When I finished my graduate studies in 1974, I had thewonderful fortune of doing postdoctoral work with Harvard Medical School’sJudah Folkman. Dr. Folkman had a theory that the progression of tumors could be arrested by cutting off theirsource of nourishment. He suggested that tumors emit a substance calledtumor-angiogenesis factor, which causes surrounding blood vessels to growtoward it, supplying nutrition and removing waste. Folkman hypothesized thatthis 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 weresimply due to inflammation.But Folkman persevered,and eventually he proved that such chemical substances do exist. Today, fourdecades later, such substances have been used to treat more than 10 millionpeople with neovascular diseases such as macular degeneration andmany different forms of cancer.
I had a similar experience when I was working in his lab,trying to isolate the first inhibitorsof blood-vessel growth (which were large-molecular-weight substances). Thisrequired developing a bioassaythat 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 otherlarge-molecular-weight substances slowly and continuously in the body –something that scientists were convinced was impossible. However, after twoyears of work, I discovered that I could modify certain types of polymers to releasemolecules of virtually any size over a 100-day period.
For several years, many of the field’s most respectedchemists and engineers said that our work had to be incorrect. The negativefeedback had practical consequences, inhibiting my ability not only to secureresearch grants, but also to find faculty positions (especially given thework’s interdisciplinary nature, which made it difficult to fit into a singleuniversity department). But I kept at it, and, step by step, addresseddifferent key issues – such as biocompatibility, manufacturing, reproducibility of release, and bioactivity.Today, systems based on these principles have been used to treat more than 20million people.
Another area I started thinking about involved creating newpolymer materials. Working in a hospital, I saw that almost all polymers used in medicinewere derived from household objects. For example, the materials used in girdles for women areused in artificial hearts because of their good flex life. The polymers in mattress stuffing are used in breastimplants. Yet such an approach often leads to problems. Artificial hearts, forexample, can cause clotsto form when blood hits their surface – the girdle material – and these clotscan cause strokes and death.
So I began thinking that we needed to find alternatives tosolving medical problems other than by searching for materials in everydaysettings. I believed that researchers could take an engineering-designapproach: Ask the question, “What do we really want in a biomaterial from thestandpoints of engineering, chemistry, and biology?” and then synthesize the materialsfrom first principles.
As a proof of principle, we decided to synthesize a newfamily of biodegradable polymers, called polyanhydrides, for medical use. The first stepwas to select monomers– a polymer’s building blocks – that would be safe in the human body. We thensynthesized 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 JohnsHopkins Hospital, we thought we could use these polymers to deliver drugslocally in the treatment of brain cancer. But I had to raise money for thisproject, so I wrote grant applications to government agencies that werereviewed by other professors. Their reviews were very negative.
In our first grant proposal, in 1981, the reviewers saidthat we would never be able to synthesize the polymers. Yet one of my graduatestudents synthesized the polymers for his doctoral thesis. We sent the proposalback for another review, only to be told that the grant should still not befunded, because the polymers would react with whatever drug we wanted todeliver.
Several researchers in our lab showed that there was noreaction. We returned the proposal for another review; it came back with thecomment that the polymers were fragile and would break. This time, two otherresearchers addressed the problem. The revised proposal was sent again forevaluation, and now the reviewers’ reason for rejecting it was that newpolymers would not be safe to test on animals or people. Another graduatestudent showed that the polymers were safe.
Such reviews continued for a long time; but, in 1996, theFood and Drug Administration approved the treatment – the first new treatmentfor brain cancer to be approved in more than 20 years. Moreover, the FDA’sapproval of polymer-based local chemotherapy created a new paradigm in the drug-deliveryfield, helping to pave the way for drug-eluting stents and other local delivery systems.
Something similar happened when Jay Vacanti, a surgeon at MassachusettsGeneral Hospital, and I had an idea in the 1980’s to combine three-dimensionalsynthetic polymer scaffoldswith cells to create new tissues and organs. Once again, the idea was met withgreat skepticism, and it was extremely difficult to obtain peer-reviewedgovernment grants. Today, this concept has become a cornerstone of tissueengineering and regenerative medicine, leading to the creation of artificialskin for patients with burns or skin ulcers – and someday, one hopes, to the creation of many othertissues and organs.
My experiences are hardly unique. Scientists throughouthistory have often had to fight conventional wisdom to validate theirdiscoveries. In modern times, Stanley Prusiner’s discovery of prions, Barry Marshalland Robin Warren’s findings that bacteria can cause peptic ulcers, and DanShechtman’s determination of the structure of quasicrystals are just a fewexamples (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 recognizethat you may pay a price for it career-wise in the short run, even if you are correct. But therewards of scientific discovery are worth it: technology advances, and the worldcan become much better for it.