Magic in the Matrix

When Alan Spievack arrived at Professor Maxwell Elliott Power's office in the spring of 1952, he wasn't sure what to expect. Power began by looking over his glasses at the freshman from Cincinnati and declaring that Spievack was the first person to tally a perfect score on one of his notoriously difficult anatomy exams. But Power wasn't about to congratulate him on the feat.

"He asked me a series of questions clearly designed to see if I had cheated," remembers Spievack, who graduated cum laude in 1955.

When Power determined that Spievack wasn't dishonest, just uncommonly smart, he strongly suggested that he pursue honors in biology. Then, about a week later, Power summoned him to his office again. This time he loaded Spievack up with gear and they headed to the Kokosing River. The professor instructed Spievack to roll up his pants and get to work catching what appeared to be tiny black bugs. They were actually salamander larvae. Spievack's job was to raise them, occasionally cut off their arms, legs, and tails, and figure out how they regenerate their limbs.

"He set up a private tutorial for me," Spievack says. "He showed me how to use a microscope, how to make tissue slides, how to use lab equipment and conduct experiments."

In high school, Spievack had tried to create a perpetual motion machine. Clearly, research and experimentation appealed to him, and he quickly got so engrossed in the regeneration project that he didn't want it to end when the summer break arrived. Neither did Power. So they packed up all the equipment, including the salamanders, and relocated to Spievack's family home in Cincinnati, where he reassembled the lab in his basement. The salamanders took up residence in his mother's pie pans, and his younger brother, Lee, fed them hamburger and fish food with tweezers.

Spievack's collaboration with Power was cut short when the professor died in 1954. Spievack was "devastated" by the loss of his mentor, but he was not about to abandon the interest in regeneration that Power had sparked on the Kenyon campus.

He won a Fulbright Scholarship to Bologna, Italy, but chose instead to attend Harvard Medical School, and forged a distinguished career as a surgeon before he began another collaboration with a scientist named Stephen Badylak in 1996. Their work has revolutionized research into the human ability to regenerate skin and--someday, perhaps--even arms, legs, and organs. And it's not all theoretical; Spievack has already helped his brother Lee regenerate a fingertip he lost in an accident, and more than 500,000 patients have used regeneration treatments worldwide.

"People used to think it was Buck Rogers science to talk about regenerating tissues," Scott Bruder recently told the Wall Street Journal. He is vice president of Regenerative Therapeutics, one of several companies using regenerative technologies to provide medical treatment. "This is the new wave."

After Kenyon and medical school, Spievack finished his training in general surgery at Boston City Hospital in 1965. He joined the Harvard Medical School faculty the same year and began practicing in Boston and Cambridge. Not bad for a student who racked up his share of C's--or worse--in high school.

"I flunked freshman algebra," he says. "I felt good about that because Albert Einstein did the same thing."

The years sped by, and Spievack was consumed with his medical practice, but he never lost interest in regenerative medicine. He continued to conduct research in the field, and in 1992 he worked with a small Cambridge startup on bone regeneration. That's why he was so intrigued by Stephen Badylak when he heard him lecture in Atlanta at an orthopedic surgeons' conference in 1996. Badylak, a medical doctor with a Ph.D. in anatomic pathology, was working as a researcher at Purdue University in the eighties when he conducted an experiment on Rocky, a mixed-breed mutt. He replaced Rocky's aorta with a piece of the dog's small intestine, mainly because it had a similar, tubular shape.

Over the next few months, Badylak discovered something amazing. Not only was the section of small intestine functioning properly, it was actually morphing into something very close to an aorta, with little, if any, scar tissue forming. In a 2007 Esquire magazine profile, Michael Rosenwald wrote that Badylak "had accidentally performed the biological equivalent of a magician turning a handkerchief into a dove. But this was not illusion."

"We've been spending the last twenty years trying to understand how that happened," Badylak told the Wall Street Journal.

The key to this biological magic is something called an extracellular matrix. It's the material that links cells to one another as they divide, grow, and become tissue and body parts. That's why it's often referred to as cellular scaffolding.

Badylak's research pointed to a form of extracellular matrix called the submucosa found in the intestines, bladders, liver, and other organs of all animals. To test his theories, he inserted the submucosa into the injured organs of other dogs and got the same result - regrowth and healing without scarring or even infection.

Unlike salamanders and starfish, humans (and most other complex life forms) don't kick into regeneration mode when they are severely injured. It's all about survival, so scar tissue forms instead. And scar tissue simply doesn't function as well as normal tissue.

That's not the case, however, in the womb, where humans can quickly develop and grow new parts, as well as recover from fetal surgery. This ability begins fading approximately three to four months into gestation, about the time the immune system begins to take over. Badylak says children can still regrow fingertips up until the age of two.

In a sense, the extracellular matrix fools the cells into thinking they're in the womb again. The cells begin to combine and they are soon aided by stem cells from the body's own supply in bone marrow and elsewhere. These stem cells are not as useful as embryonic stem cells, but they still play an important role in regeneration.

Badylak's work dealt with the fundamental questions that had intrigued Spievack since his Kenyon days when he was living in Beta Theta Pi housing.

"If you could do something as an embryo, why couldn't you do it again?" Spievack asks. "Or maybe even a third or a fourth time. You basically want to turn off the scar tissue mechanism and turn on the embryology. That's what interested me about regenerative medicine."

And Spievack was definitely interested in what Badylak had to say in Atlanta.

"I sat there as this talk was going on and I noticed I was getting closer and closer to the edge of my seat until I was about to fall off," Spievack remembers. "This guy had done it. He figured out that all species--birds, fish, mammals--can regrow themselves more than once."

The pair connected after the lecture and became friends and unofficial collaborators. Badylak, who is now a researcher at the University of Pittsburgh's McGowan Institute for Regenerative Medicine, acted as an advisor for the company Spievack launched in 1999 called ACell, Inc., which focuses on treating injured animals. Spievack turned to pig bladders to develop a form of extracellular matrix called urinary basement membranes. He tested it out on himself, using it to clear up a case of poison ivy. After a court fight with PurdueUniversity, he now holds the patent rights for it.

Since 2000, collaboration between Badylak and Spievack has resulted in their obtaining ten National Institutes of Health research grants under the Small Business Innovative Research Program, totaling more than $3 million. These grants have resulted in publications demonstrating the regeneration of the larynx, vocal cords, esophagus (soon to be tested in humans), urinary bladder, all the components of the muscular skeletal system, and many other tissues. Spievack presently holds nineteen medical-device patents. Studies with the United States Army hope to advance the trauma applications of this regenerative technology.

While Alan settled in Boston, his younger brother Lee stayed in their hometown of Cincinnati. An expert model builder, he's the assistant manager at HobbyTown USA. In 2005, he was inspecting the malfunctioning engine of a model plane when the propeller cut about three-eighths of an inch off the top of his middle finger. While he was wrapping his bloody finger in paper towels, he had no idea that the work he'd done with his brother in their basement lab would have a major role to play in his recovery.

He went to the emergency room for treatment and scheduled an appointment with a surgeon, who recommended a graft using skin from his thigh or forearm. Lee had his doubts about the treatment, so he called his brother from his car in the hospital parking lot. Alan told him there was no need for him to be injured twice.

So Lee canceled the appointment, and Alan sent him a vial of matrix powder, which resembled grated parmesan cheese. He applied the powder to his finger as Alan instructed. In four weeks, the wound was closed. In four months, the finger had grown back to normal size. In the winter, Lee noticed that while his other fingers chapped in the cold, the regenerated finger did not. He also has to trim the fast-growing nail on his middle finger every couple of days.

"The fingertip is only two years old now, but the rest of me is sixty-nine," Lee says. "I never had any inkling that it would not work. I've always had that kind of confidence in Alan."

There's no doubt that Lee Spievack's story is encouraging, if not amazing, and that regenerative medicine is being used to speed the recovery of patients with a variety of injuries all over the world. The military is funding studies right now to determine if regenerative medicine can help soldiers injured in combat. But the reality is that doctors and scientists are really just beginning to fully explore this field.

"We are very uninformed about how all this works," Badylak recently told the Associated Press. "There's a lot more that we don't know than we do know."

Alan Spievack played a big role getting the field of regnerative medicine to this exciting juncture, a role that began when he aced an exam in Professor Power's anatomy class at Kenyon. It's fitting that Spievack was the first recipient of the Maxwell E. Power Prize in Biology, awarded on Honors Day in 1955. Despite all that he's accomplished, Spievack is still wondering what's next.

"There's a question that haunts me," he says. "What's on the next page?"

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