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The Problem Solver

Cancer. Diabetes. Liver disease. If there’s a bioengineering challenge, Robert Langer, ScD ’74, is ready to tackle it.

When Robert Langer completed his doctorate in chemical engineering in 1974, he received around 20 offers from oil and chemical companies, including four from Exxon. Many of his peers went to work in the industry, but when confronted with the possibility of a professional life devoted to increasing oil yield by a fraction of a percent per year, he balked. “I don’t want to insult those companies,” he says, “but I hoped to have a greater impact on people’s lives.” After a protracted job search, he accepted a low-paying postdoctoral position at Children’s Hospital Boston, in the laboratory of the renowned surgeon and medical researcher Judah Folkman.

“I was the only engineer in the whole place,” he says. “Everywhere I turned, I saw medical problems I could use engineering to solve.” That work evolved into lifelong collaborations and laid the groundwork for novel approaches to delivering drugs that treat cancer, diabetes, liver disease, and many other conditions. “It was the pivotal moment in my career,” says Langer, who now oversees one of MIT’s largest laboratories, bustling with more than 150 chemists, biologists, doctors, engineers, and budding entrepreneurs—plus an additional 30 to 50 UROP students each semester. The David H. Koch Institute Professor at MIT, he has more than 1,000 patents issued or pending worldwide, has licensed or sublicensed technology to over 300 companies, and has helped found more than two dozen technology startups.

For his colleagues, the impact of Langer’s work is clear. “To me, Bob is the greatest chemical engineer of our time,” says Mark Davis, a professor of chemical engineering at Caltech. “There is no doubt that because of Bob, chemical engineering now plays an important role in medicine.”

A medical engineer
Little in Langer’s early life would have predicted this stardom. He was born in Albany, New York, where his father owned a liquor store. He played basketball and baseball and toyed with a chemistry set in his parents’ basement, making solutions change color and producing rubber. “I was a pretty regular kid,” he says. “I had trouble sitting still in school.” But he liked math and science and went on to study chemical engineering at Cornell and then, at the graduate level, at MIT. From 1971 to 1972, while pursuing his doctoral degree, he also worked at an alternative school for at-risk teenagers, called the Group School. “I was much more excited about the school than I was about my PhD research,” he confesses, adding that he has always loved teaching for the direct effect it could have on students’ futures.

A pioneer of targeted drug delivery, Robert Langer has won more than 220 major awards, including the 2015 Queen Elizabeth Prize for Engineering.

When Langer arrived at Children’s Hospital, Folkman was trying to isolate compounds that would impede the growth of blood vessels, which is known as angiogenesis. The idea was that such compounds might thwart tumors, which require a large blood supply in order to grow. The first challenge, though, was to identify angiogenesis inhibitors. Folkman believed they might be found in cartilage, which does not contain blood vessels. But experiments with rabbit cartilage, from a small number of animals in the lab, had not produced enough material for testing.

So it fell to Langer, the new engineer, to help figure out which substances would work, and then “scale up.” He found a meatpacking plant in South Boston where local slaughterhouses sent cow bones, and he managed to procure large quantities by visiting three times a week. After driving the bones back to Children’s Hospital, he separated the cartilage and purified around a hundred compounds from it. Still, it was not easy to determine whether any of them would have potential as cancer drugs. Lab members hoped to test them against tumors in rabbits’ eyes, where blood vessel development would be readily apparent. But they got stuck on how, exactly, to deliver the molecules. Langer’s achievement was to develop biocompatible polymers that could be implanted safely in the animals and would gradually release the desired compounds. This would allow the researchers to assess their impact on tumor cells over time.

At the time, most chemists doubted that relatively large molecules like proteins would move through solid polymers, whatever their composition. They thought it was like asking people to walk through walls, Langer says. But he made it possible by creating polymers with small, interconnected pores. As the drug took its winding, tortuous path through these pores to the surface, he could control the rate at which it was released. This let Langer and his colleagues test the sustained effects of potential angiogenesis inhibitors on the growth of blood vessels around tumors. Today, numerous angiogenesis inhibitors are on the market, including Avastin, Nexavar, and Votrient—and they combat cancer by hindering blood vessel growth, just as Folkman predicted.

Rethinking drug delivery
In 1984, a neurosurgeon named Henry Brem, who had also worked in Folkman’s lab, wondered about treating brain cancer with direct, local release of medication. “I thought maybe the reason chemotherapy failed was that it wasn’t being delivered properly to the brain,” Brem says. He asked Langer, who had joined MIT in 1978 as an assistant professor, about his progress on the controlled release of large molecules such as angiogenesis inhibitors. The two began to collaborate on a novel system: a polymer “wafer” that could be loaded with drugs and implanted in the brain near tumors. The key challenge, says Langer, was that they didn’t want this wafer simply to “become spongy and fall apart”; rather, they wanted it to “dissolve steadily like a bar of soap,” releasing its therapeutic payload over time. The product that Langer and Brem’s work gave rise to was approved by the Food and Drug Administration in 1996 and has been used widely as an adjunct to brain surgery for patients with glioblastoma, a deadly form of brain cancer. “Historically, neurosurgery was all about removing things from the body,” says Brem, who is now director of neurosurgery at the Johns Hopkins University School of Medicine. “But Bob has allowed us to change the paradigm, so that we are also implanting beneficial things.”

President Obama traded e-mails about stem-cell lines with Langer in 2006; in 2013, he presented him with the National Medal of Technology and Innovation.

In the early 1990s, Langer became interested in the fabrication techniques for microchips used in electronics. He thought these methods might also be used to make implantable devices that could release drugs. (He jokes that he saw a TV program about microelectronics and thought, as always, that anything new and interesting should have relevance for drug delivery.) Working with graduate student John Santini, PhD ’99 (now CEO of ApoGen Biotechnologies), and Michael Cima, a professor of materials science and engineering, Langer developed a microchip with tiny wells that could be filled with a drug and then sealed with a thin metal cap. Once the device was implanted in the body, the cap could be removed by remote control, permitting the release of whatever was inside. In 1999 Langer and Cima founded MicroCHIPS (now called Microchips Biotech) to develop the technology.

In 2012, they published the results of a small clinical trial in which they implanted microchips loaded with a hormone called parathyroid hormone (PTH) in patients with osteoporosis. Over a period of four months, they used remote control to release the hormone from the microchips in daily pulses. Langer and Cima found that the device worked as well as daily injections in treating osteoporosis, seemed not to cause inflammation (a potential concern with any implanted device), and was easier to administer than self-injected drugs—and therefore more likely to be administered at all. They are now at work on a longer trial.

The potential uses of implanted electronic devices to deliver therapeutics are almost unimaginably broad. “We create these core technologies, and I honestly don’t know all the things they might turn out to be useful for,” says Langer, who was named an Institute Professor—MIT’s highest honor—in 2005. Brem says he can envision someday using microchips for brain cancer patients. In one scenario, the patients might receive devices loaded with chemotherapy during their initial surgery. Then down the road, if the cancer recurred, the drug could be released into the brain by remote control. This would allow for direct, local treatment without requiring an additional invasive procedure, Brem says. The Bill and Melinda Gates Foundation has also approached Langer about creating microchip devices to to release hormonal contraception. These chips would remain in women’s bodies for 16 or 17 years but could be turned on and off wirelessly. So far, Langer says, his team has created prototypes but has not yet begun human trials. Long-acting forms of contraception, including versions that are implanted beneath the skin, are already in use. But current products cannot be turned on and off when they are inside the body—and while some IUDs can work for up to 12 years, none of the implanted products last more than a few years.

Of course, the prospect of implanting a concentrated, 17-year supply of hormones or other drugs in a person’s body is not without risks. Physicians might be wary of using the device, thinking that “if something traumatic happens like an automobile accident or getting hit by a bus, there could be a massive release of the compound,” says Dennis Ausiello, director of the Center for Assessment Technology and Continuous Health at Massachusetts General Hospital, who has served with Langer on several scientific advisory boards. But the system is designed to release compounds only in response to an electrical signal and Cima notes that its capacitor stores only enough energy to open a single reservoir. “The impact necessary to physically open all reservoirs would be large enough to cause massive trauma,” he says. “I don’t think your problem is the drug at that point.”

A nanotech approach
In Langer’s lab today, students and researchers are at work on yet another form of drug delivery, this one involving nanoparticles. Against one wall, several gleaming blenders whirl together liquid polymers and dissolved drugs. As these materials spin, they interact like oil and vinegar shaken together in salad dressing, creating an emulsion: tiny droplets of polymer spontaneously form, a drug trapped inside each one. Across the aisle, another researcher uses a different technique, working with microfluidic chips made of etched plastic. Each has several channels, with inlets on one side and an outlet on the other. Using a pipette, the researcher adds an aqueous drug to one inlet and lipids to another. As these substances move along the channel, ridges and bumps on its bottom cause them to mix in such a way that the lipid forms droplets encapsulating the drug. In both of these approaches, the goal is to produce nanoparticles that can protect therapeutic compounds the immune system would otherwise attack. (Langer and others have shown that particles containing certain chemicals, such as polyethylene glycol, have this protective effect.) Modifying the surface chemistry of the nanoparticles with specific proteins or other molecules helps direct them to the site where they are needed.

Cross section of Langer’s controlled-release polymer with no drug (top), loaded with a test drug (middle), and a year later, when the drug has been released.

Langer’s team has been at work for many years on a range of nano-encapsulation projects. In one, they focused on nucleic acids called small interfering RNAs, or siRNAs, which can stop specific proteins from being produced by preventing the translation of messenger RNA. The approach, called RNA interference, is thought to have great potential in medicine, but the small RNA molecules first need to get past the immune system. Langer’s team figured out how to protect them in tiny, lipid-based spheres that could evade an immune attack. Today, the company Alnylam (for which Langer has served as a scientific advisor since its founding in 2002) is testing the technology in late-stage clinical trials. Among other things, it is investigating whether a related technology that delivers siRNA molecules to the liver can treat a form of hereditary liver disease.

In another project, Langer and Omid Farokhzad, now at Harvard Medical School, designed nanoparticles whose size, shape, and surface molecules allowed them to target particular tissues and cells with greater precision than had previously been possible—while still flying under the immune system’s radar. In 2007, Langer and Farokhzad cofounded the company Bind Therapeutics, which is currently running human trials testing how the nanoparticles deliver chemotherapeutic drugs to tumors.

Beyond cancer
Langer’s lab occupies more than half a floor in the seven-story building housing MIT’s Koch Institute for Integrative Cancer Research. But the small army of researchers who work for him—Langer thinks it might be the largest bioengineering lab in academia—do not limit themselves to thinking only about cancer, and Langer is quick to emphasize the broader relevance of the group’s work. “I’ve been a technology creator, rather than thinking about a specific disease,” he says. Right now, for instance, his lab is working on several projects related to diabetes. Researchers have long tried to transplant insulin-producing pancreatic cells into patients with type 1 diabetes, which destroys the body’s own insulin-producing cells. Historically, though, the immune system has attacked the new cells, quickly reducing their benefit. While the idea of encapsulating transplanted cells to protect them is not new, it has proved challenging in practice. With support from JDRF (formerly called the Juvenile Diabetes Research Foundation), Langer and MIT chemical engineering professor Daniel Anderson have developed new and modified materials that may be better at thwarting an immune attack. “We haven’t published much on it yet,” says Langer, “but there will be papers soon.”

Elsewhere in his sprawling laboratory, a large robot helps create novel polymers from components that researchers mix and match. In another room, a large group of scientists are working with stem cells. In research overseen by Langer and Jeff Karp, a faculty member in the Harvard-MIT Health Sciences and Technology Program, they hope to create new substrates for growing stem cells, investigate how the surfaces of those substrates influence the cells’ behavior, and develop better ways of expanding stem-cell populations—especially with intestinal stem cells, which Langer says researchers can use to test potential drugs, among other applications. Ask any of the researchers hustling from room to room or bench to bench what diseases their projects might help address, and the answers range from cancer to diabetes to heart disease to all of the above. Langer has even attacked everyday problems like frizzy hair (he’s a cofounder of Living Proof, which brings high tech to beauty products) and developed a coating for button batteries that will prevent them from leaking and causing burns if they are accidentally ingested.

Tackling big problems
Langer’s track record (one version of his CV is 96 pages, single-spaced) and outsize reputation surely inspire the legions of postdocs, students, and other researchers who gravitate toward him from all over the world. A member of the National Academy of Sciences and the National Academy of Engineering, he has authored more than 1,300 articles and won a torrent of awards, including the National Medal of Science, the National Medal of Technology and Innovation, and the Charles Stark Draper Award, long considered the equivalent of the Nobel Prize for engineers. In February, he added the Queen Elizabeth Prize for Engineering, worth one million pounds. Polaris Venture Partners estimates that research from his lab has affected more than two billion people.
At the same time, he is famously accessible, replying—often in minutes—to e-mail from students, colleagues, and reporters. Having taught numerous courses in engineering and biotechnology (including Integrated Chemical Engineering, better known as 10.361, which he taught for 23 years), he now guest-lectures two to five times a week in other professors’ classes—and continues to lead a seminar called Biomedical Applications of Chemical Engineering. And he is volubly proud of his students, many of whom have gone on to auspicious careers in industry and academia themselves. “I still haven’t figured out how his brain works, but he has a remarkable ability to know what everyone is doing,” says postdoc Mark Tibbitt. “He will pass you in the hall and ask a specific question about what is going on in your work or life. It’s remarkable for such a big lab.”

Langer’s attitude, Tibbitt adds, is that with plenty of resources and a big group of people from a rich array of backgrounds, his lab is in a position to say “Let’s find the big problems and tackle them.” The key is to give those people the freedom to explore. In the case of Tibbitt and fellow postdoc Eric Appel, that freedom led them to develop a “self-healing” hydrogel composed of nanoparticles (developed in the Langer lab) that can be loaded with drugs for controlled release; because it recovers from physical stress, the gel can be injected into different parts of the body, providing a local reservoir from which drugs can be released in a controlled manner. They are pursuing applications for patients with macular degeneration (who now rely on frequent injections) and those who’ve had heart attacks and might benefit from sustained release of drugs near the affected heart muscle.

With so many demands on his time, Langer says, he prioritizes work he believes will translate into direct health benefits. He is both visionary and relentlessly practical. “There’s always a period with new technologies where they run around and look for a problem to be used for,” says Cima. Langer, he says, is gifted at “connecting technologies to true medical needs.”

In the 1980s, a close friend from Folkman’s laboratory, surgeon Joseph “Jay” Vacanti, approached Langer about trying to create artificial livers for patients in urgent need of transplants. Working with Linda Griffith, now a professor of biological engineering at MIT, they went on to create biodegradable polymers that could be seeded with living cells to grow new tissue. Their work helped found the field of tissue engineering, which has led to a range of medical applications, including artificial skin for burn victims and patients with diabetic wounds (though still no full-fledged livers).

“A lot of areas I’ve gotten into because this friend or postdoc or company was interested,” Langer says. When he responds to people with a particular medical problem in mind, his neurosurgeon colleague Brem says, “he comes up with solutions nobody else has thought of.” And, he adds, “they work.”

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