The Search for Genetic Material — Introduction

Every cell that has ever existed arose from a pre-existing cell, and every offspring resembles its parents far more closely than it resembles an unrelated member of the same species. This simple, everyday observation hides one of biology's deepest questions: what physical substance inside a cell actually carries hereditary information from one generation to the next, and how is that information copied faithfully enough to explain why a child's traits track its parents' traits so closely, generation after generation? By the early twentieth century, biologists had already worked out, through careful microscopy, that chromosomes behave exactly the way Mendel's abstract hereditary "factors" were predicted to behave — segregating and reassorting during meiosis — which told them genes must lie somewhere on chromosomes. But chromosomes are made of two very different kinds of molecule intimately packaged together, DNA and protein, and for a long time most biologists actually favoured protein, not DNA, as the more likely candidate for the genetic material.

The case for protein looked strong on the surface: proteins are built from twenty different amino acids, so they can be strung together in an almost unlimited variety of sequences, which seemed necessary to encode the huge diversity of hereditary traits a cell must specify. DNA, by contrast, was known to be built from only four different nucleotide bases, and an early (and, as it turned out, mistaken) model called the tetranucleotide hypothesis proposed that DNA was a very simple, monotonously repeating structure — the same four bases arranged in a fixed, boring block, over and over — which seemed far too simple a molecule to carry the enormous informational complexity of heredity. This is the intellectual backdrop against which this chapter's central drama unfolds: a sequence of ingeniously designed experiments, spanning several decades and several different organisms, that step by step ruled out protein and definitively established that DNA — not protein — is the molecule of heredity.

This chapter traces that search for the genetic material through three landmark experiments (bacterial transformation by Frederick Griffith; the biochemical identification of the "transforming principle" by Avery, MacLeod and McCarty; and the bacteriophage-labelling experiment of Hershey and Chase), and then builds outward from that established fact — DNA is the genetic material — into the full molecular machinery a cell uses to store, copy, read out and regulate that information: the double-helical structure of DNA itself, how the very long DNA molecule is packaged to fit inside a microscopic nucleus, how DNA replicates itself with each cell division, the "Central Dogma" that describes the one-way flow of information from DNA to RNA to protein, the processes of transcription and translation that carry out that flow, the genetic code that specifies exactly how a sequence of nucleotides is read as a sequence of amino acids, an example of how gene expression itself is switched on and off (the lac operon of the bacterium Escherichia coli), and finally two of molecular biology's most consequential applied outcomes — the Human Genome Project (and its Indian companion effort, the Rice Genome Project) and the forensic technique of DNA fingerprinting.