Controlled Success

Fri, 12/14/2012 - 11:42am
Paul Livingstone

From an early age, the 2012 Scientist of the Year knew that his knowledge of chemistry could make a difference in medicine. He’s still exploring just how much impact that can be.

Dr. Robert S. Langer, one of 14 Institute Professors at MIT in Cambridge, Mass., is the most highly cited researcher in history. His contributions to medical science have changed the way we treat many diseases. Image: MITDr. Robert S. Langer of the Massachusetts Institute of Technology (MIT) is often called the “father of controlled release” in recognition of his most high-profile innovation: synthetic polymers that biodegrade in the body, releasing their cargo of drugs directly to target tissues.

However, a more accurate title could be “father of efficient R&D” in recognition of the productivity and rigor he brings to everyday research.

As he has throughout his career of nearly 40 years, he continues to publish research at a breakneck pace. He teaches. He manages a laboratory of more than 100 students working on dozens of projects. He generates funding for his projects and for startups. He patents his work on a regular basis. He is on the management board of 12 companies—which he founded or co-founded—and advises four more. He reportedly finds times for at least two hours of exercise every day. He is famous for responding to emails almost immediately, no matter how trivial.

And while doing all of this, he continually generates new ideas. He has published 1,175 works, a pace that equates to about 30 papers a year, or about one every other week. His 811 patents and patents pending are among the most ever obtained by a single scientist.

But Langer doesn’t much dwell on the numbers. And while he described his methods for science as rigorous and “Edisonian”, he doesn’t operate as a sleepless solo scientist, toiling away in his laboratory. He thrives among people, spreading his ideas and seeing which take hold. And in the back of his head is his core goal.

“My mission has always been to produce new ideas that work and that contribute directly to improving health,” he says.

His ideas have done this. From developing the first blood vessel inhibitors to halt tumors to the latest transdermal therapeutics, Langer has produced valuable technologies on an almost continuous basis. For this reason, the editors of R&D Magazine have selected Dr. Langer, the David H. Koch Institute Professor at MIT, for the 2012 Scientist of the Year Award. This award celebrates a career of achievement in research and development and acknowledges the high level of influence Langer has on his field of work.

A crucial decision
Langer’s career arc has bucked conventional wisdom. For all of his influence on medicine, his education set him up to be an entirely different sort of scientist. Born and raised in Albany, N.Y., he first went to Cornell University, earning a degree in chemical engineering. In 1974, he graduated first in his class at MIT in chemical engineering. Upon graduation, Langer had a host of immediate job offers, including Shell Oil.

“In the 1970s, when I graduated, almost everyone who was a chemical engineer went to work for the oil companies, because they were the companies that had all of the money and they were paying well,” says Langer. “I thought I’d do that, too, but when I went to interview at those companies I wasn’t that excited about what I’d be doing, so I looked for other jobs.”

Unlike other aspiring chemists, Langer wasn’t afraid to consider crossing disciplines. Some of his post-doctoral work at MIT had given Langer the idea that his expertise in chemistry could be useful to the medical community. Today, the idea of a chemical engineer entering the medical field isn’t surprising. But 40 years ago, the move was considered controversial.

In a 2003 interview for the American Academy of Achievement, Boston Children’s Hospital surgeon Judah Folkman described how Langer showed up in his office with this interest. At the time, Folkman was exploring a new area of research in angiogenesis, which deals with the growth and replication of blood vessels. For the time, the work was being done at a small scale, and development was difficult—it involved not just medical principles, but engineering concepts as well. He was looking for help trying to get synthetic molecules to diffuse like tumors. It was a task not for a surgeon, but a chemist.

To Langer, who recognized how to approach the problem, the project was fascinating. He did not enter the position blindly, however, Langer was offered six months of work just to see how the research went. Folkman, he knew, was conducting research on a shoestring budget, and in an area that seemed both difficult and potentially without near-term results. In his initial job interview, Langer told Folkman that he had been warned by no less than four MIT professors not to join the project. Not only would the pay be poor, Folkman recalled, the medical field had a stigma for chemical engineers, who were frequently told that physicians tend to treat engineers like technicians.

“One of the early discoveries was figuring out how to design polymers that could deliver molecules over embryonic size and over a few hundred molecular weight,” says Langer. One of the problems encountered by medical researchers trying to find a way to fight cancer with drugs was that effective therapies were typically digested before they could reach their target or blocked when inhaled. So delivering a drug directly to its target became a priority.

“The reason we did it was to see if we could isolate the first angiogenesis inhibitors, which are molecules that stop blood vessel growth,” says Langer.

This work resulted in two groundbreaking papers published in Science in the 1970s. The first paper, which discussed using molecular inhibitors to halt the growth of blood vessels, became crucial in drug development efforts in the 1980s and 1990s. Langer played a principle part in this research, which isolated the first inhibitor, a macromolecule.

The second paper, which dealt with the specialized polymers Langer had been developing, helped pave the way for controlled-release microspheres. He believed that the inhibitor, packaged in a synthetic wafer, could be implanted in a tumor. Further, he believed the design of the polymer wafer could be done in such a way as to control the release of the molecule.

“I was trying to involve two things, first trying to find something to stop blood vessels from growing. We used cartilage as a starting point, because cartilage doesn’t have blood vessels, and next was developing a bio-assay,” says Langer. They used the eye of a rabbit because there were no background blood vessels in the eye.

“Those papers really helped things get started, and helped pave the way to angiogenesis inhibitors,” says Langer.

There was a problem with Langer’s early papers, however. Nobody believed it would work. Part of the skepticism could be attributed to lack of knowledge of the precise action of angiogenesis. Despite the rigorous and methodical approach that had demonstrated inhibitors can and did work, he was met with incredulity.

“Later on we discovered the mechanisms, but early on we didn’t know,” says Langer. Throughout the 1970s, grant applications were not accepted, and Langer felt his position at MIT, which he had garnered in 1977, might be in jeopardy.

The concept of angiogenesis and its role in tumor-like diseases was still a new and poorly understood field of medicine. Folkman had proposed the term in 1971 to describe the way tumors appeared to develop and grow. Like normal blood vessels, tumors expand by employing growth factors that help them create their own blood vessels, which develop and divide. Unlike conventional cells, cancer cells have no control over their replication, causing growth that threatens the well-being of conventional cells.

The notion that this out-of-control process could be halted by stopping these growth factors—in a sense short-circuiting the growth loop—was a radical one.

“Early on, I built little gel assays to see if enzymes were coming out in active form,” says Langer. He later applied these results to the rabbit eye model, which had been implanted with tumor, to see if any of the formulations would stop the tumor from growing.

Early on, angiogenesis was seen as a potential “silver bullet” for stopping tumor growth. But as Langer and others would find out, the practice was not simple or direct. Even after solving the tricky problems of the right kind of biocompatible polymers—Langer has invented many of them—and the proper molecule size, researchers have encountered other difficulties. Many direct growth factors and cancers exist, and often diseases can use several different kinds.

In the 1990s, Langer and fellow MIT professor Michael J. Cima started work on a microchip capable of deliverying drug doeses inside the body. This microchip, an example of that technology, allows physicians to wirelessly control drug delivery. Image: MITHowever, controlled-release drugs have made a major impact on medicine.

“Today, thanks to the work Genentech and other places, they are among some of the widely used biotech drugs in history,” says Langer.

An education in entrepreneurialism
When the medical community finally began to accept the early findings on angiogenesis, many claimed the results were obvious and could not be patented. Langer got an early lesson in intellectual property from this experience, and it helped set the stage for his approach to business in the future.

Anxious to show that his work was the first to demonstrate blood vessel inhibitors could work, Langer actually had to protect his intellectual work, scouring papers to locate evidence proving the parties in question had previously acknowledged—in print—that his discoveries regarding angiogenesis were indeed surprising and new.

“A lot times people didn’t think what we did was patentable. They didn’t think it made scientific sense, so there were all kinds of issues we had to overcome. It was not easy,” he says.

Even today, Langer calls his 1976 paper on controlled drug release one his favorite pieces of work, but it took a number of years before established drug companies and many in the medical community would latch on the idea of practical applications. In 1983, Langer’s luck started to turn. He began to work with Northbrook, Ill.-based International Minerals & Chemicals Corp., which intended to use the polymers Langer invented to administer hormones to animals. This work allowed Langer to obtain a license, and later attracted the attention of a big pharmaceutical company, Eli Lilly & Co.

In that year he also began working with Dr. Jay Vacanti, a surgeon at Massachusetts General Hospital, on tissue engineering technology that would lead to a variety of breakthroughs and is today one of the two major areas of research for Langer.

Things were looking up. But Lilly lacked enough patience for the technology.

“We did have licenses from a couple of large companies, but they didn’t work out so well,” says Langer. “Around that same time, we licensed one of our polymer systems to a little company called Nova Pharmaceutical, and that led to a wafer used to treat brain cancer."

Eventually, Langer’s successful experience with Nova caused him to think about starting his own company, and with MIT colleague Alexander Klibanov, they founded Enzytech, a Boston area startup that put him on the map as an entrepreneur. Enzytech was successful, and the company later split into two companies. Enzytech became part of pharmaceutical company Alkermes.

A people’s scientist
Langer’s appetite for working with small companies and interacting on a personal level is reflected in his taste for working with a variety of experts in the medical field. Such interactions helped provide Langer with his most valuable work.

“I’d already had an interest in developing good collaborations before I started any companies,” says Langer.

His work with Dr. Henry Brem, a neuroscientist at Johns Hopkins University, centered around his efforts to treat brain cancer with his polymer wafer technology. The technology’s ability to function within the body allowed physicians to perform less invasive treatments, and the system they developed was far less detrimental to the patient with few side effects. Most importantly, the wafer gave doctors a five-fold improvement in saving the lives of victims of brain cancer.

Nearly 15 years after Langer and Dr. Jay Vacanti began working together, the surgeon became famous in 1997 for growing a human ear on the back of a mouse. Vacanti has worked closely with the MIT professor to develop this tissue generation technology to treat burn victims. The system works by “seeding” Langer’s polymers with real skin cells to create a hybrid skin that can be transplanted without risk of rejection by the patient.

Highlighting the web-like relationships of his many research efforts, Langer’s polymer technology complements new tissue growth efforts centered around 3D scaffolding. He has published papers as recently as August 2012 describing how tissue growth can be controlled in 3D and be utilized in vivo. The latest collaboration that includes colleagues at Harvard University and Boston Children’s Hospital is refining electronic sensors made of silicon nanowires that can monitor the activity in these scaffolds, screening drug candidates or controlling drug release. This work hints, says Langer, at the possibility of tissue-engineered hearts in the not-so-distant future and he says it is one his most exciting projects.

“Today, drug delivery and tissue engineering are the two big areas we work on,” says Langer.

One of his best known and most successful recent inventions is a technology that sprung out of his early work at Boston Children’s Hospital. Over the years, the wafer-based drug delivery technology originally conceived for a general drug delivery tool was developed to become the Gliadel, a wafer licensed by Esai Inc. to treat chemotherapy. The development of this wafer required the contribution of several support technologies, each being developed by its own small company. Momenta Pharmaceuticals is responsible for the sugar-sequencing tools. The chip itself is made by T2 Biosystems, Cambridge.

Ultimately, Langer’s success can be traced back to combination of firm dedication to generation of ideas and a recognition that human interaction is a critical component to get both the research and the money flowing. This attention maintaining and enhancing relationships has allowed him to find consistent success, even in harsh economic conditions. It doesn’t hurt that he has built a reputation for founding successful businesses. Langer has found significant funding for several new companies in the last two years, including Stemgent Inc., Cambridge; Arsenal Medical Inc., Watertown, Mass.; and T2 Biosystems, which raised $23 million in financing in 2011.

A lasting impact
Langer’s success in developing useful new ideas and commercial medical products can be traced to his understanding of fundamental chemistry. A wide variety of life-threatening conditions are rooted in the health function of cell replication, and angiogenesis inhibitors can be used to affect these processes in a basic way.

“Now, I think it affects 100 million people a year,” says Langer. “I certainly did not know how important it would eventually be.”

His long career in academia has also helped foster a legendary penchant for new ideas. He has taught and mentored thousands of students over the year, and MIT’s Langer Lab, which now has a research budget of more than $10 million a year, has become a breeding ground for biotech startups and entrepreneurs with fresh ideas about both chemistry and medicine. The blending of chemistry with medicine has begun to include electronics and computers as revolutionary concepts in implantable circuitry and lab-on-a-chip technologies find practical applications. No matter what type of work is happening in the laboratory, Langer takes a role in helping to shape it.

“We have a tremendous group of students and post-docs who have a lot of their own ideas,” says Langer.

Although he certainly finds time to pursue his own research, he spends a lot of time, he says, discussing work with students and post-doctoral researchers. This, he finds, is a highly effective use of his time because of his deep experience. He and the students can quickly find useful directions for research, and can identify areas where a new and valuable paper could be published, or a new idea or technique can be explored.

“Over time,” he says, “you just know how to do it. It just kind of comes to you.”

His work has also earned a dizzying array of accolades, with notable standouts the 1998 Lemelson-MIT Prize for Invention and Innovation; 2002 Charles Stark Draper Award, a distinction from the National Academy of Engineering that’s often referred to as engineering’s Nobel Prize; the 2007 U.S. National Medal of Science; and the 2012 Priestley Medal from the American Chemical Society.

Though meaningful, and often helpful in funding his research and business ventures, these honor don’t distract him from what he clearly sees as a growing field of opportunity.

“I think there are a lot of challenges ahead,” says Langer. He sees a variety of areas where some of his concepts and the technologies he’s worked on could be vastly improves. “I think in the future we can do better with targeting drugs to specific cells, create smart delivery systems that can respond to signals in the body, and get more molecules through the body by non-invasive means, by the skin or through the lungs.”

And chances are, he’ll help found a company for each new idea.


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