Concept 16 One gene makes one protein.

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George Beadle loved gardening. Wherever he lived, he made sure he had green space to use as a garden. He would place bets with his gardening friends as to who grew the sweetest corn or the largest pumpkins.


Beadle had successful research careers in corn and Drosophila genetics. Why did he switch to yet another system, Neurospora, to do his "one gene, one enzyme" experiments?

Hello, I'm George Beadle. In 1941, Edward Tatum and I did experiments using Neurospora crassa — red bread mold. Our experiments proved Archibald Garrod's 1902 theory that hereditary diseases are "inborn errors of metabolism" — missing or false steps in the body's chemical pathways. For most of its life cycle, Neurospora is a haploid organism. This means that there is only one copy of each gene, so we didn't have to worry about dominant and recessive alleles, as had Mendel. In the lab, Neurospora grows well on "minimal" agar that contains only a few simple sugars, inorganic salts, and the vitamin biotin. Neurospora must have enzymes that convert these simple substances into the amino acids and vitamins necessary for growth. We reasoned that if we mutate any one of the genes that makes an enzyme, for example gene A, we should get a Neurospora strain that cannot grow on minimal medium. The mutant would be able to grow if we add the enzyme product as a supplement. Edward Tatum and I set out to find these nutritional mutants. In 1927, Herman Muller showed that X-rays cause mutations in genes. So, we irradiated a Neurospora culture with X-rays. We expected to get some rare mutants that would not grow on minimal media. We grew the offspring of the irradiated Neurospora on "complete" media that contained all the vitamins and amino acids. Next, we tested the ability of each of these cultures to grow on minimal media. We grew the offspring of the irradiated Neurospora on "complete" media that contained all the vitamins and amino acids. Next, we tested the ability of each of these cultures to grow on minimal medium. Most of these cultures grew on minimal media, meaning they didn't have a genetic mutation of the kind we were looking for. However, the 299 the culture did not grow on minimal medium. We then tried growing Culture# 299 on minimal media supplemented with either amino acids or vitamins. We found that Culture# 299 did not grow on minimal medium with amino acid supplements, but did grow on minimal medium with vitamin supplements. Therefore, Culture# 299 must not be able to make one of the vitamins. We then had to figure which vitamin was missing in Culture# 299. We did this by testing Culture# 299's ability to grow on minimal medium supplemented with single vitamins. We found that Culture# 299 grew only if we provided the vitamin B6 . This was our first Neurospora mutant. It could not make vitamin B6 on its own because one of the enzymes in the B6 synthesis pathway must be affected. Thus, the gene making this enzyme must have been mutated by X-rays. By adding vitamin B6 as a supplement to the minimal medium, the mutation could be compensated for and Culture# 299 could grow. Using this method of selection and supplementation, we isolated many different types of Neurospora mutants. Genetic mutations affect metabolic pathways, and we confirmed the synthesis pathway for many vitamins and amino acids. For example, the amino acid arginine is synthesized in a step-wise process catalyzed by enzymes. A precursor molecule is converted into ornithine then citrulline and finally arginine. If one gene makes one enzyme, there should be a genetic mutation for each step of this synthesis pathway. Among the arginine mutants there should be strains that need either ornithine or citrulline or arginine as supplements. In 1944, our colleagues, Adrian Srb and Norman Horowitz, found these mutant strains. They started with Neurospora strains that needed arginine as a supplement. These strains had mutations in different genes. For example, Mutant# 1 couldn't make ornithine. So, the gene that makes the enzyme for ornithine synthesis must have been mutated. If ornithine is added to the media, citrulline and then arginine would be made and Mutant# 1 could grow. Similarly, a genetic mutation in Mutant# 2 affected the enzyme that makes the arginine precursor citrulline. Adding citrulline as a supplement complemented the mutation and drove arginine synthesis to completion. And a genetic mutation in #3 affected the final step of arginine synthesis — the conversion of citrulline to arginine. By adding arginine as a supplement, the mutation was complemented and Mutant# 3 could grow. With each mutated gene, only one step of the metabolic pathway is affected. Therefore, one gene is responsible for one enzyme or protein. We had biochemical proof of Sir Arthur Garrod's 1908 proposal of the"inborn errors of metabolism."