Robert Langer is easily one of the most prominent scientists in the world. He is one of the twelve Institute Professors at MIT, and co-founded Moderna.
To quote from his Wikipedia entry:
Langer holds over 1,400 granted or pending patents. He is one of the world’s most highly cited researchers and his h-index is now 299 with currently over 363,000 citations. He is a widely recognized and cited researcher in biotechnology, especially in the fields of drug delivery systems and tissue engineering. He is the most cited engineer in history and 4th most cited individual in any field, having authored over 1,500 scientific papers. He is also a prolific entrepreneur, having participated in the founding of over 40 biotechnology companies. Langer’s research laboratory at MIT is the largest biomedical engineering lab in the world, maintaining over $10 million in annual grants and over 100 researchers.https://en.wikipedia.org/wiki/Robert_S._Langer
Yet Langer faced many early rejections from academic positions and from the NIH. It is a testament to his perseverance and determination that he stayed in science at all. Part of that story is told here.
After I asked about his early experiences, Langer wrote up the following essay to provide further details. Don’t miss the ending, where he tells a story of grant rejection that stretches over some 15 years and is almost comically risk-averse.
A central question for funding agencies and science policy is how we can do more to encourage people like Robert Langer–or at least stop discouraging them.
FROM ROBERT LANGER
My interest in understanding how to control the movement of molecules began in an unusual way. I started my postdoctoral career working with the late Judah Folkman, attempting to isolate the first inhibitor of angiogenesis (blood vessel growth). To do so, it was critical to develop a bioassay for angiogenesis inhibitors, nearly all of which were macromolecules. We conceived of using a rabbit cornea assay where we could directly visualize blood vessel growth (Langer et al. 1976) through an ophthalmic microscope.
However, that assay could take up to several months, so it was critical to have a very small biocompatible controlled release polymer system that would not cause inflammation in the cornea, and that could slowly and continuously release macromolecules (e.g., peptides, proteins, and nucleic acids) for long time periods.
When I started my investigations, it was widely believed that only low molecular weight lipophilic compounds—but certainly not ionic molecules, peptides or proteins—could be slowly released from biocompatible polymers.
Dr. Folkman contacted many experts, including Paul Flory, a Nobel laureate in chemistry for his work on polymers, and they told him this couldn’t be done—large molecules couldn’t slowly leak out of a biocompatible polymer for any appreciable period of time (Cooke 2001). Nonetheless, after 200 attempts to solve this problem failed, I discovered a way to deliver macromolecules, including nucleic acids (e.g. DNA, RNA, and proteins) from tiny particles. (Langer & Folkman, 1976)
This discovery was initially ridiculed by the scientific community. My first 9 grant applications were rejected. No chemical engineering department in the country would hire me as a faculty member.
So, I ended up joining the Nutrition Department at MIT. But the year after I joined, the department head who hired me left, so the senior faculty told me I should leave too. As my colleague, 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” (Lash 2014).
Much later, the National Academy of Sciences would cite this work as “being responsible for much of today’s drug delivery technology” (National Academy of Sciences 1999) and Nature would cite this work for “founding the field of controlled release drug delivery,” (Pearson 2009).
These repeated rejections at this early stage of my career were devastating to me.
I also remember Dr. Folkman suggesting we file a patent. In the 1970s, Boston Children’s Hospital, where I started the research, had not filed a patent before. However, but they agreed to let us file one. Yet for 5 years in a row, the patent examiner rejected the patent application. Then the head of the Hospital’s Technology Transfer Office told me the patent would never be allowed and that I should stop trying to convince the examiner, since explaining the science wasn’t working. However, I don’t like to give up. However, as discussed earlier, when we started our research, many people told us this was impossible—that it could never work. I wondered if anyone had written that down. So I did a citation search of our 1976 paper in 1982 and I found many papers citing us. One of them, written by 5 of the top polymer scientists in the world, 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” (Stannett et al. 1979).
“Surprising” was an important word for the patent examiner. When the examiner saw that, he said if I could get affidavits from all 5 scientists that they really wrote that, he would allow the patent. I wrote them and they were all nice enough to write back that they really wrote it, and so the examiner agreed to allow the patent (U.S. Patent 4,391,797).
Over time, this discovery enabled the practical use of many peptides, charged low molecular weight pharmaceuticals, proteins, and nucleic acids. Since, such molecules have extremely short half-lives in the body (minutes in some cases), a controlled release system must often be used and is the key for lasting therapeutic effects (I discuss some examples later).
This study established that angiogenesis inhibitors did, in fact, exist and the above controlled release polymer systems have proven fundamental to the isolation and study in vivo of nearly all angiogenesis stimulators and inhibitors (for examples, see Polverini et al. 1977; Schor et al. 1979; McAuslan and Gole 1980; Pliskin et al. 1980), including inhibitors of epidermal growth factor (Gospodarowicz et al. 1979), fibroblast growth factor (FGF) (Shing et al. 1984), and vascular endothelial growth factor (VEGF) (Connolly et al. 1989).
The references just cited are but a few early examples of the thousands of studies that have used these polymer systems to isolate and test angiogenesis factors. Without this bioassay, the isolation of these inhibitors would likely not have been possible.
As Judah Folkman noted in his abstract for the 2006 Symposium Celebrating Thirty Years of Robert Langer’s Science:
“Early research in tumor angiogenesis was propelled by the pioneering work of Robert Langer who discovered how proteins and other macromolecules could undergo sustained release from polymers that could be implanted into the avascular cornea of animals and into other tissues. This advance provided a general platform for the subsequent discovery and purification of angiogenesis regulatory molecules. It is difficult to imagine how such proteins could have been isolated and their angiogenic activity identified without Langer’s contribution.”
Similarly, as Cramer has written, “The first proof that numerous angiogenic proteins stimulate new vessel formation arose from an elegant feat of chemical engineering by Robert Langer, who devised a polymer bead. The bead, when placed in the avascular cornea, slowly and continuously released these proteins to stimulate the formation of new vessels” (Cramer 1998). The National Academy of Sciences’ 1999 Beyond Discovery Report, Polymers and People, notes that “Robert Langer and Judah Folkman used this approach to isolate the first angiogenesis inhibitor.” Numerous angiogenesis inhibitors have now been approved by regulatory authorities and are in clinical use. They are expected to be used by 500 million patients worldwide (Carmeliet 2005).
The above controlled molecular release research has also had a significant impact on developmental biology, starting with Silberstein and Daniel’s paper in Developmental Biology (Silberstein and Daniel 1982), where they used our ethylene acetate-based implants to study the development of mammary and salivary glands. Many other investigators have used these molecules involved in implants to release different substances to study developmental processes. Park and Hollenberg provide an early review of this research and its impact (Park and Hollenberg 1993) and numerous investigators have used these implants to study such areas as eye specific segregation (Reh and Constantine-Paton 1985; Cline et al. 1987), development of neural maps (Simone et al. 1992), development of visual cortex (Liang et al. 1995), spinal cord development (Kalb and Hockfield 1990), and many other developmental processes.
The principles established for the controlled movement of molecules have been essential to the development of numerous clinically used therapeutics. As former Nature editor, Phil Ball, described the field:
“It was widely believed at first that … delivery systems would not be equal to the task. But in 1976, Langer and colleagues found that certain polymers, generally ones that were highly hydrophobic (water-repellent) such as copolymers of ethylene and vinyl acetate, could be mixed with powdered proteins and formed into microspheres that would release the proteins at a steady, slow rate, persisting sometimes for up to one hundred days. There seemed to be no limit to the size of the large molecules that could be released controllably in this way, nor to their nature: proteins, nucleic acids, and polysaccharides (sugar polymers) could all be used. In 1989, a controlled release system of this sort—microspheres made from a safe biocompatible copolymer of lactic and glycolic acid—was approved by the Food and Drug Administration (FDA) for use with a large-molecule peptide drug that combats prostate cancer. This was the first polymeric controlled-release system for peptide-based drugs to find medical approval, and it now provides the mostly widely used treatment for advanced prostate cancer.”(Ball 1997)
There are numerous controlled release polymer systems used by patients worldwide that continuously release these peptides for up to 6 months from a single injection (Lupron Depot, Zoladex, Decapeptyl). Similar microspheres or other related 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 (see timeline below). These systems have been used by many millions of patients every year. Similarly, tiny particles (in this case composed of lipids) have been crucial to the delivery of SiRNA (OnPattro) and all Covid mRNA vaccines, including that of Moderna, which I co-founded.
One of the key issues in academic research, of course, is receiving funding. Our drug delivery research received a very negative reception when we tried to get funding to support its development.
We wrote grants to the National Institutes of Health and other funding agencies. These grants are then reviewed by study sections, which consists of other scientists.
When I wrote our first grant in 1981 on a new class of biomaterials, it was reviewed by chemists who stated that we would not be able to synthesize the polymers.
However, Howie Rosen, one of my graduate students at the time, synthesized them for his thesis (Rosen et al. 1983).
After Rosen had accomplished this synthesis, we sent the grant back for another review, which stated: “The grant should still not be funded because the polymers will react with whatever drug molecule you put in.”
However, Kam Leong, Robert Lindhardt, and others in our lab showed there were no such reactions (Leong et al. 1986).
When we returned the grant for the next review, we received the comment that, although we’d solved some problems, the polymers were fragile and would be likely to fracture because of their low molecular weight, which was 7000.
This time, Avi Domb, in our lab, found the right catalysts, reaction times, and temperature conditions to increase the molecular weight of the polymers to 250,000, at which point they were not fragile (Domb and Langer 1987). Edith Mathiowitz developed these systems into microspheres (Mathiowitz et al. 1988; Mathiowitz et al. 1990).
After the grant had gone back for yet another evaluation, the reviewers said that it should not be funded because new polymers would not be safe.
Another former graduate student, Cato T. Laurencin (a minority and National Medal of Technology recipient), did extensive studies showing the polymers were very safe in animals (Laurencin et al. 1990).
Then we returned the grant, and the reviewers stated the drug would not diffuse far enough in the brain to be effective. Mark Saltzman showed this statement to be incorrect (Fung et al. 1996; Fung et al. 1998; Haller and Saltzman 1998).
These kinds of negative reviews continued until 1996 (fortunately we were able to receive industrial funding), when the Food and Drug Administration approved this treatment—the first time in more than 20 years that the FDA had approved a new treatment for brain cancer, and the first time they had ever approved polymer-based local cancer chemotherapy (it would also lead to drug eluting stents).
What’s the moral of this story?
Federal funding agencies could fund more high-risk, high-reward research, without almost always being so focused on preliminary data and an individual’s educational background (as if an engineer can’t contribute to biology). Peer reviewers and program officers should think about the benefits if a researcher succeeds, rather than trying to come up with all the reasons that the researcher might fail. It might be good for universities to think that way as well.
Ball P (1999). Made to Measure: New Materials for the 21st Century. Princeton, NJ: Princeton University Press, p. 241.
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Cline H, Debski E and Constantine-Paton M (1987). N-methyl-D-aspartate receptor antagonist desegregates eye specific stripes. PNAS 84, 4342–4345.
Connolly D, Heuvelman D, Nelson R, Olander J, Eppley B, Delfino J, Siegel N, Leimgruber R and Feder J (1989) Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. Journal of Clinical Investigation 84, 1470–1478.
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Langer, R., Brem, H., Falterman, K., Klein, M. and Folkman, J., Isolation of a cartilage factor that inhibits tumor neovascularization. Science, 193: 70-72, 1976.
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