Dream Team

Laman Gray Jr., M.D., has been called a lifesaver, a great doctor, a pacesetter and a visionary -- and he is all of those things. In addition, he is the Jewish Hospital Distinguished Chair in Cardiovascular Surgery at the University of Louisville School of Medicine. Now, as medical director of the Cardiovascular Innovation Institute (CII), he has taken on the role of a great coach.

Like a coach, he has used the past successes of a program to recruit the very best players to move his team's agenda forward. In this case, he's not looking for a national championship. Rather, this "dream team" is stalking a killer - heart disease - and they intend to make inroads quickly.

Gray is a veteran of the fight. With UofL cardiovascular surgery professor Robert Dowling, M.D., he was the first to implant the Abiocor artificial heart in a patient. Gray and Dowling also have been integrally involved in the development and testing of other bridge-to-transplant technologies and leading-edge therapies for patients who have exhausted all the conventional treatments for heart failure.

According to the Centers for Disease Control and Prevention, heart disease is the leading cause of death in the United States and is a major cause of disability. Almost 700,000 people die of heart disease in America each year, accounting for about 29 percent of all deaths in this country. In Kentucky, 20 counties report deaths from chronic heart disease at a rate 25 percent higher than the national average.

That's why, in 2003, the University of Louisville and Jewish Hospital came together to create the CII - a groundbreaking research center designed to bring together the best minds in the field to improve quality of life for heart failure patients by building on the success of both organizations' previous work with ventricular assist devices and artificial hearts.

The CII's state-of-the-art building, opened in January 2007, includes expanded research facilities plus training and administrative space equipped with the latest technology. Funding for the facility included a $15 million investment from Jewish Hospital; $6.2 million in federal earmarks secured by Sen. Mitch McConnell; $4.2 million from the University of Louisville; portions of a $5 million grant from Kosair Charities; $5.5 million from the Kentucky Cabinet for Economic Development and the Department of Commercialization and Innovation; and $1.5 million from the Gheens Foundation.

Strategic Hires

Gray is used to thinking big, and the CII's board backed that vision -- using their collective leadership to recruit Stuart Williams, Ph.D., an internationally known bioengineering scientist, and his research team from the University of Arizona. Funding for the new UofL posts was secured through private donations and matched by the state's Research Challenge Trust Fund, more commonly known as Bucks for Brains.

"Dr. Williams is a fantastic example of a strategic hire, enabled by the Bucks for Brains match from the commonwealth," says James Ramsey, UofL president and CII board vice-chairman. "His track record as a scientist and entrepreneur complements the work being done by the faculty we already have in place at UofL."

Bob Shircliff, president and CEO of Jewish Hospital & St. Mary's HealthCare, says the decision to invest in the CII was an easy one.

"We've asked ourselves: How can Louisville distinguish itself as being great in the health sciences?" says Shircliff, current chair of the CII board (he and Ramsey swap roles as chairman and vice-chairman each year).

"The answer is by building on the strengths built here by people like Drs. Laman Gray, Rob Dowling and (highly regarded UofL cardiologist) Roberto Bolli by recruiting world-class experts with complementary strengths."

Gray points to the recent hire of Dr. Sanjeev Aggarwal, M.D., as another great example of team-building. He says that Aggarwal, who completed a fellowship in ventricular assist devices, cardiac transplantation and minimally invasive surgery at Columbia University Medical Center New York-Presbyterian Hospital, demonstrates the program's ability to attract experts in both cardiovascular research and clinical medicine.

Growing Track Record

Williams and his colleagues join a group of scientists who are already attracting national attention.

"I was attracted to Louisville because there is a core group of highly innovative people in the School of Medicine and the Speed School of Engineering who are committed to finding new ideas that can be translated quickly into commercial solutions that will benefit patients," says Williams, who now holds the Jewish Hospital Distinguished Chair in Cardiovascular Innovation.

Support from UofL administrators is vital, too, Gray notes.

"This is really a great collaboration, with support from Dean Mickey Wilhelm in the Speed School, Dean Edward Halperin in the School of Medicine, the executive vice president for research, Manuel Martinez, and the executive vice president for health affairs, Larry Cook," Gray says.

Williams cites Rob Keynton, Ph.D., as a major asset for the CII. Keynton, chair of the Department of Bioengineering, has made significant contributions in biomedical MicroElectroMechanical Systems (BioMEMS), micro Total Analysis Systems -- known as "labs on a chip" -- and cardiovascular mechanics.

Keynton is also the principal investigator of a grant designed to develop the entrepreneurial skills that scientists need to move discoveries from the lab to the marketplace, one of the CII's primary strategic objectives.

Another valued team member is Steven Koenig, Ph.D., associate professor of bioengineering and surgery, who has developed a counterpulsation device with tremendous potential for rehabilitating the heart in cases of heart failure -- before patients need a ventricular assist device or other intervention.

The device's development has been funded by the National Institutes of Health's Small Business Innovation Research program in cooperation with the Louisville biosciences company SCR Inc.

"It's like physical therapy for the heart," Koenig says. "We know that in rehabilitation the situation is often 'use it or lose it,' and this device takes some of the load off of the heart to help it get stronger - breaking a physiological cycle that can lead to severe heart failure."

Koenig's other efforts in the CII include work on the institute's Good Laboratory Practices and data acquisition systems for testing cardiovascular devices and analyzing the resulting data.

A second joint professor of bioengineering and surgery at CII, George Pantalos, Ph.D., has been a cardiovascular explorer for more than
35 years.

"I have spent a lot of time working to understand how to treat heart failure with mechanical devices, including artificial hearts and ventricular assist devices, in patients with two legs and with four legs, with big hearts and with little hearts," he says.

Most recently, Pantalos made news with a NASA collaboration focused on understanding the biomechanics of performing cardiopulmonary resuscitation in zero gravity. This experiment grew out of his longtime work with the space program aimed at understanding cardiovascular adaptation to the weightlessness of space flight and a return to Earth.

He has flown 25 research missions on NASA's Zero-G airplane and led the development of a cardiovascular experiment that included an artificial heart which has been flown twice on the space shuttle Discovery.

Meanwhile, UofL surgery professor and CII researcher Sufan Chien, M.D., and a team that includes surgery professor Gordon Tobin, M.D., recently received a $1.2 million grant from the National Institutes of Health to study a new treatment that may help more than 5 million patients who are debilitated by chronic wounds each year, many resulting from complications of diabetes.

Chien started with the idea that problems with healing may be related to cells' ability to transport energy within tissue, rather than external factors like wound dressings. The team is studying the biochemical process by which oxygen is converted to energy in the form of adenosine triphosphate (ATP). Chien has developed a unique way to transport ATP through the cell wall so that additional energy can be absorbed by the cell.

Completing the Dream Team

Williams, like many successful longtime researchers, is involved in multiple projects with a network of collaborators. Two of those investigators, Jay Hoying, Ph.D., and Chad Stiening, Ph.D., moved from Arizona to Louisville to join the CII.

"We saw the ability to attract a group of talented people, whose work comple-ments and expands on the work already being done at the CII, as a real plus in bringing Dr. Williams on board," says Ron Greenberg, CII executive director.

"The breadth of this team's work and their extraordinary commitment to translational research made it easy to support Dr. Williams' candidacy for scientific director," adds Larry Cook, M.D., UofL's executive vice president for health affairs.

"He immediately saw what we want to do here and can clearly articulate what it's going to take, scientifically, to get us there," Cook says.

Talking to Williams can be dizzying, as he moves from describing projects to improve the coatings on cardiac stents, to an approach that uses stem cells from fat tissue to regenerate small blood vessels, to sensors with the potential to monitor physiological functions ranging from blood glucose to eye pressure in glaucoma patients.

His explanations seem to verge on science fiction as he describes efforts to create a system that could build new body parts for amputees that would be compatible with their own tissue - allowing for tissue replacement without a lifetime of immune-system suppressing drugs.

Despite the wide-ranging nature of Williams' projects, his work shares a unifying theme, and his approach to the work is guided by a consistent set of principles.

"The scientific core of our work is focused on two mechanisms: communication between cells in the body and the communication and interaction between the body's cells and materials that may be implanted in the body," he says.

"Our approach to the work is informed by the principles that we want to develop effective technologies that are potentially beneficial to a large number of patients, are easy for doctors to use, are as non-invasive as possible and are cost-effective.

"This focus helps us be as successful as we can possibly be in moving technologies from the lab to the patient," he adds.

Hoying, now an associate professor in the Department of Surgery, has built his career around these themes and notes that they were a major influence in the team's decision to come to Louisville.

"Dr. Keynton and the other bioengineers at UofL not only share many of our research interests, but also understand how important it is to apply these 'real-world' tests to the development of new technologies. We can develop amazing cures, but for them to help people, they have to be viable for commercialization," he says.

Stiening, who holds dual undergraduate degrees in biology and finance and who completed his Ph.D. and a postdoctoral fellowship in molecular genetics at the University of Arizona, agrees.

"The CII presents an opportunity for me to merge my interests in biomedical engineering and business in a way that isn't possible at a lot of academic institutions," he says.

"It wasn't a hard sell to come to Louisville. There's momentum here and a lot of excitement about setting up the CII to lead the way in translational research."

One such area of leadership is in Good Laboratory Practices (GLP), led by Lauren Unger, Ph.D.

"GLP gives potential partners - both academic and commercial - the confidence that everything we do on a given research protocol is completely documented and can be repeated in exactly the same way," Greenberg says. "It's a huge selling point for the CII as a research partner, and Dr. Unger's collaborative leadership has been instrumental in getting us to this point."

Clinical Strengths

In addition to GLP, all three newly recruited scientists say the partnership between UofL and Jewish Hospital was an important factor in their decision to join the CII.

Citing Dr. Gray and Dr. Bolli's firsts and the strength of the clinical base in cardiovascular medicine, Williams describes the interplay between the bioengineer and the physician in bringing new technologies to patients.

"As a bioengineer, there is a point at which you have to let go of your work," he says. "The physicians are the ones who review the clinical trials protocols and select the sites for the clinical trials. It's important for me to know that our technology is in good hands, and the UofL/Jewish Hospital partnership has a strong track record."

"The strength in cardiovascular medicine, the access to clinicians and the commitment to translational research are all here as the result of this partnership," Hoying adds.

Looking to the Future

Gray is visibly excited when he talks about the future of the CII.

"We are building momentum. Despite the fact that we are somewhat new on the scene, we have more than $7.9 million in NIH funding in place and another $3.2 million of funding for Dr. Williams' team is being transferred here," he notes.

As this article went to press, Hoying and Williams received notice that another NIH grant, worth more than $2 million over four years, had been awarded to fund their research focused on finding new therapies for all kinds of diseased and damaged tissue by creating replacements in the laboratory that can easily be integrated by the body.

Gray lays out the game plan like a great college coach.

"We're taking the state of the art in terms of technology, whether that's bioengineering, assist devices or regenerative medicine, and focusing it on key problems that will really make a difference to patients," he says.

Using regenerative medicine and assist devices together, for example, might allow the heart muscle to become stronger without needing a long-term assist device or a heart transplant. For heart-failure patients who need a vascular assist device as a bridge to transplant, maybe there's a gene therapy that we can give them at the time they get the assist device that will help us rehabilitate the heart and, over the long term, take the device out - removing the need for a transplant."

"I know it sounds like science fiction sometimes," Williams says, "but this is the real thing, and we're doing it in Louisville."

"It's nice to see all of the pieces come together," Gray says. "For the last five years, we've been building in terms of creating the institute and hiring the right people with the help of Bucks for Brains."

His colleagues feel the same about being here in Louisville.

"If you surround yourself with great people, good things happen," Stiening says.

Closer Look: Repairing heart attack damage with engineered tissue

olleagues feel the same about being here in Louisville.

In October, Williams and Hoying published a study showing that transplants of engineered heart tissue show promise for repairing heart attack damage in mice.

The study, published in the journal Tissue Engineering, demonstrates that tissue containing small blood vessels can be grown in three dimensions in the laboratory with cells taken from fat tissue and transplanted to the surface of the heart after an acute heart attack.

In many types of heart attacks, the primary damage is caused when blood vessels become blocked, stopping the flow of blood and its accompanying oxygen to parts of heart muscle. This can cause those areas to die, forming scar tissue that impacts the overall function of the heart.

The scientific team, in collaboration with a colleague from Yale University, is investigating whether laboratory-grown heart patches, designed to contain the muscle's natural network of tiny blood vessels, can be transplanted to repair the heart after a heart attack.

The condition of the tissue, blood vessel networks and overall heart function were evaluated at seven, 14 and 28 days after the mouse tissue transplants took place.

The scientists found that as early as seven days after the transplant, the small blood vessels began to grow together with the host heart's blood vessel network. Fourteen and 28 days after transplant, heart function continued to improve, and the dead tissue area caused by the heart attack was smaller. The engineered tissue itself grew and integrated with the host heart tissue.

"This study is very promising for future cardiac repair and regeneration in humans," says Williams.

"We continue to investigate the use of heart patches. Previous studies using a cell-based heart patch have now entered Phase I clinical trials in humans. This latest study represents a new generation of heart patch that can be created using a patient's own cells."