Wednesday, November 26, 2014

Going Against Conventional Wisdom

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.

Read more from our "The Innovation Revolution" series.

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    1. CommentedAmira Khaled

      sometimes the fight against conventional wisdom is very very hard ..thank you for this wonderful article ..

    2. Portrait of Nils-Göran Areskoug

      CommentedNils-Göran Areskoug

      A Confirmation from Stockholm.
      Robert Langer provides a series of beautiful examples as proof of a core insight: that true progress requires a transgression of the frontier of science controlled by funding agencies. If the implementation of creative ideas all the way along the path towards useful and effective innovation goes beyond the horizon of political imagination (as often the case among bureaucrats in a small country with state-governed agencies) neither “adequate interdisciplinary training” (Health Care’s Voyage) nor “willingness to challenge the dogma” may be sufficient to melt the ice. Crucially, the recognition and inclusion of new modes of creative cognition are needed to enable crossdisciplinary fertilization. As the value for society of the products of a great inventive mind (epitomized by Langer’s bio) is measured in terms of their usefulness to human quality of life it is by no means surprising if the sources of inspiration need to originate from domains outside strictly scientific disciplines. Here comes the option to enrich scientific thinking by experiencing arts and culture and to learn to understand the sociology of values that build human societies.
      One surprising conclusion from Transdisciplinary Dialogues with Nobel Laureates in 2001 was the emphasis on their concern and deep involvement in the cultural roots that had nurtured them and provided them with the tools of imagination and creative processing until the moment of their key discovery. Science evolving in society thus seems to share roots with the origin of creative cognition in a more distinct way than is generally recognized.
      Technologic advances may well depend more on a permissive context of cultural environment than intradisciplinary self-breeding. The challenge invites sociology of sciences to work towards better solutions of its primary task - and to rethink forms and processes to allow more of transdisciplinary and crossfaculty integration: How to overcome the thwarting influence of anemic abstractions in the conceptual framework of administrators whose experiential competence have been distorted by political bias?

    3. CommentedProcyon Mukherjee

      Robert Langer's learning on the limits of conventional wisdom is actually universal and applies to social engineering area as well, where conventional wisdom or rather the 'wisdom of crowds' have fallen prey to information cascades.

      In the infinite world of apathy to take the unconventional step, the one which does not have a history of success is the one that is more likely to work; but for the herds, who want to stick together in good times and bad times, we have a deluge of abnormal good and abnormal bad, as equally likely possibilities.

    4. CommentedNathan Coppedge

      It is clear to me that especially in medicine, the difference between a specialist and a bad student is dramatic, and can have dramatic consequences.

      In an economic context, we are just learning that some variables are 'conscious', and some paradigms exponential. What Dr. Langer seems to be saying is that it is the same way in medicine. That sounds profound and encouraging. Perhaps someone should develop a general rule of medicine that affects research developments. Perhaps there is one. And maybe some conservatives are reacting to philosophy, and not medical or business practice.

    5. CommentedZsolt Hermann

      The conclusion of the article is very exciting and it can actually offer a glimmer of hope for all of us stuck in the depth of the ongoing and deepening global crisis.
      We seem to have concluded that evolution, ever changing existential conditions do not apply to modern humans, thus all our discoveries, inventions, our main body of knowledge is good enough to provide the basis for our ongoing existence.
      As the article rightly suggests at the same time the cutting edge of classical research "quietly" pushed, and still pushing the boundaries of our perception of reality, and especially through the prisms of quantum physics, and the various quantum theories many of our long held dogmas started to break down. And this even within the same framework we have been researching so far.
      The global crisis, that goes way beyond economics, politics or finances, basically engulfing our whole present human system is a good example of it, when previous, seemingly perfectly suitable, working methods and tools have become obsolete, moreover destructive.
      Today most of human invented, created institutions are slipping through our fingers and while we try to use, and reuse all previously know and refined solutions instead of improvements we get worse states. This is all because the conditions of the system we exist in have changed, almost none of the conditions we based our previous lifestyle on remained intact.
      The definition for the state of mind the last paragraph of the article points at is "faith above reason".
      This is very different from the definition "faith" as it is normally used.
      "Faith below reason" is a state when we ignore common sense and stubbornly believe in something that has no known natural foundations, but we choose to believe in it against reason for traditional, cultural, religious reasons.
      "Faith within reason" is the usual, classical, dogmatic scientific approach, when we only believe in what we can grasp, evaluate and prove within our resent framework, with our present mind.
      "Faith above reason" is the state when we examine, fully understand where we are, what is available within the present framework, but the available data, while on one hand proving the deadlock within the present framework points at a possibility solving the problem "above reason" using a different "state of mind".
      To achieve that possibility requires a "leap of faith" but not fully blindly, but based on how we know for fact that with our present mind we cannot solve our present situation, and solution can only come by "changing our present mind to a new one".
      "Faith above reason" is only possible after the full, honest, maximally precise examination of the present state, understanding the futility of the present state, understanding the necessity of changing the observer's point of view, starting anew.
      The whole of humanity stands at this stage today, we have to fully understand where we are, why we have arrived here into this dead end, how we simply cannot solve our present crisis with our previous and present methods and tools, and we have to embark on a new discovery in "faith above reason", changing ourselves, the observers first.