Dr Robert Langer was the recent recipient of the Queen Elizabeth Prize in Engineering, for his groundbreaking research into controlled, targeted drug delivery. eyeforpharma unravels his past achievements, discusses his present research and offers his future vision of medicine.
With his groundbreaking research into large-molecule biodegradable polymers, controlled and targeted drug delivery, nanotechnology and tissue regeneration, as well as his entrepreneurial focus and influential role tutoring some of the brightest students from across the globe, Dr Robert Langer occupies an unparalleled position in science, business and education.
He’s currently the David H. Koch Institute Professor in the Department of Biochemistry at MIT – the highest honor a faculty member can hold; has over 1,000 patents issued in his name – 250 of which have been licensed, or sub-licensed to companies; his laboratory at MIT, with over 100 students, post-doctorates and visiting scientists, is the world’s largest academic biomedical laboratory, maintaining US$15 million in annual grants.
He’s also the recipient of countless awards and prizes, including the 2008 Millennium Prize, the Priestly Medal – the supreme accolade of the American Chemical Society; the 2013 Wolf Prize, 2014 Kyoto Prize and now the 2015 Queen Elizabeth Prize for Engineering, the highest honor in Engineering. Even more significantly, more than two billion lives have been improved, or saved by Dr Langer’s breakthroughs in science, chemistry and medicine.
First Steps to First Principles
From childhood, Dr Robert Langer was captivated by chemistry after receiving a Gilbert chemistry set from his parents, when he was eleven. After setting-up a small laboratory in the basement of his home in Albany, New York, he began conjuring up chemical concoctions and synthesizing simple plastics. It was the start of his lifelong fascination with chemical engineering and its many interdisciplinary applications.
“That chemistry set was magical. I loved the reactions which made things change color and being able to turn something into rubber, or make plastics,” he recalls, smiling fondly. “But I never imagined where it would lead, or that one day I’d win the most prestigious award in Engineering, as a result. That definitely wasn’t on my radar!”
Instead, I wanted to feel that I was doing something useful, which would have a major impact on people’s lives, by making them healthier and happier – just making mankind better.
Those early experiments did, however, fuel his imagination and after excelling at maths and chemistry at Milne School, in his hometown, Langer attended Cornell University, where he majored in Chemical Engineering. After graduating in 1970, he enrolled at the Massachusetts Institute of Technology (MIT), where he undertook his doctorate. Whilst there – and with the world beset by an oil and gas crisis - he and his colleagues were targeted by petrochemical companies recruiting chemical engineers to investigate new and more efficient fuels. But, despite receiving 20 job offers from oil conglomerates like Shell, Chevron and Exxon, Langer embarked upon a very different journey from his contemporaries: applying chemical engineering principles to medicine, not industry.
“I really felt that I wanted to use my knowledge of Chemistry - and chemical engineering - to help people, rather than work for a petrochemical company, in an entry-level job, where I would just be trying to increase the yield of certain substances by tiny amounts. That idea wasn’t rewarding or exciting to me at all,” he explains. “Instead, I wanted to feel that I was doing something useful, which would have a major impact on people’s lives, by making them healthier and happier – just making mankind better. Partly, that came from my upbringing and partly from helping start a school for poor children, where I developed a maths and chemistry curriculum, which I could see made a difference.”
Langer’s altruism led to him targeting hospitals and medical schools for research opportunities and he eventually secured a research position at Boston’s Children’s Hospital, working for Dr Judah Folkman, Chief of Surgery. Folkman was undertaking unorthodox cancer research centered around the theory that the spread of cancer and the growth of tumors could be controlled if angiogenesis – the process by which new blood vessels are created and tumors grow – could be arrested, through drug intervention.
Angiogenesis and the Creation of Controlled, Timed Drug-Release Systems
Under Dr Folkman’s guidance, Langer began a painstaking analysis of hundreds of substances (antiangiogenic agents) to determine if they could inhibit the growth of new blood vessels, thereby averting the spread of cancer and tumor growth. Eventually, after two years of testing and corresponding work in an allied field of research – creating polymers (large molecules or macromolecules composed of many repeated subunits, like plastics, proteins or
“What I did early on was what I’d call Edisonian,” he explains. “It was very experimental; a lot of trial and error. I tried hundreds of different substances to see if I could find a way to prevent angiogenesis and also deliver controlled levels of drugs, over time, to treat diseases. Almost all of them failed, but I persevered because I believed it would work - even if most scientists at the time considered it impossible. Eventually, we were successful with both projects: we did isolate the substance that stopped blood vessels growing and we did create these polymer systems. It was for this latter contribution that I received the Queen Elizabeth award.
“In the beginning, the goal was simply to try and isolate the angiogenesis. But to do that we needed to create a bioassay, to allow us to study the blood vessels. However, as there weren’t any bioassays we could use – that’s usually the problem in this type of research - I had to invent them,” Langer explains. “Typically, that’s a very slow process – it often takes months – so that’s why I felt I had to create a controlled-release polymer that could slowly discharge these [bioassay] substances for several months. Consequently, the key step in the angiogenesis research was to create the polymers so I could test bioassays. Once I’d done that, I could also isolate the angiogenesis inhibitor.
“Eventually what we built was a polymer matrix with an incredibly intricate porous pathway through which the drugs would travel,” he adds. “The way we puzzled it out was using micro-structural studies, early imaging analysis, kinetic studies and mathematical-modeling studies. But when we put it all together it seemed like a pretty clear picture, which has held up over time.
“We also had to ensure the polymers were very pure and highly biocompatible, so they did not cause harm to the body. That was hard,” admits Langer. “In many cases, we also had to make the polymer biodegradable but ensure it degraded at the right rate, in the right way, which was very challenging.”
Part of the reason for Langer’s breakthroughs lay in the interdisciplinary approach he adopted and also the application of chemical engineering principles to medicine, a consequence of him working within a medical setting.
“Working in a hospital was like being a kid in an intellectual candy shop,” he laughs. “I’d see surgeons approaching problems from a purely clinical perspective but, because of my chemical engineering background, I’d look at it in a very different way.
“A classic example is surgeons would often use existing materials to make tissues or organs. So, an artificial heart was made from a ladies’ girdle because they needed a material that was highly flexible, while one of the early breast implants used mattress stuffing, because it was squishy. I thought about it differently, looking at it from a biological, engineering and chemistry standpoint,” he asserts. “I asked chemical engineering design questions, like what do you want from the material and could we synthesize it from first principles?”
It was this approach that Langer applied to his research into angiogenesis, testing and trialling hundreds of materials before ultimately creating a whole new type of biodegradable plastics – polyanhydrides – which were key to delivering controlled, targeted doses of drugs to patients with brain cancer.
Reaction and Response
In 1976, when Dr Langer presented his initial findings at a conference of polymer chemists and engineers, his results were met with widespread scepticism. Similarly, his first nine requests for research grants were all rejected by the National Institutes of Health (NIH) and various other agencies, while his application for a patent for a ‘polymer system of controlled release of macromolecules’ was dismissed five times between 1976-1981. Eventually, he succeeded in obtaining a patent, but the US Government still rejected his application for a grant to support the development of biodegradable polymers for the delivery of brain cancer drugs.
“It was very demoralizing and depressing that I got my first nine grants turned down and I also had a lot of big issues, career-wise,” he says, explaining his precarious position at MIT, in the Nutrition and Food Science faculty. “But at the same time, I believed in my research and knew it was right, so I kept pushing.”
Innovation, Entrepreneurship and Venture Capitalism
I soon figured out that the only way we could get these discoveries to market was to do it that way, with smaller companies, or do it ourselves".
Without research grants and with established, big-business companies rejecting Langer’s findings or dismissing their importance in tackling cancer, diabetes, female birth control and diseases like malaria and polio, he resorted to an innovative way to attract funding: targeting smaller businesses, start-up ventures and even establishing his own companies to develop, then deliver his discoveries to market. His first partnership was with Nova Pharmaceuticals, in 1985, who licensed one of Langer’s patents for the delivery of brain cancer treatment, using a wafer inserted into tumors. In 1987 he and a colleague, Alexander Klibanov, founded Enzytech, a company which subsequently merged with Alkemes and developed Langer’s microsphere drug delivery system, which has since been used to treat alcoholism, narcotic addiction and diabetes.
“I naively thought companies would be interested in my discoveries, but they just weren’t,” he concedes. “But then we filed patents - some of which were bought by some start-up companies - and I soon figured out that the only way we could get these discoveries to market was to do it that way, with smaller companies, or do it ourselves.”
In the 1990s, Langer’s innovative business plan radicalized R&D in pharma, with new companies being set up by him or his students for every genuine breakthrough that offered the possibility of an exclusive patent and multiple clinical applications. By collaborating with his students in their start-up businesses, Langer mentors them as both scientists and entrepreneurs, with many of these companies discovering and perfecting new treatments for cancer, heart disease, diabetes, polio and osteoporosis.
“We’ve trained over a thousand students in the lab and they all go out and do related research, become professors at Universities all over the world, or set-up their own businesses, which means there’s now enormous momentum in these areas [of research],” says Langer. “Training these students and turning out the next generation of leaders is one of the key principles that guides me now, along with coming up with new ideas that I think will change the future of medicine and then getting those ideas to work in the lab and, ultimately, the clinic.”
Initial Breakthrough: The Gliadel Wafer
In 1996, the FDA finally approved the use of an anti-cancer drug for brain cancer based on the research Langer had begun 28 years earlier, while working for Dr Folkman in his surgical laboratory at Boston’s Children’s Hospital. It was the first significant brain cancer treatment approved by the FDA in over 20 years and the first ever approved targeted treatment, with chemotherapy delivered directly to a tumor site.
Developed with Dr. Henry Brem, a neurosurgeon at Johns Hopkins Medical School, the Gliadel wafer is a dime-sized refinement to Langer’s original work on biodegradable anhydride polymers. Impregnated with carmustine, a potent anticancer drug, it slowly dissolves in the brain, providing a controlled drug-delivery system for the treatment of glioblastoma multiforme (GBM), one of the most common and deadly forms of brain cancers.
As it is inserted directly at the site of a brain tumor and dissolves evenly, like a bar of soap – unlike other degradable polymers which can become spongy and fall apart unevenly - it allows a controlled dose of chemotherapeutic drugs to be directly targeted where they are needed most, negating the possibility of an overdose and also overcoming the debilitating side effects of conventional chemotherapy, as its impact is localized. Additionally, it’s a quick but effective intervention that takes just a few extra minutes, during surgery, to line the tumor with up to eight wafers which slowly dissolve over a two-to-three week period.
“A good analogy is a sniper versus shotgun effect because it [the wafer] is a very precise, controlled intervention,” says Langer. “You can control the dose and deliver the drug to exactly where it’s needed, which has the benefit of less harm to the body and fewer side-effects.”
A good example is female birth control systems, which we’re currently working on: we’ve now developed a microchip that we can administer a controlled dose for up to 17 years, from one implant".
In 1999, Langer and Michael Cima formed MicroCHIPS to develop a silicon chip-based drug delivery system. A spin-off of the Gliadel wafer, it involves inserting a wireless silicon chip into the body with doses of drugs stored in individual reservoirs, each encased in a thin film of platinum and titanium. Using wireless technology, signals are sent to the microchip to administer controlled doses of drugs when they’re needed.
Microchip technology has been trialled by Langer and his associates on a wide range of diseases and conditions, including female birth control, osteoporosis, cancer and diabetes. But there are far-reaching pharmaceutical possibilities, as he explains.
“It could potentially be used for many diseases as well as for vaccine delivery, or in cancer where you could have combination therapies with different drugs housed in separate reservoirs or microchips. Longer term, you could have implants in the body which slowly release a drug over a very long period of time,” he says. “A good example is female birth control systems, which we’re currently working on: we’ve now developed a microchip that we can administer a controlled dose for up to 17 years, from one implant.”
The treatment for osteoporosis is a good example of the impact of microchip technology in medicine, as it offers long-term delivery. It’s also why I believe that a microchip [implant] could eventually lead to us having a pharmacy on a chip, which can deliver controlled doses of different medicines, on demand, from outside the body - either in a hospital, or as an out-patient".
In 2012, MicroCHIPS completed more groundbreaking research: the first human trials of a wireless controlled microchip that can deliver a controlled drug dose, in response to wireless electric signals, to stimulate bone formation in osteoporosis.
“The treatment for osteoporosis is a good example of the impact of microchip technology in medicine, as it offers long-term delivery. It’s also why I believe that a microchip [implant] could eventually lead to us having a pharmacy on a chip, which can deliver controlled doses of different medicines, on demand, from outside the body - either in a hospital, or as an out-patient,” he suggests.
“Ultimately, as we learn more about the body and more about [genetic] markers, I think we could develop very intelligent systems which will sense what’s going on in the body and respond to it accordingly, using microchip technology,” Langer surmises. “By having sensors in microchips being able to detect signals from the body, like glucose and insulin levels, and then telling the microchip how much to deliver, in response, that would allow drug dosage and administration to actually be controlled by the body, internally, rather than remotely by a computer.”
The potentially far-reaching implications of using such nanotechnology, according to Langer, is that related systems could eventually be used to deliver controlled doses of a cocktail of chemicals – so called Blend Therapeutics - across a person’s lifetime, which target specific illnesses in response to signals from the body itself.
The microchip is not the only nanotechnology that Langer and his associates have been developing and trialling. Their latest breakthroughs have been in ModeRNA for modified messenger RNA delivery, targeted nanoparticle-based therapeutics, nanofiber-based drug delivery and nanoparticle-based diagnostics.
“We’ve created nano-particles and targeted nano-particles that will hopefully be able to zoom-in on parts of the body, like the sniper effect I mentioned earlier. That’s very exciting,” he enthuses. “I think some of the nano-technology approaches we’re developing will lead to targeted delivery of drugs direct to specific sites, like tumors.
Again, the potential benefits of Langer’s nanotechnology are widespread, with the potential for genetic medicine delivery and more precision – or personalized – medicine based on an individual’s genetic markers.
“In the future, I think nanotechnology will lead to ways of delivering new types of genetic medicines because some of the new, large molecules, like siRNA and mRNA, could potentially be more revolutionary than the large molecules we’ve already engineered. I really think we’re seeing the dawn of the clinical implementation of [large molecule] gene therapy – ways of turning genes on and off – which will allow for targeted therapies and also precision medicine, whereby drugs, medicines and healthcare can be tailored to an individual’s genetic makeup. That’s very exciting because it will allow for more personalized medicine.
“However, if you want to deliver genetic medicines or certain types of drugs to specific cells, I don’t think it’s going to be very easy to do - unless you use nanotechnology for delivering siRNA or messenger RNA,” he cautions. “I think you’ll need some kind of nano-particles because you need to get them right into the cell; they won’t do it themselves. So that’s another application for nanotechnologies that’s intriguing, but needs far more research.”
Tissue Engineering and Regenerative Medicine
Another breakthrough technology based on Langer’s early work with polymers, which has – quite literally - grown from science-fiction to science-fact, from controversial to commonplace, has been tissue regeneration. Along with Jay Vacanti, a surgeon at Boston Children’s Hospital, Langer combined three-dimensional synthetic polymer scaffolds with living cells to create new tissues and organs in the laboratory.
“It was an idea that Jay Vacanti and I had, while I was doing my post-doctorate research, when he was the Head of the Liver Transplant program. One day he asked me if it would be possible to find a way to create new tissues and organs for patients he was treating, particularly liver transplant patients,” Langer recalls. “We talked about polymers and came up with the idea of three-dimensional polymer scaffolds, then putting cells on them. This was back in the early 1980s and what we came up with then has since become the basis of a lot of what’s now happening in tissue engineering and regenerative medicine, like creating artificial skin for severe burn victims and diabetic ulcers.
“Now we’re moving into areas like cartilage formation, bone regeneration, eye diseases and even spinal cord repair,” he continues. “We already have tissue-rebuilding clinical trials taking place in many of these areas, for example spinal cord repair, which I think will one day be widely used in regenerative medicine and continue to change the medical field, as they already have to a certain extent.”
Langer’s Future Vision of Medicine
Eventually, it could lead to people having a whole pharmacy stored on a chip that delivers drugs across a person’s lifetime, all controlled by wireless signals or, ultimately, by signals from the body itself".
“It’s a remarkable time in medicine,” Langer says, animatedly. “In the future, I think we’ll see new genetic medicines, the use of nano-technology, regenerative medicine, more targeted therapies and personalised precision medicine. But these things will take a lot of time and money, because most are still in early stages [of development].
“In terms of microchip technology, I believe that in some manifestation – although not necessarily the manifestation we currently have – it will lead to ways of controlling medicines [stored] in the body from outside the body. Consequently, you could regulate and administer a patient’s dose remotely without them having to come into a hospital or clinic. Eventually, it could lead to people having a whole pharmacy stored on a chip that delivers drugs across a person’s lifetime, all controlled by wireless signals or, ultimately, by signals from the body itself.
“Similarly, I think the other nanotechnological approaches we’re developing will lead to targeted delivery of drugs direct to specific sites, like a tumor. I also think nanotechnology will lead to ways of delivering new types of genetic medicines, by allowing us to turn genes on and off. Potentially, that means that new, large molecules like siRNA and mRNA could pave the way for gene therapy.
“Tissue engineering will lead to new ways of creating new tissues and organs,” he adds. “Up to a certain extent they already have, with artificial skin now being used in burn and diabetic ulcer cases, so I think regenerative medicine will become even more widely available and continue to change the medical field.
“Lastly, in terms of cancer treatment, I think there are some exciting things going on right now, like angiogenesis inhibitors, targeted drug therapy and nanotechnology, but it’s still a challenging time,” admits Langer.
“I think traditional approaches, like radiotherapy and chemotherapy, will possibly be replaced by more targeted forms of chemotherapy as technology improves, such as the wafer I developed for brain tumors. Ultimately, I don’t know what the treatment for cancer will be, if it’ll be targeted, or involve nanotechnology, gene therapy or even the immune system, but I’m positive they’ll be far, far better cancer treatments than now.
“But not knowing what will happen with medicine in the future is exciting: it’s what motivates me to keep experimenting and keep exploring the possibilities,” he concludes, cheerfully. “You know, there are three, key principles that guide me now: coming up with new ideas that I think will change the future of medicine and improve people’s lives, getting those ideas to work in the lab, then a clinical setting and also training my students and turning out the next generation of leaders and innovators.”
It’s a bold, brave vision for the future of medicine but, given Dr Langer’s remarkable discoveries, groundbreaking achievements and unparalleled successes, it could easily become fact rather than fantasy, reality rather than theory.
Photo Credit (Cover Shot): QE Prize
Photo Credit (Lab Photo): Ben Tang
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