HARVARD GAZETTE ARCHIVES
Tissue engineering at a crossroads
Symposium takes a look at advances in - and costs of - scientific pursuit
By Corydon Ireland
Harvard News Office
Scientists visiting Harvard this month gave an audience of 180 a glimpse into the future of medicine - a world of implantable arteries, "bioartificial" organs, and replacement cells for failing hearts.
"Frontiers of Tissue Engineering," a daylong symposium on Nov. 3 cosponsored by the Radcliffe Institute for Advanced Study, brought together seven American, Canadian, and Dutch experts at Maxwell Dworkin.
Tissue engineering is a fast-moving interdisciplinary pursuit that combines medicine, cell biology, materials science, and nanotechnology. It promises to transform acute and chronic care and create a brave new world of engineered cells, microscopic drug delivery systems, implanted medical devices, and replacement organs.
"These are pretty heady days in tissue engineering," with Boston as "a bit of a Mecca," said Kit Parker, assistant professor of biomedical engineering in Harvard's Division of Engineering and Applied Sciences, the event's other co-sponsor.
Cutting-edge technology is emerging, he said, in engineered gene networks and cell networks - along with a few "bench-to-bedside" applications. "We're talking about products now," said Parker.
H. David Humes, a professor of nephrology and internal medicine at the University of Michigan, talked about a kidney-replacement device that combines manmade pumps and tubing with human cells. The "bioartificial kidney," costing a few thousand dollars, could be on the market soon, after nearly a decade of trials. It took a partnership of engineers, clinicians, and scientists to build and test the machine. Innovation, said Humes, "is at the interface" of disciplines.
But progressing from idea to actuality means confronting a series of scientific, design, and regulatory hurdles, he pointed out - to say nothing of the cost. (Humes estimated it takes $100 million to move a product to market.)
On the plus side are potential cost savings. Humes said end-stage renal disease, which would be relieved by a bioartificial kidney, consumes 20 percent of the present Medicare budget, and affects 400,000 Americans a year.
The Michigan kidney device, in human trials, nearly doubled patient survival rates when compared with conventional therapies.
But the device faces the same technical obstacle that ran like a thread through the symposium: scaling up. For wide use, any tissue-engineering project would mean isolating and growing a vast number of cells. For devices, scaling up would require maintaining quality during fabrication, distribution, and storage.
Molly Shoichet, who directs a bioengineering laboratory at the University of Toronto, talked about engineered neural tissues that would treat or reverse spinal injuries. One of her research teams is injecting growth factors, antibodies, and scar-dissolving enzymes into the spinal columns of paraplegic mice. Another is implanting sleeve-like tubes around the severed spinal columns of mice and adding cocktails of cells, "creating a permissive environment for nerve regenerations," said Shoichet.
The strategies show promise, she said - one video clip showed a paralyzed mouse that had regained some mobility.
But another problem is cropping up - cell loss. Replacement cells seem to have limited life spans.
In her Netherlands laboratory, only about 12 percent of replacement heart cells survived a mouse experiment, said Christine L. Mummery, a professor of developmental biology at University Medical Center Utrecht. "As time goes on, we lose a lot of cells," she said. In the mice, about 1 million cells were injected into the heart wall. Humans, with far larger hearts, would require about 100 million of the hard-to-grow heart cells for therapy, said Mummery. To make that many, culture reagents alone would cost $10,000.
"It's not just a technical problem," she said, summing up another prominent tissue engineering issue. "It's an economic problem."
Mummery also mentioned the other big concerns in the tissue engineering world: ethical questions (the heart cells that specialize in beating, called cardio myocytes, were derived from human embryonic stem cells); safety (engineered heart cells, for one, can cause fatal arrhythmias); and immune rejection.
Safety is the paramount concern in any kind of human application of tissue engineering, said presenter Michael R. Rosen, director of the Center for Molecular Therapeutics at the Columbia University College of Physicians and Surgeons. He and three other researchers are working on a "biological pacemaker." It would require no external power because it would prompt heart cells to improve the electricity-like structure that regulates cardiac rhythm.
"If we don't get it right," he said of the project, still in its animal-testing phase, "we have no business sticking it in people."
Rosen said a biological pacemaker involves isolating a pacemaker gene found in the heart (HCN2), boosting its expression in heart cells grown from bone marrow, then injecting it into the left ventricle of the heart.
The technique has worked in dog models, but questions remain regarding toxicity, rejection, cell migration, malignancy, and cell loss (up to 40 percent in the first two weeks).
It may take until "the next century" to perfect a biological pacemaker, including human trials in tandem with conventional pacemakers, Rosen said. "But I think it will happen."
Using injected cells to teach a damaged heart to beat properly again, without a machine, offers a lot of advantages. There would be no need for a battery and no risk of infection. A biological pacemaker, unlike a battery-operated one, would also make the subtle changes in heart rhythm required by the autonomic nervous system, which responds to exercise and emotion.
During the day-long symposium, the visiting experts mixed freely with the audience of engineers, medical doctors, bench scientists, graduate students, and venture capitalists. "They all had questions for each other," said Barbara Grosz, dean of science at the Radcliffe Institute for Advanced Study.
Mummery, a world pioneer in stem cell research, called the Harvard event "the best tissue-engineering meeting I've ever been to."
Once a year for five years, the institute has sponsored a themed symposium, designed to emphasize interdisciplinary approaches. (Past themes: computational biology, computer security, biodiversity, and "designing biology," which explored the intersections of biology and physics.)
Grosz called Radcliffe "a convening force" that brings together a variety of disciplines in workshops, lectures, and the annual symposia.
"Frontiers of Tissue Engineering" this year delivered a particularly resonant message at Harvard, which is expanding its bioengineering resources and programs. There are eight - three of which are new or forthcoming.