Monday, February 04, 2008

JUDAH FOLKMAN (1933-2008)

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Image: LA Times, Boston Globe

All living entities need a pipeline to survive. In case of most living organisms, this pipeline consists of blood vessels that provide essential nutrients and oxygen and carry out waste products. As we all know, our organs would not survive for long without the intricate blood vessel network- the vasculature as it's called- that supplies them. But what's true for organs is also true for entities gone haywire- tumours. Like organs, tumours also need blood vessels that would supply oxygen and nutrients to their hungry cellular machinery.

Angiogenesis, the growth of new blood vessels, is important to both tumours and healthy organs and a mainstay of life itself. One would think that starving tumours of their essential needs by choking off this pipeline of capillaries would be detrimental to them. But just how detrimental it would be and what important ramifications it would have was not at all obvious 30 years ago. In fact even today, tumour vasculature is one among dozens of factors responsible for the growth of cancer, a disease whose newly discovered complexity continues to stun us every day.

The exact and overriding importance of angiogenesis for tumours was first demonstrated in 1971 by a then little known doctor at Harvard Medical School, Judah Folkman. Folkman crucially demonstrated that tumours cannot grow beyond a certain size if they are deprived of a generous dose of blood vasculature and angiogenesis. Moreover and more importantly, he also showed that tumours secrete proteins that promote angiogensis. Think of a tumour as initially hanging off a cliff by a thin thread, struggling to hold on. Then the proteins it secretes and the ensuing blood vessels that grow would constitute lifelines- deathlines for us that is- that the tumour throws to clasp on to the cliff. The growth of these lifelines and their integrity can make the difference between life and death, both for us and the tumour. In his seminal 1971 paper, Folkman suggested that the very difference between a benign and malignant tumour can be made by how strong and fortified this process of angiogenesis around the tumour is.

What was speculation and based on relatively scant research in 1971 has rung more than true since then. In the ensuing years, dozens of proteins and growth factors have been discovered that are oversecreted by tumours to facilitate their growth. Concurrent with these discoveries, proteins that naturally inhibit angiogenesis have also been discovered. The growth factors promote angiogenesis by binding to crucial receptor proteins on the tumour cell surface. This fact also obviously points towards a possible therapy for treating cancer- by halting this angiogenesis. If one can design drugs that prevent these growth factors from binding to their receptors, then the growth of new blood vessels would be prevented. Shrink this growth, and one can possibly shrink the tumour, either to its death or to a withered state that is no longer capable of metastasis and cancer.

Since Folkman's pioneering description and speculation in 1971, the understanding of angiogenesis as being crucial to tumour promotion as well as the targeting of angiogenesis as a cancer therapy have both become central concepts in the knowledge and treatment of cancer. Angiogenesis has also proven to be important for other disorders such as macular degeneration, the leading cause of blindness in the United States.

In the last few years, dozens of drugs blocking tumour growth by blocking angiogenesis have been discovered. Several of them have now been approved as cancer therapies by the FDA. Two examples are the drugs Sunitinib and Avastin which is an antibody.

Judah Folkman's vision is now directly benefiting millions of people worldwide. In my opinion he definitely deserved a Nobel Prize and probably would have gotten it soon. But the man himself sadly and unexpectedly left us on January 14. He was due to give a talk at my university a couple of months ago. I could not attend it because of a prior commitment. Now I wish I had. But his dream and contributions survive. And they provide one of the best recent examples I know of how basic biomedical research can bring practical and humane benefits to millions.

Obituaries: NYT, WSJ, Boston Globe

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