Light cast on a darkling gene - retinoblastoma

White and Cavenee concluded there were two ways for a cell to lose its retino blastoma genes: either a portion of the chromosome could be deleted altogether, or the gene could be mutated to uselessness, perhaps by a change in one or more of its chemical bases.

The model was now firmly established. The next question was one of the biggest of all: Which was the retinoblastoma gene? ''That was something we knew would be very difficult to answer,'' says Gallie. ''We were talking about finding a gene that wasn't doing anything in tumor cells, and that was doing something completely unknown in normal cells.''

Until then retinoblastoma researchers had cooperated to an impressive degree. Gallie and William Benedict, a pediatrician at the University of Southern California, had helped supply Cavenee with the tumor samples he needed to screen for q14 aberrations. Dryja had made several of the DNA probes that Cavenee used. But when the race to identify and clone the gene began -- ''Oh, it was a race all right,'' says Gallie -- most of the labs went their separate and occasionally fractious ways.

The competition at first resembled the Dodo's Caucus-race in Alice's Adventures in Wonderland, with contestants running every which way and nobody quite sure about the shape of the course. Gallie and Phillips believed they had an edge; Gallie had dedicated herself solely to retinoblas toma since 1974 and probably knew more about it than anyone else. Because retino blastoma tumor cells were similar to the normal, rapidly dividing eye cells of a fetus, she and Phillips tried to discern some key trait of prenatal cells that the retinoblas toma gene controlled -- a trait that would lead them to the gene.

In California, UCLA geneticist Robert Sparkes, Benedict, and Benedict's post-doc Wen-Hwa Lee also thought they had the upper hand. Sparkes had known that the gene for a protein called ester- ase D was located close to the ret inoblastoma gene (a relationship that can be established by studying how often the two are inherited together). By late 1984 he and his colleagues had determined exactly where in the q14 region the gene for esterase D was. Then

Lee began ''walking'' along the chromosome from the position ofthat gene, a complicated and pains- taking procedure that required thousands of man-hours of clon- ing, probing, and screening. Lee hoped that as he slowly crawled across the vast expanse of the five million DNA bases in q14, he would stumble upon the eye cancer gene. ''What we were doing was very hard and very tedious,'' he says. ''Maybe some people thought we were crazy to do it.''

Even crazier approaches were in the offing. Dryja, an ophthalmologist who wanted to polish his skills as an experimental scientist, adopted what might be called the needle in the haystack method to find the gene. He began making DNA probes for the q14 region almost at random, hoping that one of them would disinter the retinoblastoma gene. But the odds of each new probe being the right one were as low as one in ten thousand.