Caltech Scientists Synthesize Larger Protein Hormone
Caltech scientists have chemically synthesized a protein hormone that may have anti-cancer and other therapeutic potential like its much-heralded sister compound, interleukin-2.
The hormone, called interleukin-3, or IL-3, is by far the largest protein that has been chemically synthesized in significant amounts. The scientists’ feat makes it possible for researchers to study the hormone in a pure form for the first time and to obtain a better understanding of its biological activity.
Investigators hope that IL-3 will be useful in treating cancer patients because it is believed to play a key role in regulating the formation of blood cells by the body’s immune system.
Last month, physicians at the National Institutes of Health reported that interleukin-2 could be used to activate a cancer patient’s white blood cells so that the cells would destroy the patient’s tumor.
The technique for synthesizing proteins was originally developed in the late 1960s by R. Bruce Merrifield of Rockefeller University--a feat for which he was awarded the 1984 Nobel Prize for Chemistry. His approach also made it very easy to automate the synthetic procedure.
Stephen Kent and his colleagues at Caltech report in today’s issue of the journal Science that they have increased the efficiency of the process so that they are able to synthesize proteins containing as many as 200 amino acids--making them about four times as large as proteins produced with conventional synthesizers. IL-3 contains 140 amino acids.
The technique takes about 70 hours to synthesize half a gram of purified IL-3--about the weight of a small paper clip.
Pure IL-3 had previously been available only in quantities of a few hundred-thousandths of a gram.
Obtained From Mice
The Caltech group actually constructed a form of IL-3 obtained from mice because the hormone, unlike IL-2, has never been found in humans, although scientists are confident that it is there. In fact, pure IL-3 has not been obtained from mice either. Instead, Ian Clark-Lewis of the Caltech team, working with investigators at the Hall Institute of Medical Research in Australia, isolated the mouse gene that codes for IL-3.
“From that gene, we were able to deduce the amino acid sequence of IL-3 and synthesize it,” Clark-Lewis said in a telephone interview. The synthetic IL-3 they produced, he said, had the same effect on blood cells as a crude solution of IL-3 isolated from mice.
The Caltech group could have inserted that gene into a bacteria to obtain significant quantities of the hormone. They chose the chemical synthesis because they thought that purification of the product would be easier with that technique.
They also wanted to make variants of the hormone in which the identity of one or more amino acids was changed in order to study the relationship between its composition and biological activity. In this way, they might find a variant that would persist longer in the blood or that would be more effective. Chemical synthesis provided the simplest way to make such variants.
