The gospel according to Langer

One of the most influential people in Yale’s fledgling Department of Biomedical Engineering (BME) is not on the faculty, nor is he a student. He never attended Yale, though he received an honorary degree at Commencement in May. In fact, he has never held any position in New Haven, and works miles away in Cambridge, Mass. Nonetheless, his picture hangs prominently in the office of W. Mark Saltzman, Ph.D., the department chair, and his vision permeates daily life in the BME labs in the Malone Engineering Building on Prospect Street.

This potent force is Robert S. Langer, Sc.D., Institute Professor and the Kenneth J. Germeshausen Professor of Chemical and Biomedical Engineering at the Massachusetts Institute of Technology (MIT), and mentor to a new generation of Yale engineers bent on inventing their way around any obstacle to improve the diagnosis, treatment and prevention of disease.

Want to deliver a killing blow to stubborn brain tumors? Try surrounding them with chemotherapeutic wafers that leak a toxic drug onto nearby cancer cells and leave healthy tissue alone. Need to mend a spinal cord, severed in a disabling accident? Try implanting a plug of plastic polymer seeded with stem cells. Running out of healthy blood vessels to replace damaged arteries during a heart bypass? Take tissue-engineered vessels off the shelf, ready-made like replacement parts for a car.

The first of these visions is now reality thanks to the work of Saltzman, the Goizueta Foundation Professor of Chemical and Biomedical Engineering and professor of cellular and molecular physiology. The others are dreams in progress: Erin Lavik, Sc.D., assistant professor of biomedical engineering, has successfully repaired broken spinal cords in rats, preventing paralysis and restoring the animals’ ability to walk. Laura Niklason M.D., Ph.D., associate professor of bioengineering and anesthesiology, is on the verge of testing manufactured blood vessels in people.

All three began their groundbreaking work in the Langer lab. By their own accounts, Langer is a daunting role model (See sidebar). A hard-working and phenomenally successful researcher and inventor, he also finds time to be an attentive and thoughtful advisor, and even a booster when cheerleading is called for. Most importantly, they say, Langer is a visionary who believes that nothing is impossible. And somehow he has inspired a new generation of engineers to believe that, too.

As the heirs to his scientific legacy, the three Yale engineers have found success by taking Langer’s favorite advice to heart. Langer sums it up in five simple words:

“Think big. Don’t give up.”

Delivering the goods

As a graduate student in the Langer lab, Saltzman remembers sitting with colleagues and trying to analyze what made Bob, as everyone calls him, so successful. What special combination of attributes would young researchers need to cultivate just to approach their mentor’s achievements? “We never quite figured it out. We knew that Bob is ridiculously brilliant and that he works really hard,” Saltzman says. “Brilliance is hard to emulate, but one thing we figured out is that we could always try to work really hard.”

By working hard, Saltzman has come far. He runs a lab, teaches undergraduates and graduate students, and has written three textbooks, on tissue engineering, drug delivery and polymer chemistry. He has won awards for research and teaching at every stage of his career. Since he arrived at Yale in 2002 to form the new department, he has seen his faculty group grow to 19 members. That number includes researchers from other departments gathered at last in one place, plus three new recruits.

But back in 1981, as Saltzman was finishing his undergraduate degree in chemical engineering at Iowa State, he was adrift. After four years he realized that he had no interest in manufacturing or going into the oil industry—the things that chemical engineers usually do. Fortunately, he happened into a lecture on biomedical engineering, and he was hooked. “I saw that the things I knew how to do could be used in a different way than I’d ever thought.”

At MIT, he found a kindred spirit in Langer, who had also veered toward biology from chemical engineering. Langer’s claim to fame at that time was his invention of biodegradable polymers for drug delivery. These pellets and wafers of honeycombed plastic could be loaded with proteins or medicines and implanted within the body. As the polymers slowly broke down in blood or cells, the capsules delivered the goods, then disappeared. Because of the packaging’s novel porous structure, it could deliver molecules that were far larger than previously possible. For his doctoral thesis, Saltzman studied the molecular properties of the polymers and fine-tuned them to deliver proteins and other therapeutics.

After receiving his Ph.D. in 1987, Saltzman left for a faculty position at Johns Hopkins University and took along some advice from his mentor. Langer suggested that he focus on drug delivery to the brain, an interesting and unexplored area. Even more important, Langer introduced Saltzman to a young neurosurgeon, Henry Brem, M.D., now the Harvey Cushing Professor of Neurosurgery, neurosurgeon in chief and chair of the Department of Neurosurgery at Hopkins.

With Langer supplying the biodegradable polymer, Saltzman and his colleagues developed ways to load it with carmustine, a cancer drug, and track the medication’s release, while Brem led the testing in patients. The result was Gliadel, a dime-sized, drug-impregnated wafer that surgeons now use routinely to extend the lives of patients with deadly brain tumors. In 1996, Gliadel became the first of the polymers to be approved by the Food and Drug Administration for human use.

“Bob has a knack for getting the right people together,” Saltzman says. The ability to be a scientific matchmaker is critical in biomedical engineering, a discipline in which you do not get very far on your own, Saltzman says. “We borrow skills and techniques from so many different places, you must have those connections.”

When Saltzman was recruited to head up the new biomedical engineering department, he recognized Yale as a good place to foster such connections. He cites the medical school’s Interdepartmental Program in Vascular Biology and Transplantation (VBT) as just one example. “We have cell biologists and immunologists and surgeons and pathologists and bioengineers all working together in an ideal environment for interdisciplinary work. I think that’s a very rare happening among universities,” he said.

Today, Saltzman continues to work on drug delivery to the brain, and he is also working with colleagues at Yale on genetically engineered blood vessel cells that could be turned into vascular bandages for restoring blood supply to damaged tissue.

Making a difference

Lavik spent 11 formative years at MIT, receiving a bachelor’s degree and a master’s in materials science, and then completing her Sc.D. in the Langer lab. She is not only a stellar researcher, but also a writer and director of plays and a master cake decorator. She lives in Davenport College, where she is a resident fellow.

As an undergraduate, Lavik intended to study civil engineering. But the minutiae of cement dam construction left her cold, so she switched to materials science. She even started graduate school working on the same topic, but as interesting as it was, she feared her work would never change anyone’s life. She wanted to do something that would have a bigger impact on the world.

Lavik was considering leaving MIT when by chance her mother set her on a new course. Flying home to Virginia from a visit to MIT, Mrs. Lavik found herself chatting about her daughter’s predicament with her seatmate, who turned out to be Martha L. Gray, Ph.D., the Edward Hood Taplin Professor of Medical Engineering and Electrical Engineering at MIT. “Mom called me up all excited and told me Martha Gray told her I should consider going into biomedical engineering, and think about biomaterials,” Lavik remembers.

After talking to Gray, Lavik made the rounds of biomaterials labs at MIT. “It was clear that Bob’s lab was Mecca,” she says.

Taking a cue from a friend who worked on new treatments for spinal cord injuries, Lavik saw her chance to make a difference. Lavik envisioned using engineered tissue to replace broken pieces of spinal cord, reconnecting severed nerves and allowing patients to overcome their injuries.

She saw a chance to use what she knew about materials, but with little background in biology, Lavik was taking a big risk. Over the next five years, she created and tested polymer scaffolds, searching for the perfect structure to support the growth of neuronal stem cells and replicate the complex architecture of the spinal cord. The gamble paid off, and by 2002 Lavik had developed an implant that gave rats with severed spinal cords a full recovery. In 2003, that success earned Lavik a coveted spot among rising research stars when she was chosen as one of the MIT Technology Review magazine’s top 100 innovators under 35.

Since coming to Yale in 2003, Lavik has continued using animal models to improve the spinal cord implant, but more work is needed. She is also finding ways to protect other types of neurons that can undergo injury or degeneration. Her lab is trying to make a replacement retina, and she is collaborating with researchers in Boston and Denmark on the controlled release of nerve growth factors into the eye to help preserve neurons at risk of dying. All these experiments are still in the animal testing stage.

Lavik remembers a demanding but encouraging environment in the Langer lab. “There is definitely a sense of sink or swim, but the upside is that we had incredible resources. I had no background in the field, and really no business doing this research, but Bob supported it financially and intellectually.”

“From Langer’s example, Lavik said she realized that her work would be only as good as her students. She also saw clearly that her job is to facilitate their research. “I am blessed to have some of the best students I could possibly hope for, and the most important thing for me is to make sure they are well-funded and have the support they need to do the work they want to do.”

The direction those students are now pursuing under her guidance addresses a problem at the center of tissue engineering. Lavik wants to find ways to create scaffolding for blood vessels. A vascular network is a critical step to making a template for engineering new tissues. “One of the reasons tissue engineering started with cartilage is that it’s not very vascularized. The spinal cord, however, is a highly vascularized tissue. Our hope is that if we can start to make stable microvascular networks, we can use that as a basis for engineering other tissues,” she explains.

“A lot of people have done beautiful work making microvascular networks, but it has been hard to make those networks stable,” Lavik says. Recently, she figured out a way to do just that.

In the body, vascular cells normally live in close proximity to neuronal cells. It occurred to her that they might be helping each other out. She came up with the idea of using a mixture of neuronal stem cells and blood vessel endothelial cells to seed a 3-D scaffold. To make the scaffold, Lavik produced a water-soluble polymer that looked like a network of microscopic blood vessels. Then, she cast a more stable polymer around it. Finally she dissolved the first scaffold to leave a lacy network of pores in which endothelial cells and neuronal cells could interact to form a vascular bed.

In collaboration with Joseph A. Madri, M.D., HS ’76, Ph.D., professor of pathology and of molecular, cellular and developmental biology, Lavik started to grow cells on the scaffold. The researchers found that mixing neuronal stem cells and endothelial cells on the new support resulted in blood vessels that last up to 12 weeks, compared to just a few weeks for previous attempts. When they put the whole assembly under the skin of a mouse, the implant fused with the mouse blood supply, and they could watch under a microscope as blood filled the engineered vessels. Best of all, the blood was still flowing three months later.

An idea from the OR

Unlike her fellow Langer alumni, Laura Niklason did not start out as an engineer. She knew early on that she wanted to be a physician-scientist, and after completing an undergraduate degree in physics she went right into the M.D./Ph.D. program at the University of Chicago. It was much later, while working in the operating room, that she decided to grow blood vessels for a living.

That was in January of 1995, after Niklason had moved to Boston for a residency in anesthesiology. In her spare time, besides caring for two small children, she joined the Langer lab as a postdoctoral research fellow. “I thought tissue engineering was the coolest thing in the world and I wanted to do that,” she says.

The urge to grow arteries came directly from her clinical work. In the operating room, she would witness vascular and heart surgeons searching their patients for spare veins, often finding only vessels of very poor quality. “I’d think, gee, wouldn’t it be great if we had some replacement vessels we could pull out of a jar?”

At the time, researchers were just starting to understand how to get blood vessel cells to form microscopic tubes in a petri dish. The Langer lab was the perfect place for Niklason to pursue her dream of growing whole arteries. Because he has such an outstanding track record and a large group, she explains, Langer can place many bets, starting new lines of research. And he is willing to make some very risky bets on new ideas, knowing that he needs only a few successes to keep the whole enterprise going.

“For me, that situation was wonderful. One day I walked into Bob’s office and announced, ‘I’m going to grow an artery.’ He said, ‘That’s great, Laura. You do that.’ ”

It was a gutsy move for a young researcher, and the venture turned scary—the project yielded no results whatsoever for two years. But in the third year, Niklason discovered the trick of putting the blood vessel cells on polymer tubes in an incubator and nourishing them by pumping a blood-like nutrient solution through the tubes. By mimicking the natural forces that blood generates when it flows through vessels developing in the body, she had found a way to produce strong, supple artificial arteries. The homegrown vessels were comparable in strength to real arteries, and when she installed them in pigs, the blood flowed.

These are not the lacy microscopic networks of vessels that Saltzman and Lavik are working on, although Niklason is interested in those, too. What she’s grown are sturdy tubes about the length of a pencil and only slightly thinner. These are the plumbing supplies for heart and other bypass operations when large, hardy vessels need to be replaced. Niklason launched a company in 2005 to develop the vessels for clinical use; the firm has produced fully human engineered arteries with “spectacular” properties, she says, which are now being tested in baboons.

Niklason’s confidence was tested at Duke University, where she went after leaving Langer’s lab. During her first years there she wrote 30 grant applications before accruing enough funding to run her lab. “I started to think, ‘Well, maybe my ideas aren’t very good after all, and maybe I really can’t do this.’ At that time Bob was very stalwart and kept telling me, ‘Your ideas are very good, Laura, just keep working at it.’ ” Eventually, the money started coming in, and today she supports a lab of 12 researchers working on arteries and heart tissue.

Niklason joined the Yale faculty one year ago. The growing bioengineering group, together with what she calls the “world-class” VBT program, was a combination she could not pass up. Her current work involves collaborations with her BME colleague Themis Kyriakides, Ph.D., assistant professor of pathology, and several VBT researchers, including program head William C. Sessa, Ph.D., professor of pharmacology, and former head Jordan S. Pober, M.D. ’77, Ph.D. ’77, professor of pathology, immunobiology and dermatology.

“Yale is unique in having a collection of people who all think about blood vessels on many different levels,” she says. “What’s more, they all talk to each other—that’s absolutely unique in my experience, and was very important to my decision to come here.”

“Of course, having other Langerites here was a draw, too,” Niklason says with a laugh. She and Saltzman have worked together on several large grant applications to expand the research activities in the department. With Lavik, she has made a bond that never existed at MIT, even though they overlapped in the Langer lab for a year. “Bob’s lab was so large, and since I was ‘vascular’ and she was ‘neural,’ we didn’t intersect very often,” Niklason says. At Yale the two meet frequently. With their shared experience and vision, they are not only upholding the Langer legacy but at the same time creating their own. YM