The Struggles And Dreams Of A Young Chemical Engineer

Following is Robert S. Langer's Priestley Medal address.

I feel tremendously honored to receive the Priestley Medal. First, it’s a terrific honor to be in the company of the remarkable chemists who have received it. I am truly humbled. Second, as was written previously in Chemical & Engineering News, this is the first time in 65 years this award has been given to a chemical engineer. I also believe it’s the first time it’s been given to a bioengineer.

But my path here was not at all straightforward. It started simply enough. I was drawn to chemistry as a young boy and was 11 years old when my parents gave me a Gilbert chemistry set. I set up a little lab in the basement of our small house in Albany, N.Y., where I would mix chemicals together and watch solutions turn different colors, and I’d make polymers and rubber.

In high school, I wasn’t very good in classes like English and French, but I did well in science and math. So, when I was ready to apply for college, my father and guidance counselor said I should become an engineer. I actually thought engineers ran railroad cars and I didn’t understand why science and math would help someone do that, but I did apply to engineering schools and was fortunate to be accepted to Cornell University. In my freshman year, chemistry was my favorite subject by far, so I decided to major in chemical engineering. When I finished, I received a couple of job offers to run chemical plants, but I didn’t think I’d be very good at it and it wasn’t exciting to me. I decided to apply to graduate school and entered MIT.

I finished graduate school with a doctorate in chemical engineering, and I still didn’t know what I wanted to do career-wise. I graduated in the 1970s and at that time, just like a few years ago, there was a gas shortage. But it was even worse then. Not only did the price of gas go way, way up, but you had to wait in line at the gas station for hours to fill up your car, at least in Boston. The consequence of that was that if you were a chemical engineer, you got a lot of job offers. In fact, nearly all of my classmates in the 1970s joined oil companies. They had many openings, and that’s really where the high-paying jobs in chemical engineering were at that time. I got 20 job offers from oil companies—four from Exxon alone. I also got offers from Shell, Chevron, and others. Perhaps the only oil company that I didn’t get an offer from was British Petroleum. One job interview made quite an impression on me. I went to this interview at Exxon in Baton Rouge, La., and one of the engineers there said to me that if I could increase the yield of a particular petrochemical by about 0.1%, wouldn’t that be wonderful? He said that would be worth billions of dollars. I remember flying home to Boston that night, thinking to myself that I really didn’t want to do that.

What did I want to do? Well, I had this dream of using my background in chemistry and chemical engineering to improve people’s lives. I had spent a lot of my time as a graduate student starting a school for poor high school kids and developing new chemistry and math curricula. One day, I saw an advertisement for an assistant professor to develop a chemistry curriculum at City College in New York. So I wrote them a letter, but they didn’t write me back. But I liked that idea, so I found all the ads I could for an assistant professor position to develop chemistry curricula. I wrote to all of them, but I don’t think any of them wrote me back.

Another way I thought I could help people was through health-related research. So I applied to a lot of hospitals and medical schools. None of them wrote me back either. Then one day, one of the people in the lab where I worked said I should write to a surgeon named Dr. Judah Folkman at Harvard. He said, “Sometimes he hires unusual people,” and Folkman was kind enough to offer me a job. So I took what, at that time, seemed to all chemical engineers like a huge risk and began doing postdoctoral work in a hospital. It might seem more common today, but at that time few, if any, chemical engineers had done postgraduate work in a surgery lab.

The projects that I began working on involved two related problems: first, trying to discover the first substance that could stop cancer blood vessels from growing (and thus stop tumor growth), and second, developing polymer systems that might be able to slowly release these and other high-molecular-weight substances for a very long time in the body. Before I worked on this problem, no one had been able to develop ways to continuously release these kinds of substances for a long time from biocompatible polymers, and in fact, scientists thought this was impossible to do. Maybe the only thing I had going for me was that I hadn’t read the literature saying it was impossible.

I spent two years working on this project, and I found about 200 different ways to get this to not work. But finally, I made the discovery that I could modify certain types of polymers and use them to slowly release those molecules. We used these polymers to create bioassays that enabled us to discover the first substances that stop cancer blood vessels and help stop cancer.

As an aside, it took 28 years from our earliest publication in this area until the Food & Drug Administration approved the first blood vessel inhibitor. Today, such drugs are among the most successful new biopharmaceuticals for treating cancer and other vascular diseases such as macular degeneration, a leading cause of blindness.

About two years after I started working on the polymer drug delivery project, I was asked to give a talk to a very distinguished audience of polymer chemists and engineers in Michigan. I had never given a big talk before. In fact, the last talk I had given was in eighth grade when I had to give a minute-and-a-half speech. The night before my eighth-grade talk, I rehearsed for four hours in my parents’ bedroom in front of a mirror. The next day, I started to give the talk, but after one minute of speaking, I couldn’t remember the next word and I froze. Eventually the teacher told me to sit down and gave me a very poor grade. I think it was an F.

So now when this Michigan talk came about many years later, I was very nervous. I stopped working two weeks in advance of it, and I kept practicing my talk over and over into a tape recorder, until finally, the day came when I was going to give it. I got up and gave that talk, and I actually was pretty pleased by the end of it. I hadn’t forgotten too much of what I’d intended to say, and I didn’t stammer too much. I thought that when I was done with that talk that all these much older, distinguished chemists and engineers in the audience, being nice people, would want to encourage me, this young guy.

Instead, a number of people gathered around me and they stated: “We don’t believe anything you’ve just said. We know that you can’t get these molecules that you’re talking about to slowly diffuse through these polymers.” It wasn’t until several years later that other people began repeating what we did, and then the question shifted to, “How could this possibly happen?” In fact, I spent a good part of my early career at MIT understanding how these polymer drug delivery systems functioned and trying to make them useful for different applications.

Also, shortly after that talk, I tried to receive funding to support my research and wrote a number of grants. My first nine were turned down. I remember I wrote one grant to the National Institutes of Health for some of the cancer research I was doing, and when I got the reviews back, they were very, very negative. They not only turned me down, but they said, “Well, how could Dr. Langer do this? He’s a chemical engineer. He doesn’t know anything about biology and knows even less about cancer.”

When I was done with my postdoctoral work, I applied for faculty positions in a number of chemical engineering departments. But I had trouble getting faculty jobs because people felt that, at that time, what I was doing wasn’t engineering. They thought it was more like biology. So I ended up joining what was then the nutrition and food science department at MIT. But the year after I got the position, the department chairman who had hired me left, and a number of the senior faculty in the department decided to give me advice: They told me that I should start looking for another job.

So there I was, getting my grants turned down and people not believing in my research, and it appeared I would not even get promoted to associate professor. Fortunately, within the next few years, scientists in the pharmaceutical industry and at different universities started using some of the principles and techniques I developed, and slowly things began to turn around.

I wanted very much to have the inventions and materials we developed get to the point where they could help patients. This was difficult because it takes a great deal of money and people to develop medical products. So I began writing patents on our work. Today, we have licensed and sub­licensed those patents to over 250 different companies, and I even helped start a number of companies with my students. I have found that this type of mentoring allows young graduate student and postdoctoral entrepreneurs to help realize their potential as leaders in the business community who end up creating new chemical products to improve people’s lives. I should add that when I wrote the patents and helped start the companies, many scientists looked down upon it. They thought it wasn’t a very good thing for a professor to do. But today, these companies have made all kinds of products that treat patients with cancer, heart disease, and many other sicknesses. These companies have also created many thousands of jobs across the country and the world.

As an example, I’d like to expand on what I mentioned previously—when we developed polymer systems that could slowly and continuously release large molecules. One of the challenges was getting a patent. We filed a patent in 1976 and the patent office turned it down. I believe they turned it down five times between 1976 and 1981. My lawyer told me I should just give up, but I’ve never given up easily and I started thinking about new ways in which we could get this patent allowed. The patent examiner said that what we had done was obvious, but I knew that wasn’t true since, as I mentioned, scientists said it was impossible. So I scoured the literature and discovered that there had been a paper published by five famous chemists and chemical engineers in 1979 that referred to our work by saying, “Folkman and Langer have reported some surprising results that clearly demonstrate the opposite of what scientists had thought before.” I showed this to our lawyer, who said, “Oh, this is very interesting,” and he showed it to the patent examiner, who said, “I will allow this patent if Dr. Langer can get affidavits from the five chemists and engineers saying they really wrote this.” All five scientists that wrote this were kind enough to sign the affidavits, and we got this very broad patent. We then licensed it to two very large companies—one in animal health and one in human health. Both companies gave us grant money and they promised to do experiments to develop our invention, which I was very excited about. However, these companies were very large; they’d do one or two experiments, and if those didn’t work right, they’d give up. So a few years later my MIT colleague, Alex Klibanov, Novartis Professor of Chemistry & Bioengineering, said, “Bob, why don’t we start a company ourselves?” I was able to get these patents back and we started a little company called Enzytech, which later merged to become Alkermes. This company has now developed polymeric drug delivery systems for all kinds of drugs. One of them has been used to treat schizophrenia in over 4 million patients. Others are now being used to treat alcoholism, narcotic addiction, diabetes, and many other diseases. The company has some 25 different products on the market. And many of the principles we developed are now also used to create nanoparticles for medical applications, an area I am very excited about for future research and clinical application.

Another area I started thinking about involved creating new polymer materials. Working in a hospital, it became clear to me that almost all polymers used in medicine were derived from household objects and their medical use was driven by clinicians who wanted to use them in medical areas based on their physical properties. For example, the polyether urethanes used in ladies’ girdles are used in artificial hearts because of the good flex life. The polyurethanes in mattress stuffings are used in breast implants. Yet such an approach often leads to problems. Artificial hearts, for example, can cause clots to form when blood hits their surface—the ladies’ girdle material—and these clots can cause strokes and death.

Against this background, I began thinking that we needed to find ways of solving medical problems other than to search for materials in everyday settings. As a chemical engineer, I believed that researchers could take an engineering design approach: Ask the question, “What do we really want in a biomaterial from engineering, chemistry, and biology standpoints?” and then synthesize the materials from first principles. As a proof of principle, we decided to synthesize a new family of biodegradable polymers, polyanhydrides, for medical use. The first step was to select the monomers—the building blocks of the polymer. I asked Mike Marletta, who was then at MIT and is now the president of Scripps Research Institute, what monomers, from a list of substances we thought might make good polymers, would be safe in the human body. We then synthesized these polymers and discovered that by changing compositions we could make them last in the body anywhere from days to years. Then with Henry Brem, who is now chief of neurosurgery at Johns Hopkins, we thought we could use this polymer to locally deliver drugs to treat brain cancer. But I had to raise money for this project, so I wrote grants to NIH and other funding agencies. These grants were then reviewed by study sections composed of other professors. Their reviews were very negative. In our first grant in 1981, the reviewers said that we would never be able to synthesize the polymers. However, Howie Rosen, one of my graduate students at the time, synthesized the polymers for his graduate thesis. Rosen ultimately became president of ALZA Corp., a very successful company, and is also a member of the National Academy of Engineering. After Rosen accomplished the polymer synthesis, we sent the grant back for another review, and received the reply: The grant should still not be funded because the polymers will react with whatever drug you put in. But several postdocs—Kam Leong, now the James B. Duke Professor at Duke University, and Robert Linhardt, who is now the Ann & John H. Broadbent Jr. ’59 Constellation Professor of Biocatalysis & Metabolic Engineering at Rensselaer Polytechnic Institute—showed there was no reaction.

Then we returned the grant for another review, which came back with the comment that the polymers were fragile and would break. This time, two other postdocs in our laboratory, Avi Domb, who later became chair of medicinal chemistry at Hebrew University, and Edith Mathio­witz, who is now a full professor at Brown University, addressed this problem. The revised grant was sent again for evaluation and this time, the reviewers said that it should not be funded because new polymers would not be safe to test on animals or people. Another graduate student, Cato Laurencin, who would become the dean of medicine at the University of Connecticut as well as a member of the National Academy of Engineering and the Institute of Medicine, showed that the polymers are safe, supporting Marletta’s early analysis.

These kinds of negative reviews occurred for a long time, but in 1996, FDA finally approved this treatment. It was the first time in more than 20 years that FDA approved a new treatment for brain cancer, and the first time they ever approved the concept of polymer-based local chemotherapy.

You can probably tell from the way I’m speaking that I’m very proud of how well our graduate students and postdocs have done. They’ve become heads of major corporations and very successful professors at top universities. The reviewers, unfortunately, haven’t done that well. I should add that the funding that we obtained to support our research was based on broad patent coverage on polyanhydrides that we received from a company that licensed our patents. Sixteen years after their approval, these polymer systems are still used for treating brain cancer patients. They provided an entirely new paradigm in the drug delivery field, helping pave the way for drug-eluting stents and other local delivery systems.

In a final example, Jay Vacanti, a surgeon at Massachusetts General Hospital, and I had an idea in the 1980s to combine three-dimensional synthetic polymer scaffolds with cells to create new tissues and organs. Once again, this idea was met with great skepticism, and it was extremely difficult to obtain government grants. However, our patents were licensed by companies that, in turn, gave us funding for our research. Today, this concept has become a cornerstone of the field of tissue engineering and regenerative medicine, leading to the creation of artificial skin for patients with burns or skin ulcers and, hopefully someday, many other tissues and organs.

Throughout all of this research—with its challenges and setbacks—I’ve been incredibly excited about the potential of materials and the value of chemistry and chemical engineering to change the world and transform human health care. I believe that we are only at the tip of the iceberg in synthesizing and developing materials for all types of applications that can profoundly relieve suffering and prolong life. I’ve also learned a great deal from the challenges and setbacks I have faced, and if there is any advice I might give to the young people who might want to follow the kind of career I’ve chosen, it would be to dream big dreams that could change the world, don’t give up on those dreams, recognize that conventional wisdom is not always correct, and consider collaborating and learning from scientists whose skills are often very different from your own.

I feel incredibly fortunate that I’ve had such a wonderful staff at MIT and such super students, postdocs, and collaborators. I’ve been very lucky to have a wife who, as a Ph.D. herself, understands what a life in science is like and has been so supportive. I would not be here without having had so much support and help from so many people. Once again, I’m honored to be chosen as a Priestley Medalist and to have had the wonderful opportunity to share my thoughts, struggles, and dreams.