PK: Did your graduate work foreshadow what you were going to do as a post-doc or was it completely new?
RL: My graduate work was on enzyme reactions. In a mild way it foreshadowed my interest in the biological aspects of engineering. But I didn’t really feel that particular work was that worthwhile, where my work with Folkman was very worthwhile. It wasn’t just getting a paper done that motivated me. I wanted to do something that I thought, if we were successful, would really change people’s lives.

PK: After joining Judah Folkman’s lab, what was it specifically that made you decide what project you were going to work on?
RL: At that time, people weren’t even sure that angiogenesis existed. Angiogenesis was viewed as almost a theory and many people thought it was wrong. So, my goal was to isolate and purify the first angiogenesis inhibitor, which was some substance from cartilage. In trying to develop bioassays for those molecules, I felt it was critical to develop a slow release polymer system. For the rabbit assay that Folkman wanted to use, it was important to be able to release something for 30 days and the system had to be safe and not cause inflammation. The molecules we were testing were relatively large, like what might be in cartilage. 

So, what happened was I got involved in the idea of angiogenesis and also worked on these slow release polymers, which were pretty controversial at the time. Slow release polymer technology is not so controversial now. A lot of products are based on it, but at the time, when I first published or talked about it, people said it was impossible. "It couldn’t work. You can’t get big molecules out of polymers slowly." So, I started trying to better understand the mechanisms involved.

Also, being an engineer, working in Children’s Hospital was a great opportunity for me. I would see many medical problems and I started to have a lot of ideas about how to approach them. It was almost like being in a candy shop. I had a very different perspective by being an engineer. I could see how using chemistry could address this problem or engineering could address that problem. I would be riding up the elevator with clinicians and they would say, "Well we have trouble with this." I would say, "Well, maybe we could solve it this way."

PK: What made you feel that you could solve a problem, such as the slow release of large molecules, that so many experts said couldn’t be solved?
RL: Some people would say that at the time I didn’t know anything about polymers, and so I didn’t know how hard it was. But, also, I don’t think there is very much that is impossible. I didn’t think it then, and I certainly don’t think it now. Working with Folkman was a good experience too, because he felt that way. I don’t think he believes there is much that is impossible. So, you decide you want to work on big problems. You might not know exactly how to solve something at the time, but you work on it and you keep going after it and eventually you make some headway. Like I say, there is not a lot that is impossible. You don’t know how long it will take you to solve the problem, but if somebody was around a little over a hundred years ago, they would be pretty shocked at what there is out there today. It is pretty amazing what has happened, airplanes, cars, television, computers, the medical revolution. 

PK: You started working on slow-release technology in Folkman’s lab in 1974?
RL: That is right.

PK: And it wasn’t until 1976 that you first presented your work at a large conference?
RL: Right, that is true.

PK: And so, for those two years that you were working, were there incremental successes that helped you to keep working on such a problem? Two years is a long time to spend on a problem that everyone says can’t be solved.
RL: Yes, right. That is true, and a lot of it wasn’t incremental – I would say over the first year probably I wasn’t successful. A lot of it happened in the second year.

PK: Why not drop it after the first year?
RL: I am pretty stubborn, and I really felt this is what Folkman asked me to come to do, to solve this inhibitor problem. I wanted to solve it. I’m not good at giving up. I would like to try to say that I had some great scientific reason, but it is probably more a personal attribute that I felt like we would solve the problem. It was more belief that we would do it.

PK: What if you had started working on a problem that was truly intractable…something that you could have spent 20 years on and it still wouldn’t have worked? Do you feel that you would have known to quit?
RL: I hope so. I would like to think that I would know. Certainly as I have gotten more experience over time I have learned to do that. I do it better now than I probably would have done it then, but it is very hard to know.

PK: Did you have the urge to patent your work even back then in Judah Folkman’s lab?
RL: No, I didn’t. You know, they changed the policy at Children’s Hospital shortly after I got there. So, before that, I think they didn’t allow patents. In fact, our patent was the first patent in the history of the hospital. Folkman suggested when we came up with the slow release polymers that it would be a good thing to patent. When we patented the slow-release polymer technology and when I could see interest coming later, it certainly made me well aware of just how valuable patents could be.

To Topic Index

A Career of Patents...

PK: So, did the first patent generate interest immediately?
RL: No, in fact, it is interesting that I started working on controlled release of macromolecules in 1974. The first paper was 1976. The first patent, 1979, and there was no commercial interest until 1982. Even then, it was very mild. But finally, genetic engineering had started and people were beginning to make large molecules. Some of them had delivery problems, and so I think the first time I started discussing these issues with companies was in 1983. We licensed the first patent to a company doing some animal health work. They wanted to deliver animal growth hormones. After that, interest grew year after year. Then there was interest from another large company in licensing our patent. In other words, we finally began to see interest, but it was years, many years, after I came up with the first ideas.

PK: When did the patents first start rolling out?
RL: Well, the first patent came out in 1979. 1982 was the next one. By then, I was at MIT and then we really started writing patents.

PK: Almost 400 so far…
RL: Yes, I think that is probably fair to say. It is probably a steady stream from 1982 onward.

PK: And I imagine that each patent doesn’t stand alone. Companies probably license the technologies as groups of related patents?
RL: Yes, it varies. Some patents are, or start out to be, stand-alones, but usually what you do then is create subsidiary patents. Then it becomes a package, but very often there is a key patent which is used to create a company or give key licenses to companies.

PK: Can you give me an overview of some of the patents you have generated throughout your career?
RL: Yes, okay. The earliest ones involved controlled release of macromolecules. We first made a license to the animal health company, which was then International Minerals and Chemicals, and then we made a license in human health to Eli Lilly. Those companies moved slowly, and wouldn’t do experiments very quickly. Ultimately, they really didn’t continue with it that much. Because of those licenses, we got a lot of grant money. Being in academics, I was thrilled to receive grant money, but I was also discouraged by the fact that those companies just didn’t move very quickly. So, in 1987, Alex Klibanov, a colleague and friend of mine in the Chemistry Department at MIT, and I started Enzytech. I was able by 1988 to get back those licenses for controlled release of macromolecules and had them put them into Enzytech. That is essentially the initial basis for what Alkermes’ Prolease system is today--injectable microcapsules. Also in the 1980s, another company, Takeda, developed a relationship with our lab (sending a person a year to our lab for several years) and learned about the technologies. They developed a number of successful products like Lupron Depot.

I also conceived of degradable polyanhydride systems, and we licensed that originally to a company called Nova Pharmaceuticals. They merged with Scios, and then they spun off Guilford. That system led to a new way of treating brain cancer, which we had been working on with Henry Brem at Johns Hopkins.

Another example was the whole idea of tissue engineering.Jay Vacanti and I thought about a way of using polymers and cells to make new tissues, and that led to Neomorphics, which subsequently merged with Advanced Tissue Sciences. A portion of these patents got licensed to Reprogenesis, which is now part of a new company, Curis. Now we will probably have some of the nerve regeneration work licensed to Global Medical Products.

A set of patents developed by David Edwards when he was a post-doc in my lab, led to Advanced Inhalation Research. Acusphere was originally based on another paper we wrote, another set of patents; Microchips out of another. One thing that happens that is nice is that the students in the lab see other students and post-docs launch startup companies. There are probably over 70 or 80 of my former students who are professors now, but some of my students are very excited about starting companies or being involved with startups. They see the more senior members of the lab having had those opportunities and successes. Certainly Dave Edwards has been a tremendous success and a role model for younger people in the lab. Three or four of them have launched their own companies in much the same manner Dave did: John Santini with Microchips, Andreas Lendlein with Mnemoscience, Yosi Kost with Sontra. We have been able to use that model very successfully to generate ideas and move them out of the laboratory and into a company. Ultimately, companies get a lot more funding than academic labs, and so you can make real products that help people. It is very rewarding for anyone who has worked in our lab to see what has happened with the brain cancer program. You write a chemical structure on the blackboard, and today you see it treating over 10,000 patients; it’s a wonderful thing. So, a lot of my students, undergraduates, graduates, and post-docs are inventors on patents. They find it very exciting.

To Topic Index

Inside the Langer Lab...

PK: That is fantastic. I have heard a lot of people are dying to get into your lab. How do you select them?
RL: We used to receive over a thousand applications a year, and then Science magazine wrote an article on us – they used it as a cover story – on being a post-doc in our lab. That was last September. Now we probably receive between two to three thousand applications.

PK: That’s like running a college admissions office.
RL: Yes, well, it is worse in some ways because there are two or three thousand applicants for maybe four positions. I select them based on the quality of the person, as judged by what their advisor says, what kind of schools they have gone to, what they have done, what they have published, things like that. Certainly people who go to Harvard or Cal Tech or MIT are very good candidates. Another important quality to me is that they get along well with people. I have a pretty big lab, and I want to make sure that the people interact well. You can learn a lot from calling someone’s advisors on the phone and seeing what they say about those people.

PK: You mentioned earlier that 70 professors came out of your laboratory.
RL: Yes, over 70.

PK: That is incredible. You keep in touch with most of them?
RL: I do. One of my goals is to see that people who leave the lab are as happy and successful as possible. I want them to get grants, receive awards, and publish papers in places like Science or Nature. I do whatever I can in terms of giving them my advice if they want it. I am still in touch with almost everybody that has ever worked in my lab in some manner or other.

PK: So, how many people do you have in the lab now?
RL: Well, we probably have 60 in the lab, depending on how you count. It is one of the biggest bioengineering labs in the world and it is probably the biggest it has ever been. I am very proud of the people in the lab. They are really outstanding scientists, and the lab is very diverse. We probably have ten different disciplines represented. I am a chemical engineer myself but we have everything from physicists to molecular biologists, cell biologists, synthetic chemists, and three practicing clinicians. 

PK: How about just bypassing industry and launching pharmaceuticals directly out of your own laboratory?
RL: That would be hard to do for a couple of reasons. First, the amount of money it takes to launch these technologies is incredibly high. Secondly, there are manufacturing issues. We really aren’t able to manufacture in the lab. Third, you want students and post-docs to do cutting edge research. Just to pick manufacturing as an example, you have to do it over and over again and on a large scale. It has to be done in a certain way, and I don’t know that we could do it or that I would want students to do it.

PK: MIT has core facilities. There are people who only do one thing, such as sequencing – that is their job.
RL: You are right, but it would be a huge cost just to do manufacturing. Making microspheres at the lab scale probably costs a couple of dollars. But to make microspheres for patients, Alkermes put in a whole building and it cost probably $15 million or $20 million, maybe more. That building has more space than I have for all the things I do.

Each manufacturing process is far different; it’s a huge deal. I once remember asking one of the VPs at Repligen many years ago, "Why do you think you didn’t do better?" And he said, "Well, you know, the biggest problem that we have is that we have four different products and they require four different manufacturing procedures. They are all different." I think that is such a key thing. You want to build a platform technology, so you can use the same manufacturing procedure over and over again. The successful companies succeed because they focus. They have 100, 200, 300 people working on taking a technology and driving it all the way through, whereas I think what we are good at here at MIT is inventing the sort of core technologies which people say will never work. The student or post-doc really needs to do a thesis or a post-doctoral pro,ject solving a pretty basic science or engineering problem.

PK: Has there ever been a problem with the students not being able to publish a paper, because of agreements with industry or delays applying for patents?
RL: No. MIT has very clear rules on this so there couldn’t be such problems. We wouldn’t accept money from a company, if there was even a chance of that happening.

PK: Going back to the very first moment when you started to get involved in forming companies, when did that first start to happen?
RL: First, I started doing consulting in 1980 or 1981. In 1986, Alex Klibanov talked to me about starting a company, which would ultimately become Enzytech. I guess our thinking was that we had done consulting, but, by helping form a company, we could probably have more of an impact.

To Topic Index

The Langer Startups...

PK: So, when did you first start Enzytech?
RL: 1987. 

PK: What was starting up like for you? Did you have connections at that point already?
RL: Venture capital people or investors started talking to me even before that, and I never really thought much about it…

PK: They would just call you up?
RL: Yes. They would ask if I wanted to do one thing or another. I didn’t know anybody and I didn’t know anything. I was very naïve. Alex Klibanov and I had this idea we would like to start the company but it wasn’t clear exactly what we were going to do. We had some visions of what the company would do, but I certainly didn’t have any clear idea of which people to talk to.

PK: What did Enzytech specialize in?
RL: Alex’s idea was to use enzyme-based technologies in the food additives area, in which I would help and also in the drug delivery area. When we started Enzytech I also wanted to get back the drug delivery technology we had licensed to Lilly and IMC. We had extended the idea of enzymes to proteins, and I had always had this dream of practically developing delivery systems for peptides and proteins, so people could use them. So, I wanted to get those patented and used. There was a 1979 and a 1983 patent which was the earliest basis for doing this kind of work, and these were the patents that Folkman and I wrote that enabled the controlled release of macromolecules. We also developed additional technologies. Some of the people in my lab like Larry Brown, when he was a graduate student, and Mike Sefton, when he was on sabbatical in 1983, worked on a way to make microspheres out of this original system. That is the initial basis for what the Alkermes Prolease process is today. When Larry moved from MIT to Enzytech (which later merged with Alkermes), he was one of my students at the time. My vision was to transfer the idea from a model polymer, which was ethylene-vinyl acetate, to a more practical polymer which was lactic glycolic acid. He and some of the others changed the procedure for that; they got it to work.

PK: What was your role in Enzytech?
RL: The first thing I did was to find people who wanted to work there. Four of my students went to Enzytech at the time.

PK: Did they finish their PhDs?
RL: I probably wouldn’t have liked it if they didn’t. They finished their PhDs or they were post-docs. Another role I played was giving scientific direction. I was also on the board of directors and I was involved in conceiving new patents. Raising money was another role.

PK: So with no experience starting companies, you went out and raised money?
RL: Well, but raising money then wasn’t so hard. There were people, such as individuals from this company DH Blair and Chris Gabrielli of Bessemer Ventures, that were willing to give the initial money to us. When you start a company, you have to keep raising more money. The first round then was the easiest. It is still probably the easiest. You then get a second round, third round, and fourth round after reaching certain milestones. You get deals with large pharmaceutical companies. So one of the things that I spent time doing for every financing round was giving talks. I also gave talks to pharmaceutical companies.

PK: And you recruited a management team to the company?
RL: Well, yes. That was probably not the greatest thing we did. Alex knew Len Stark who was a director at a large food company and Alex introduced him to me. Alex and I did not have enough appreciation of what the qualities of a great CEO should be. We originally thought about Len Stark being CEO, but the venture people convinced everybody that he should be president and we should recruit a CEO. You get search firms and they look for these people.

PK: So, was each subsequent startup that much easier? By now do you feel it is just an automated process?
RL: They are all unique. It is easier now for a several reasons. First, I think I do know more what I am doing now. I also have been very happy with Polaris Ventures as a venture firm. I really like working with them. I work with a lot of companies and venture firms, but I have been particularly impressed with Terry McGuire of Polaris. We have had a great business relationship, and he is incredibly honest. So, if I have an idea, I will probably go to him first, and I don’t want to say he will fund it every time, but he would probably fund a lot of things we do. If somebody in the lab or a friend wants to start a company and I think it makes sense, then I would probably introduce him or her to Terry or somebody like him. You get a feeling over time of what makes sense and what doesn’t. If we have a technology paper that I feel is good enough to publish in Science or Nature and it gets in there, it means it has passed a pretty critical review. Generally those are the technologies that would interest a venture group.

PK: So, I imagine a lot of people must ask you to serve on their board of directors.
RL: Yes, they do.

PK: How do you pick and choose which companies you serve on as a director?
RL: Usually it has to do with how involved I am with the technology. If it is a technology of a company that I have been really involved in, then I feel happy to be on the Board of Directors. To me it is not the most exciting thing to be on a Board of Directors. A lot of those meetings are pretty boring, and you are dealing with a lot of the financial side of the business. I like the action, the planning, the thinking of how to make the technology happen.

PK: How about the Scientific Advisory Boards?
RL: I am on a number of scientific advisory boards and I consult for a number of places.

PK: How many requests do you get to join a Scientific Advisory Board?
RL: Probably over one a week. As to whether I join or not depends on what the technology is; how well I know the people; to some extent the compensation package; but ultimately, whether I feel like I will enjoy it. Another thing that is important to me because I have little kids – they are ten, nine, and six – is that I do not want to travel a lot. I really have tried to stay away from companies that aren’t in Boston.

To Topic Index

The Big Picture...

PK: What is the next big thing coming up?
RL: Well, in bioengineering, I think the whole micro-fabrication and nanotechnology area is one. Some of the things we are working on now in the lab are gene therapy delivery, trying to come up with synthetic polymers that could behave the same way viruses do, but without any negative affects. We are working on tissue engineering. With Evan Snyder we are finding ways of solving nerve regeneration that could help people who are paralyzed. We are working on embryonic stem cells to try to figure out ways to get them to differentiate into the right cell types. We are also working on new ways of trying to remove substances from the body that are unhealthy using enzymes or antibodies. There are also a whole bunch of other ongoing studies – transport through skin, transport through the gut, which in turn might lead to new delivery systems or other things like that.

PK: Here is a totally different question, but probably one that would be very valuable to have a perspective on. A lot of people complain that US pharmaceuticals cost way too much. "It is so expensive. The pharma companies are ripping off patients." What would be your comment on that?
RL: Well, first I have not done a cost analysis. But, I can’t think of one single thing I would rather see money spent on than health care research. I am much more interested in seeing money spent on health care research, because I am concerned that my kids and other kids have healthy lives. I would rather motivate research and see products that will help my children and other children’s health than motivate research in other modern developments such as the computer industry and the internet. So, if money goes into one thing – I am not saying this because I do it, but because I believe that creating drugs and technology that relieve suffering and enhance people’s health is the most important thing we can do – I would rather it go into things that will help save people’s lives.

So, how does that address what you asked? What would concern me is if there was not enough of a profit motive for the start up biotech companies. Venture capitalists and investors make a decision on whether to fund an internet company or a drug company based on financial return. For the last few years, a number of venture capital firms have felt that the amount of profit that pharmaceutical companies make, the startups, isn’t enough, because the initial investment is so high. What you see to a certain extent is money moving away from pharmaceutical or medical startups due to competition with internet or telecommunications startups. I would rather see the incentive to solve human health problems be higher, because that is what I value the most from a personal standpoint for the future of our children.

PK: Where do you see medical technology ten, twenty years from now, if that is something that can even be predicted?
RL: To me, there are a number of things going on in my area of interest that are really exciting. You will see more once a month injections of molecules you now inject daily; maybe once a year injections. You will see non-invasive ways of delivering complex molecules, like proteins, and you will start to see engineered tissues. You will probably also see gene therapy delivery. It is hard for me to know whether these advances are ten years, twenty years or 50 or 100 years away. A hundred years from now, I think everything will be radically different. Ten years? I do not know that things will change as fast as people want, mostly because clinical trials and the regulatory process is slow.

PK: How do you feel about politically imposed threats on research? Should scientists regulate what is or isn’t moral? Should corporations have input? The public?
RL: I think it depends. I think the problem is politicians are politicians and do not always do things for the best reasons. Some reasons for not using human embryos for doing stem cell research strike me as not being terribly well thought out. I think that is a shame, because that is an area which could really help people. I want to see research done, because it will help people’s lives, and you hate to see any research impeded that you feel will fundamentally enable children to live healthy lives. If you see a kid dying of cancer or AIDS, or somebody burned badly, somebody lose a liver, you would love to be able to solve problems like that.