The Major Questions - Research

How do we "know" when we have an infection? What are the receptors that alert us? How do we discriminate self from non-self, and why does the immune system sometimes attack our own cells and tissues? Why does it sometimes fail to eradicate infectious microbes? The tools of genetics have been used to address these questions, and answers have begun to emerge.

For more than a century, and in fact, since microbes were recognized as the cause of infections, it has been clear that mammals are genetically programmed to recognize them. Moreover, it has long been an obvious corollary that certain molecules of microbial origin must trigger a host response, and that specialized receptors of the host must mediate recognition of these molecules. This, after all, is how biological systems operate. But what were these receptors? A genetic approach was required to answer the question.

The Beutler laboratory systematically employs a forward genetic approach to identify genes that are essential for the mammalian innate immune response, and to determine their functions relative to one another. The forward genetic approach entails: (i) the induction of thousands of random germline point mutations on a defined genetic background (C57BL/6J) using N-ethyl-N-nitrosourea (ENU), (ii) the phenotypic screening of many thousands of mice for specific defects of immunity, and (iii) the positional cloning of those transmissible mutations that are detected. This classical genetic method does not depend upon hypotheses, nor upon assumptions about how innate immunity "should" work. Hence, it is unbiased, and errors of interpretation are extremely rare.

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