CAMBRIDGE – When I finished my graduate studies in 1974, I had the wonderful fortune of doing postdoctoral work with Harvard Medical School’s Judah Folkman. Dr. Folkman had a theory that the progression of tumors could be arrested by cutting off their source of nourishment. He suggested that tumors emit a substance called tumor-angiogenesis factor, which causes surrounding blood vessels to grow toward it, supplying nutrition and removing waste. Folkman hypothesized that this process, angiogenesis, is crucial to the tumor’s survival.
This theory went strongly against conventional wisdom. Scientists who reviewed Folkman’s grants said that the new blood vessels were simply due to inflammation. But Folkman persevered, and eventually he proved that such chemical substances do exist. Today, four decades later, such substances have been used to treat more than 10 million people with neovascular diseases such as macular degeneration and many different forms of cancer.
I had a similar experience when I was working in his lab, trying to isolate the first inhibitors of blood-vessel growth (which were large-molecular-weight substances). This required developing a bioassay that would enable us to observe the inhibition of blood-vessel growth in the presence of tumors.
Given that tumors take several months to grow, biocompatible systems had to be developed that could release proteins and other large-molecular-weight substances slowly and continuously in the body – something that scientists were convinced was impossible. However, after two years of work, I discovered that I could modify certain types of polymers to release molecules of virtually any size over a 100-day period.
For several years, many of the field’s most respected chemists and engineers said that our work had to be incorrect. The negative feedback had practical consequences, inhibiting my ability not only to secure research grants, but also to find faculty positions (especially given the work’s interdisciplinary nature, which made it difficult to fit into a single university department). But I kept at it, and, step by step, addressed different key issues – such as biocompatibility, manufacturing, reproducibility of release, and bioactivity. Today, systems based on these principles have been used to treat more than 20 million people.
Another area I started thinking about involved creating new polymer materials. Working in a hospital, I saw that almost all polymers used in medicine were derived from household objects. For example, the materials used in girdles for women are used in artificial hearts because of their good flex life. The polymers in mattress stuffing 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 girdle material – and these clots can cause strokes and death.
So I began thinking that we needed to find alternatives to solving medical problems other than by searching for materials in everyday settings. I believed that researchers could take an engineering-design approach: Ask the question, “What do we really want in a biomaterial from the standpoints of engineering, chemistry, and biology?” and then synthesize the materials from first principles.
As a proof of principle, we decided to synthesize a new family of biodegradable polymers, called polyanhydrides, for medical use. The first step was to select monomers – a polymer’s building blocks – that would be safe in the human body. We then synthesized these polymers and discovered that by changing their composition, we could make them last in the body for a period ranging from days to years.
With Henry Brem, now the chief of neurosurgery at Johns Hopkins Hospital, we thought we could use these polymers to deliver drugs locally in the treatment of brain cancer. But I had to raise money for this project, so I wrote grant applications to government agencies that were reviewed by other professors. Their reviews were very negative.
In our first grant proposal, in 1981, the reviewers said that we would never be able to synthesize the polymers. Yet one of my graduate students synthesized the polymers for his doctoral thesis. We sent the proposal back for another review, only to be told that the grant should still not be funded, because the polymers would react with whatever drug we wanted to deliver.
Several researchers in our lab showed that there was no reaction. We returned the proposal for another review; it came back with the comment that the polymers were fragile and would break. This time, two other researchers addressed the problem. The revised proposal was sent again for evaluation, and now the reviewers’ reason for rejecting it was that new polymers would not be safe to test on animals or people. Another graduate student showed that the polymers were safe.
Such reviews continued for a long time; but, in 1996, the Food and Drug Administration approved the treatment – the first new treatment for brain cancer to be approved in more than 20 years. Moreover, the FDA’s approval of polymer-based local chemotherapy created a new paradigm in the drug-delivery field, helping to pave the way for drug-eluting stents and other local delivery systems.
Something similar happened when Jay Vacanti, a surgeon at Massachusetts General Hospital, and I had an idea in the 1980’s to combine three-dimensional synthetic polymer scaffolds with cells to create new tissues and organs. Once again, the idea was met with great skepticism, and it was extremely difficult to obtain peer-reviewed government grants. Today, this concept has become a cornerstone of tissue engineering and regenerative medicine, leading to the creation of artificial skin for patients with burns or skin ulcers – and someday, one hopes, to the creation of many other tissues and organs.
My experiences are hardly unique. Scientists throughout history have often had to fight conventional wisdom to validate their discoveries. In modern times, Stanley Prusiner’s discovery of prions, Barry Marshall and Robin Warren’s findings that bacteria can cause peptic ulcers, and Dan Shechtman’s determination of the structure of quasicrystals are just a few examples (all received Nobel Prizes for their research).
The lessons are simple to understand, if difficult to master: Don’t believe everything you read, be willing to challenge dogma, and recognize that you may pay a price for it career-wise in the short run, even if you are correct. But the rewards of scientific discovery are worth it: technology advances, and the world can become much better for it.