A scientific road not taken
As told by Robert S. Langer

My career has not been straightforward. In a way, I followed Robert Frost’s poem “The Road Not Taken.” Although I am a chemical engineer and I’m proud of that, I took a path from chemical engineering to nanotechnology to biology and medicine. This was very unusual many decades ago. In so doing, I met with rejection and ridicule early in my career. However, by going down that path I was able to make discoveries that I hope have saved and improved lives and I’ve been able to train a great number of people who are going down the road I began traveling over 50 years ago.

My early years
I was born on August 29th, 1948 at Albany Medical Center and grew up in Albany, New York. My father, Robert, ran a small liquor store. He worked very hard. But when he came home, he would play math games with me. My mother, Mary, was a homemaker. She took care of my sister, Kathy, and I. My mother worried a lot, but she was one of the nicest people you could ever meet. I hope some of that rubbed off on me.

Among the gifts my parents got me when I was between the ages of 10 and 13 were Erector, Microscope, and Chemistry sets. I loved these sets. I would make robots and rocket launchers with the Erector set, watch shrimp hatch with the microscope, and I set up a little laboratory with the chemistry set in the basement of our small house where I would mix chemicals together and watch them turn different colors, and I’d make rubber, polymers, and other materials. I’d get other gifts as well like baseball gloves, a basketball, and a football. I loved these too and I played a lot of sports with my friends in the neighborhood.

High School and College
I went to Milne High school in Albany, New York. I was good at math and science. However, courses like English and French were challenging to me. Both my father and guidance counselor said I should become an engineer and I applied to engineering schools and was fortunate to be accepted to Cornell University. In my freshman year, chemistry was my favorite subject by far. It was the only course I did really well in, so I decided to major in chemical engineering.

"One of the biggest issues I had in high school and college was paying attention in class."

I did poorly grades-wise my first three terms. One of the biggest issues I had in high school and college was paying attention in class. Today, I realize I had what is called ADD (Attention Deficit Disorder), but at the time I thought there was something wrong with me. Nonetheless, to compensate for my inability to learn in class, I began working very hard and memorized things like the organic chemistry texts and taught myself how to do homework problems. My grade point average the last five semesters was greater than a 4.0 (An “A” was 4.0—I had a number of A+s). I also got my first taste of teaching by being a teaching assistant in a course on heat and mass transfer. I loved it and loved interacting with and teaching students just a year younger than myself. When I graduated from Cornell, I received several job offers to run chemical plants, but I didn’t think I’d be very good at it nor was it interesting to me, so I decided to apply to graduate school.

I applied to six graduate schools and chose to go to Massachusetts Institute of Technology (MIT). While at MIT, I did two things. The first was my doctoral thesis on Enzymatic Regeneration of Adenosine Triphosphate (ATP). The goal was to explore enzymes for synthetic purposes and an energy source – ATP – was required. On the positive side, my advisor, Clark Colton, was very thorough; and one of the postdoctoral fellows in the lab, Colin Gardner, taught me how to do very careful, reproducible research. But on the negative side, after the first year or two, I started to think that the research I was doing wasn’t important. I couldn’t see how it would have great impact or change the world. That discouraged me about research.

The second thing I did was to get involved in a lot of educational outreach, particularly teaching underprivileged children. During my first year at MIT, I did a lot of tutoring in poor communities. During my second year at MIT, some people wanted to start a school for poor high school students who had dropped out of the public schools. They asked me to help, and we started the Group School. I helped create and chaired the Math and Science Departments. My big goal was to make math and science interesting. I got MIT to fund a program to create a novel chemistry lab course where we would teach chemical principles by practical examples, such as making rubber illustrated a chemical reaction and making ice cream illustrated freezing point lowering because you need to lower the freezing point of water to make ice cream into a solid. I also created different math games to help make math interesting. The people at the school were very liberal, and students were not required to take math or science. I remember when I first came, only 5 of 42 students signed up for math. But one year later, 45 out of 50 did. This experience reinforced my love of teaching.

"I got 20 job offers from oil companies – four from Exxon alone."

I finished graduate school with a doctorate in chemical engineering and I didn’t know what I wanted to do career wise. I graduated in 1974 and at that time there was a big gas shortage. The price of gas went way up, and you had to wait in line at the gas station for hours to fill up your car, at least in Boston, where I lived. The consequence of that is that if you were a chemical engineer, you received a lot of job offers. In fact, many 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 then. I got 20 job offers from oil companies – four from Exxon alone. I also got offers from Shell, Chevron and others. One job interview made quite an impression on me. It was at Exxon in Baton Rouge. One of the engineers said to me that if I could increase the yield of a particular chemical 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 that I really didn’t want to do that.

What did I want to do? Well, from my college experiences I had this dream of using my background in chemistry and chemical engineering to improve people's lives. As mentioned, I had spent a lot of time starting a school for poor high school kids and developing new chemistry curricula. One day, I saw an advertisement to be an Assistant Professor to develop chemistry curricula at City College in New York. So, I wrote them a letter, applying for the job, however 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 found about 40 such ads. I wrote to all of them, but I don’t think any wrote back.

Postdoctoral Research
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 back either. Then one day, one of the people, Barry Bunow, in the lab where I worked said I should write to a surgeon named Dr. Judah Folkman at Harvard and Boston’s Children’s Hospital. He said, “sometimes he hires unusual people.” Dr. 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 before.

Dr. Folkman was trying to understand how blood vessels grow towards cancerous tumors. He postulated that the tumors grow because they produce a chemical substance that induces blood vessels to grow into them. That way, the tumor receives nutrients and can grow much larger, but if one could prevent nutrients from getting to the tumor that might stop the tumor from growing. When I started working with him, this concept was theoretical, and many people did not agree with it. Moreover, this area of blood vessel growth was difficult to study. We realized that to solve this problem, we would not only need to isolate a blood vessel inhibitor, which is often in the form of a large molecule, but as has often been the case in the development of new medicines, discoveries were hampered because no bioassays existed. So, we needed to develop one.

"When we started this work, the conventional wisdom was that it could not be done."

We chose the cornea of a rabbit to study blood vessel growth, because there are normally no blood vessels in the cornea, and the Chick Chorioallantoic Membrane (CAM) which has very few blood vessels in certain areas. We put a tumor in these places. Over time, blood vessels grow towards the tumor. We wanted to stop those blood vessels from growing, but to do that we needed a tiny controlled-release system (e.g., composed of a polymer or lipids) that could protect and deliver the different molecules. Since no delivery system existed, I tried to develop one. However, delivery of large molecules on a chronic basis faced serious challenges. When we started this work, the conventional wisdom was that it could not be done. Dr. Folkman contacted many experts, including Paul Flory, a Nobel Laureate in chemistry for his work in polymers, and they told him it wasn’t possible.

Against this background, I began working trying to see if I could make tiny particles that could deliver these molecules. Over two years, I found hundreds of unsuccessful methods. Finally, in 1976 I discovered a way to make it work (ultimately published in NATURE).

"Over two years, I found hundreds of unsuccessful methods."

That year, as a very naïve postdoc, I was asked for the first time to give a major lecture – at the Midland Macromolecular Symposium. I thought that when I finished that talk that all these older, distinguished chemists and engineers in the audience would want to encourage me, this young guy. But when I was done, people gathered around me and stated, "We don't believe anything you said.” It wasn't until several years later that others began repeating what we did and then the question shifted to "How could this happen?” In fact, I spent a good part of my early career at MIT understanding how these delivery systems functioned and trying to make them useful for different applications.

Becoming a Professor
Shortly after that talk, I tried to receive funding to support my research and wrote many grants. My first nine were rejected. They were reviewed by medical study sections who felt engineers had little ability to do experimental medical research. Also, when I was finishing my postdoctoral work, I applied for faculty positions in many chemical engineering departments. However, I could not get a faculty job 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. However, what had happened was, the year after I got the position, the department chairman who 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. As my colleague at the time, Michael Marletta, recalled:

“One evening, I went to a faculty dinner at a Chinese restaurant with Bob Langer and some senior MIT professors. A senior scientist sat quizzing us while smoking a cigar. When the older scientist heard Langer’s concepts for polymeric drug delivery, he blew a cloud of smoke in Langer’s face and said, ‘You better start looking for another job.’ I thought I was in a Fellini movie.”

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 different universities started using some of the principles and techniques I developed, and things began to turn around.

Moving Our Research Forward
One of my goals in doing laboratory work has been to move beyond just conducting experiments and publishing the results to applying that work to helping people. So, I worked with Dr. Folkman to use this delivery system in the bioassay mentioned earlier to see if we could find substances that could stop blood vessels from growing. I had isolated many different substances and tested all of them in 100 different studies. Every substance but one failed to stop the blood vessels from growing. For the one that did, we did 20 different experiments and for the first time, we saw that blood vessels growing towards a tumor could be halted. We published a paper in Science in 1976, which showed for the first time that inhibitors of blood vessel growth did exist, and provided bioassays which could and were used to isolate future inhibitors. Today, many inhibitors of blood vessel growth have been isolated and they are used by many millions of people to treat cancer and diseases of blindness, such as diabetic retinopathy.

Translating scientific discovery to benefit humankind in biology and medicine
The principles we established for the controlled movement of molecules have been essential to the development of numerous clinically used therapeutics. There are many tiny controlled-release systems used by patients worldwide that continuously release peptides for up to six months from a single injection (Lupron Depot, Zoladex, and Decapeptyl) to treat advanced prostate cancer. Similar microspheres or other polymer systems containing bioactive molecules have led to new treatments for schizophrenia (Risperdal Consta), alcoholism, opioid addiction (Vivitrol), arthritis (Zilretta), controlling bleeding (Floseal, Surgiflo), pituitary dwarfism (Nutropin Depot), type-2 diabetes (Bydureon), and many other diseases.

The original controlled-release materials we developed were small particles; in many cases, microparticles. However, nanoparticles are often critical for delivering significant payloads of any drug into cells, particularly newer potential drugs such as siRNA and mRNA. Yet, once nanoparticles are injected into the body, they are destroyed almost immediately by macrophages, and are unstable and often aggregate. These characteristics made their use essentially nonexistent. To address these issues, in a 1994 paper in Science, we defined seven characteristics we wanted to build into nanoparticles. We found that nanoparticles composed of a block copolymer of polyethylene glycol (PEG) and any other material and an added drug, could circulate for hours in vivo, be stable on the shelf for years, and not aggregate.

"These principles are now being widely used by many scientists and companies to practice ‘nanomedicine’."

Another issue with nanoparticles is that for nucleic acids, it is desirable that they be cationic (positively charged) so they can complex negatively charged nucleic acids.However, charged nanoparticles can cause toxicity.So, Dan Pack, David Putnam, and I added molecules to nanoparticles that made them neutral at physiologic pH but charged inside the cells. This approach (ionizable polymers or lipids) also enables endosomal escape by destabilizing the endosomal membrane inside cells.

These principles are now being widely used by many scientists and companies to practice ‘nanomedicine’. A lipid nanoparticle with PEG and an ionizable lipid has been approved by the FDA to treat a protein-misfolding disease – ATTR amyloidosis (Onpattro). Another nanoparticle we helped develop (Inveltys) has been approved to treat post-operative inflammation and pain following ocular surgery. Nanoparticles containing PEG and ionizable lipids are now used for all mRNA therapeutics and vaccines.

We also created new approaches for high throughput synthesis of polymers and lipids. These were developed by David Lynn and Dan Anderson when they were postdoctoral fellows with me. They synthesized large polymer libraries of materials such as poly β-aminoesters, and developed chemical and robotic methods that lent themselves to high-throughput parallel synthesis and screening approaches. We synthesized thousands of such polymers and lipids. This has led to a number of widely used gene therapy reagents (distributed by Sigma-Aldrich, Clontech, Stemgent, and others).

Controlling the movement of molecules to improve heath in the developing world
Bill Gates visited me in 2012 and asked if we could create new medicines for the developing world by extending some of the principles we developed. One area is vaccines, because patients often do not return for second or subsequent injections. In 1979, we published the first paper illustrating a single-step method of vaccination. The Gates Foundation was particularly interested in if we could create microparticles or nanoparticles that release their contents in distinct, delayed bursts. To address these issues, with Ana Jaklenec we developed a new high-resolution microstructure fabrication technique termed StampEd Assembly of polymer Layers (SEAL), which enabled us to create small particles each of which could pulse at a different pre-determined, desired period of time to deliver timed pulses of antigens, so that essentially any vaccine could be delivered on whatever schedule was desirable in a single injection.

We also developed new approaches to improve human nutrition in the developing world where micronutrient deficiencies are prevalent and impact nearly two billion people. In particular, many populations in developing world countries consume staple foods that often require extensive cooking, which introduces heat, moisture, and oxidation challenges, leading to degradation and chemical changes of vitamins and minerals. To address these issues, we hypothesized that an encapsulation system employing an appropriate pH sensitive material could potentially maintain nutrient stabling boiling water for hours yet dissolve rapidly in acidic stomach conditions. We examined over 50 materials and discovered that a material that had a unique combination of: (i) stability in boiling water for hours, yet rapid dissolution in gastric acid at body temperature, (ii) proven safety in humans, and (iii) ability to effectively encapsulate nutrients with a wide range of chemical and physical characteristics. This is now in human testing.

Creating Companies and Products
I also wanted the inventions and materials we developed to help patients. This was difficult because it takes a great deal of money to develop medical products. So, I began writing patents. We licensed or sublicensed those patents to over 400 companies and I even helped start a number of companies. I should add that when I wrote these patents and helped start these companies, many scientists looked down upon it. But today, these companies have made numerous products that treat patients with cancer, heart diseases, COVID, and many other sicknesses. These companies have also created many thousands of jobs.

Let me give a few examples. First, expanding on what I mentioned earlier – where we developed polymer systems that could 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. In fact, they turned it down five times between 1976 and 1981. The 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 searched the literature and discovered that a paper published by five famous chemists and chemical engineers in 1979 which stated,

“Generally the agent to be released is a relatively small molecule with a molecular weight no larger than a few hundred. One would not expect that macromolecules, e.g., proteins, could be released by such a technique because of their extremely small permeation rates through polymers. However, Folkman and Langer have reported some surprising results that clearly demonstrate the opposite.”

"The most well-known company I helped to start is Moderna in 2010."

I showed this to a lawyer who 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. Both companies gave us grants and promised to do experiments to develop our invention. However, these companies were large, and they’d do a few experiments and when they didn’t work optimally, they gave up.

So, a few years later Alex Klibanov, said “Bob, why don’t we start a company ourselves?” I was able to get these patents back and we started a company called Enzytech which later merged to become Alkermes. Alkermes has made long-acting injectable microspheres that have helped millions of patients who have suffered from Type 2 diabetes, schizophrenia, alcoholism, opioid addiction, and pituitary dwarfism. The most well-known company I helped to start is Moderna in 2010.

The company was initially criticized by scientists, stock analysts, and the news media who said things like the stock was overvalued (it is now trading for more than 10 times what it was when that was said) and that our messenger RNA therapeutics would not work. However, Moderna produced a COVID-19 vaccine that saved millions of lives. Many other new medical treatments for cancer and other diseases are in late-stage clinical trials. Polaris Ventures estimates that billions of people are or will be helped by products created by companies I helped start.

Teaching and my students
I’m also so proud of the students and postdocs who worked in our laboratory. When I turned 70, they had a celebration and over 700 people came. Today, over 400 of our trainees are professors, over 500 have worked in industry or started companies, and another 100 hundred or so have worked in government or other jobs. Forty-eight have been elected to the National Academy of Inventors, 23 to the National Academies of Medicine, 23 to the National Academy of Engineering, three to the National Academy of Sciences, and 40 to the Technology Review 35.

"I would not be where I am today without having had so much support and help from so many people."

My family and life today
I’ve been married for over 35 years to a wonderful, beautiful, and kind woman – my wife, Laura (Figure 4). I met Laura because she was the roommate of one of my postdocs and I’d seen her running on the track where I also ran for exercise. I thought she was very beautiful, stimulating, smart, and nice. Laura has a bachelor’s degree from Harvard and a Ph.D. in Neuroscience from MIT. Being married to someone with a scientific background has the added benefit that she knows the pressures I feel and the rewards I get from science and being able to share that with her has been wonderful. Laura is my best friend as well as my wife.

I should add that a number of years ago, my postdocs and students had a symposium for me and one of them, Edith Mathiowitz, made a graph of my productivity. She asked everyone a question: why is there a big inflection point in 1986? Her answer was that’s when Bob met Laura. We also have three wonderful children, Michael, Susan and Sam.

I feel incredibly fortunate that I’ve had such wonderful staff at MIT and such super students, postdocs and collaborators. I view my students and postdocs as an extended family, and I am so very proud of them. I would not be where I am today without having had so much support and help from so many people.