When I was out at Cold Spring Harbor Labs a few weeks back I was browsing through the bookstore and picked up a copy of an George Beadle An Uncommon Farmer. I was intrigued to see a science book written by Paul Berg and Maxine Singer and I have been delighted with the story they tell. I am about 200 pages in and the book is turning into a story of Beadle’s later years as a successful champion and elder statesman of science. This part of the book may be interesting but the first half of the book is a remarkable history of the coming of age of “biochemical-genetics.” Although focusing on Beadle and his life, it is just as much an introduction to the manner in which the biological sciecnes were taken by storm by combining clasic experimental genetics with model organisms. Prior to the “mad pursuit” that led to the 1953 realization of DNA’s double helical nature, the links betwen “genes” (or “factors” as they were called) were nebulous. It is amazing to think that the fundamental research leading to an understanding of the “Central Dogma” of biology was still ahead. No polymerases, no translation, no sequencing, no nothing. Yet there were remarkable sets of experiments providing clues to the nature of hereditable transmission of traits and to the underlying patterns of the chromosomes responsible for these changes. This book does a remarkable job of describing the heady times of experimental biology that began to piece together the fundamental mysteries of biology, and it pays homage to Beadle, who managed to be in the right place at the right time to drive the revolution.
Beadle’s scientific trajectory runs through several remarkable fields and Berg-Singer do a great job of tracing his intellectual development and describing the problems that he devoted his time to. His boyhood in Nebraska led to an unlikely education (he was expected to work the family farm and intended to) and a series of research experiences in several important areas. He worked on corn at Cornell University under Rollings Emerson whose open manner, hard work, and extensive seed collection made it a pioneering place to learn to study the transmission of traits. The tassles of the corn are the male parts while the female corn bits are down low. By detassling the corn and using tassles from specific plants, corn can be used as an excellent model system to study Mendellian genetics. The other great advantage to corn that I did not know (but should have realized) is that each individual kernel of corn is an independent fertilization event, hence the multicolor, mosaic corn you can find. Therefore a few corn plants can generate hundreds of observations in a a kernel and many more per plant, proviing the row material to tracking of frequencies of hereditary traits. Under Emerson, Beadle and others observed how the transmission of traits occured and began to work out the “linkage maps” for co -segregation of traits. These frequency maps would later be mappe don to the chromosomes, the role of which was not understood. At the same time, the field of cytogenetics was growing and we are introduced to the potent intellect of Barbara Mclintock who was developing techniques to visualize the chromosomes of corn. Between linkage maps and chromosomes stains, corn in many ways pioneered the understanding of how chromosomal arrangements and genes were linked during the dance of mitosis/meiosis although those were still largely not understood. Much of the really important work would come from the study of flies, an areas which Beadle would also rapidly find himself.
After leaving Cornell Beadle ended up in Caltech. Caltech had recruited Thomas Hunt Morgan to head up the Biology division and Beadle quickly gravitated from corn to flies. The Berg-Singer coverage of the Morgan lab and proteges alone is worth the price of the book and one really feels the good natured exploration and excitment of the Columbia University Fly room that was transported West to Caltech. As part of his experience working with flies, Beadle would become involved in one of his great successes and a percursor to his Nobel-winning work with neurospora. He, along with colleugue Boris Ephrussi, developed a technique to transplant a small piece of embryonic fly tissue into the developing tissue of another fly. In this way they could understand how the mutant fly tissue-phenotypes were affected in the presence of the Wild Type fly. This experimental system allowed them to investigate a class of mutants that were defective in the production of an eye pigment. Beadle and Ephrussi realized the color was a soluble pigment and raced to try to figure out what the pigment was. And in doing this work, the MAGIC happened. The spark-of-genius or the “chance that favors the preppared mind” set in. In mulling over the fly work, Beadle came to conclusion that the genetic knockouts causing the deficiencies in eye pigment development affected the biochemistry of known pathways: perhaps it was a single “gene” or single factor involved in at each step of biosynthesis? Perhaps an even simpler organism would allow the possiblity of a genetic-based probing of biochemistry? In retrospect these connections seem so obvious, but the work this ideas initiated would, in the words of Berg-Singer, lead to the discovery of more biosynthetic pathways in the course of two years than the entire field of biochemisty had produced (via classic isolation) in the preceding twenty years.
Beadle’s intuition about genetics and genetically tractable systems led him to choose a simple-to-use fungus and to team up with a top quality chemist, Edward Tatum. The two would use x-rays to mutate a fungal species and identify mutants defective in the basic biosynthesis of some essential ingredient (auxotrophs). They could then use a combinaiton of genetics and biochemistry to identify mutants on the same “path” as the others, leading them to the famous “one gene- one protein hypothesis” which is sometimes knwon as “one gene, one function hypothesis”. Berg recounts a talk given by Beadle to the Caltech audience (he was then at Stanford) in which he presented his experimental findings and the jaws of everyone in the room basically dropped. It seems from that talk alone Beadle gained a large amount of interest and possibly some new students and research associations. The effect on the community of this “biochemical genetics” approach was both eye-opening and jaw dropping.
What a remarkable book, really. Its a walk through the foundational ideas of modern biochemistry and genetics and an ode to power of genetics during an era of technological awakening. The book is full of stories of scientists and the ideas that drive them. It shows the power of simple mendelian genetics in corn, the rise of cytogenetics in ascertaining chromosmal structure and interaction during cell division, and the beautiful way in which model systems can be used to understand the fundamental workings of living things.
Also: I didn’t know that Joshua Lederberg, a future Nobel Laureate and President of Rockefeller University, was Tatum’s student and that his early work in bacteria was an attempt to replicate in bacteria the Beadle-Tatum work on fungi leading him to discover “bacterial sex”. Although I did not personlaly overlap overlap with Joshua Lederberg several of my colleugues remember him attending lectures late into his 80’s and he would often ask insightful, probing questions. insightful commentary.