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.
Heart Grows Back
|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
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
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
“How do you know they won't form malignancies?” Parran
“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
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
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
|> 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.”