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A nasty shock

Srivastava came to immunology with a distinctly different perspective. While others were hunting for cancer-specific therapies by sorting immune cells and immune molecules, Srivastava was tackling cancer immunotherapy like a good biochemist. He took his protective dose of proteins and split it into fractions. But when he whittled down his protective fractions to a single protein he got a nasty surprise: the magic protein, over and over again, was a heat-shock protein (hsp). Hsps are well known for helping proteins to fold into the right shape, and helping cells recover from stresses such as elevated temperature. But no one knew of any link to cell growth and cancer. Could Srivastava have been so wrong?

Hsps bind many different antigens.

"It was extremely depressing," he says. "I entered the winter of my discontent, not knowing where to go from there. I kept looking for where I had gone wrong." Quickly he looked for, and failed to find, variations between hsp genes in normal and cancer cells. Hsps were such unlikely candidate tumor promoters that "it was clear there had to be a contaminant," he says. But nothing else of any significant size was visible in his samples. "By deduction I argued it was [small protein fragments called] peptides," says Srivastava. "At the time I was attacked a lot because I had no data about the peptides."

But the data came. In 1993, Srivastava found that the critical ingredient was, indeed, peptides. Most of the peptides are identical between normal and cancer cells, but a critical few differ. Srivastava believes that the high mutation rate in cancer cells generates random changes in a random assortment of proteins. Most of the changes are not related to the process of cancer development and are unique to each cancer. But, whatever the identity of these rare divergent peptides, when attached to hsps they can be detected by immune cells. The immune cells can then recognize and attack the cancer cells – but only those cancer cells from the one original cancer, which has those specific changes.

 


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