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The lac operon is one of the most tested ideas in NCERT molecular biology, and one of the most memorised without understanding. NCERT credits it to "a geneticist, Francois Jacob and a biochemist, Jacque Monod". This post explains how they found it, using the clever genetics that NCERT leaves out, and turns that genetics into a worked problem.
Who were Jacob and Monod?
Both worked at the Institut Pasteur in Paris. Jacob's Nobel biography says he was born in June 1920 in Nancy and was studying medicine when war broke out. In June 1940 he joined the Free French Forces in London, served as a medical officer in Africa and was severely wounded in Normandy in August 1944. His injuries meant he could not practise surgery, so he turned to biology and joined Andre Lwoff's laboratory in 1950.
Monod's Nobel biography records that he was born in Paris on 9 February 1910, took his doctorate in natural sciences in 1941 and joined Lwoff's department at the Institut Pasteur after the liberation. He became Director of the Institut Pasteur in 1971. His Nobel facts page gives his death as 31 May 1976. Jacob, according to his facts page, died on 19 April 2013. The two shared the 1965 Nobel Prize with Lwoff "for their discoveries concerning genetic control of enzyme and virus synthesis".
How did two ends of a corridor meet?
In his Nobel lecture, Jacob describes a long corridor in Lwoff's laboratory. At one end Monod's group studied how E. coli switches on beta-galactosidase, the enzyme that splits lactose, when a suitable sugar is added. At the other end Jacob and Elie Wollman studied lysogeny, in which a virus sits silent inside a bacterium.
Monod knew two kinds of mutant. One could not make active enzyme. The other was constitutive: it made the enzyme even with no inducer. With Arthur Pardee, they used bacterial mating to put the normal "inducible" gene into a constitutive cell. In the 1959 paper by Pardee, Jacob and Monod, the inducible allele turned out to be dominant. Jacob explains what that meant: a special gene controls induction by forming a cytoplasmic product that blocks enzyme synthesis when no inducer is present. That product was the repressor.
How did they find the operator?
If a repressor is a signal, Jacob reasoned, it needs a receiver on the DNA. He explained the test with an analogy. Picture a house with two doors, each opened by a small radio receiver, and two transmitters sending the same "stay shut" signal. "If one of these transmitters is damaged, the other continues to send out signals and the doors remain closed." But if one receiver is damaged, "the door which it controls (but only that one) opens."
So a broken repressor gene should be recessive, and a broken receiver should be dominant but act only on the DNA it sits on, in cis. To test this they needed bacteria with two copies of the lactose genes. They built them using an F episome carrying a small piece of chromosome. Their constitutive mutants fell into exactly these two groups. The second group defined the operator. The theory was set out in Genetic regulatory mechanisms in the synthesis of proteins (1961).
Worked example: predicting partial diploids
The NCERT Class 12 chapter describes the parts: the i gene (from "inhibitor") makes the repressor, z makes beta-galactosidase, y makes permease and a makes transacetylase. The repressor binds the operator unless an inducer such as lactose or allolactose inactivates it. Use these symbols: i- means no working repressor, o^c means an operator the repressor cannot bind, z- means no working enzyme. The part after the slash is on the F episome.
i+ o+ z+. Repressor works. No beta-galactosidase without lactose; enzyme with lactose. Inducible.
i- o+ z+. No repressor. Enzyme made with or without lactose. Constitutive.
i- o+ z+ / i+ o+ z-. The episome's i+ repressor diffuses and binds both operators. The chromosome's z+ is made only when lactose is present. Inducible, so i+ is dominant.
i+ o^c z+ / i+ o+ z-. The broken operator sits next to the working z+. Constitutive.
i+ o^c z- / i+ o+ z+. The broken operator controls a broken gene. The working z+ has a normal operator. Inducible.
Cases 4 and 5 have the same alleles in different arrangements and give opposite results. That is what "acts in cis" means.
Common mistakes:
Reading i as "inducer". NCERT points out it comes from "inhibitor".
Thinking the repressor is made only when needed. NCERT says it is made all the time.
Calling glucose an inducer. NCERT notes that glucose and galactose cannot induce the lac operon.
Our molecular basis of inheritance guide places the operon in the rest of the chapter.
What can a student take from their way of working?
Look for the same pattern in two systems. Jacob writes that the analogy between lysogeny and enzyme induction "was invaluable to us".
Design the experiment that separates two ideas. Partial diploids turned two look-alike mutants into a clear test.
Explain with a simple picture. The radio-and-door analogy still teaches cis and trans.
When a diagram is not enough
The lac operon is easier to follow when you can watch the repressor bind and fall off. The Fermi Simulation Lab has interactive simulations for ideas that are easier to see than to read, and the Fermi Concept Library has a lesson for each concept in molecular biology.
Try it now: predict the phenotype of i- o+ z+ / i- o+ z-, then explain your answer in one sentence.
