within eight years his lab had become one of the institution's producers.

By the end of 2004, Hare's research team was prepared to share its most meaningful fruit. Aiming for a better understanding of the process by which cultivated stem cells had been improving heart function in animal studies for several years, the group launched a study using Yorkshire pigs. First, each pig had an induced myocardial infarction. Then, some received stem cell infusions to the injured areas, while others received no therapy at all.

Day by day, the team monitored the animals' physiology. Later, each animal's tissue was dissected for more intimate study. And slowly, team veterans Luciano Amado and Anastasios Saliaris believed they were detecting a pattern emerging in the ever-sharpening images of heart slices. It looked like more than a simple shrinking of dead tissue. They thought they could actually see new tissue. And this new layer of tissue seemed to be growing over top of the dead layers of heart muscle. This bit of new tissue came to be known as the “endocardial rim.”

By the afternoon of November 18, 2004 , there was no longer any room left for doubt. One team member applied sharper photography to the latest slices, and in one crystal-clear slide the endocardial rim structure stood out loud and proud. Any attempt by this gathering of hardened scientists to maintain clinical skepticism had been shattered.

“Wow,” Hare exclaimed, “this is too good to be true.” As Amado and Saliaris pressed in, Hare's excitement mounted. “I need to see all of the slides right now,” he said.




It's late on a tuesday in mid-August, and Hare is waiting in a conference room, alone, with papers arrayed on the table. His human stem cell trial has been on hold for some weeks, pending an examination. Today's inquest comes at the behest of Hopkins' Internal Review Board (the IRB), a cautious and thoughtful conclave that meticulously reviews every clinical study involving humans to make certain the research is sound and patients are fully informed of every potential risk.

The IRB had earlier reviewed and approved Hare's study, but it now has concerns. The group has summoned Hare because it's learned of a study elsewhere in which lab mice with suppressed immune systems developed malignancies after receiving stem cells. The IRB wants Hare to demonstrate how his study would ward off such a risk in his human patients. Hare has submitted a written response to the panel's questions, but he may not attend the ongoing discussion. If the group has questions it will call him in.

Josh Hare and trial coordinator Elayne Breton track the progress of their second stem cell patient during his infusion.  
> Josh Hare and trial coordinator Elayne Breton track the progress of their second stem cell patient during his infusion.

Hare says he welcomes the mid-August exam, which is unfolding in a discussion among 20 people gathered in Reed Hall. “It's part of the transparency of the process,” he says, adding that it's designed to protect patients and investigators like himself from risking the kinds of incidents that have harmed patients and institutions before. Hare says he respects “prudent, judicious, justified clinical research,” especially since this is a Phase 1 trial whose key purpose is to gauge patient safety. But there is, he says, a clearly demonstrable difference between the lab mice in question and his human patients. The lab mice were immuno-suppressed, meaning they were prime targets for cancer. They also received an infusion of stem cells specifically stressed to develop abnormalities because scientists wanted to find out what would happen if the cells were pushed to the limit. Hare's cells, meanwhile, are subjected to layers of careful safeguarding. He hopes the group will see this, so the study will lose no more time. But on Friday, the IRB informs him in writing that his trial remains on administrative hold. He must suspend new patient enrollments until the review is complete.

Five months after the trial's start, Hare has only been able to enroll two properly qualified human patients. By the time the IRB lifts its hold, a total of seven weeks have elapsed. Hare says his group has missed the opportunity to qualify “many candidates” for the trial, which constitutes a meaningful setback to his quest's momentum. But the study has been cleared. Its design has been deemed appropriately cautious. Josh Hare has regained the full weight of the institution at his back.

It's just one more detail in his juggling act that has abated. There are many more to come, of course, and they will always be there. After one such session, Hare strolls into the enclosed quad area in front of the Outpatient Center , and seizes the interlude to catch up on his messages. He withdraws both his cell phone and pager from his lab coat and alternately manipulates the dials on both devices. He holds the cell phone to his ear to hear messages while studying the pager in his hand, oblivious to the other health workers scurrying past him from all directions.

His trial's first two patients, meanwhile, have had monthly checkups. Schulman handled Parran's three-month visit in June, and found him “doing very well, though I wouldn't call it ‘magically' well.” By that, Schulman is simply saying that Parran hasn't exhibited such a completely full recovery that it would constitute instant confirmation of stem cells doing their intended work. Parran's next visit will happen at the six-month interval, when he'll get the full battery of tests in an overnight stay.

Parran says he is back to working out on a stationary bike and has resumed some weight-lifting. He feels “slowed down,” but doesn't know whether that's from his heart trouble or the medications that keep it at bay. His weight has dropped from a pre-heart attack 144 to 133.

Amid the trial's ongoing challenges, Hare remains very much in the game. “The past year for me has been the most exciting and rewarding of my career,” he says. “This is like the 9th inning in the World Series.” His confidence in the future of stem cell therapy for heart treatment seems boundless. Thanks to stem cell treatment, he says, “I think atherosclerotic heart disease will some day go the way of rheumatic fever.”


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