News&Notes spoke recently with Professor Emeritus Maclyn McCarty about his historic discovery with Oswald Avery and Colin MacLeod that DNA was the carrier of genetic information.

News&Notes (N&N): Can you give us a brief overview of the story leading up to the discovery that genes are made of DNA?

McCarty: The research had its origins in the study of bacterial pneumonia. It started with the finding of an Englishman, Fred Griffith, in 1928 who described a phenomenon he called the transformation of pneumococcal types. For many years, the problem was pursued for its possible bearing on the control of pneumonia, then the leading cause of death, ranking well ahead of today’s principal killers — heart disease and cancer.

But as times went on, and the nature of the transformation became better defined, it seemed clear that it must have broader implications. It involved a change in one type of pneumococcus that was induced by a substance extracted from another kind. This change was predictable and permanent, being transmitted from generation to generation on subculture of the organisms. It had all the earmarks of what we would call today the transfer of genetic information. The Avery lab, which had been studying the problem since Griffith first described it, became focused on determining the nature of the substance responsible for the transformation.

When I arrived in the summer of 1941, Avery and MacLeod had just finished a year in which they had initiated a renewed effort on this problem. With MacLeod’s departure to New York University Medical School, I fell by chance into the unexpected position of joining Avery on this project. I would say that the next two years were as exciting as laboratory research can possibly be. Gradually a number of pieces of evidence emerged from the experimental work that all pointed to DNA as the active substance.

N&N: What was known about DNA before your paper was published in The Journal of Experimental Medicine in 1944?

McCarty: DNA had been discovered in the middle of the 19th century, but very little was known about its biological activity. Chemical studies of the nucleic acids suggested they were not very diverse and they had only a small number of components. Phoebus Levine, a leading biochemist at Rockefeller, suggested that nucleic acids would not have the potential for the kind of diversity required for transferring genetic information. So, the prevailing attitude was that if any known substance was likely to be the gene, then it would probably be protein.

N&N: Were most geneticists following the Avery lab’s work as it unfolded in the ’30s and ’40s?

McCarty: No, it didn’t get picked up widely other than by medical microbiologists concerned with pneumococcal pneumonia as a clinical problem. The geneticists were, by and large, looking at chromosomal genetics and the various ways in which you could work with this in Drosophila and corn. Their experiments weren’t designed to analyze the nature of the genetic substance. In addition, bacteria were not recognized as in the same pathway of life as higher organisms. The whole idea of the genetic continuity of life had not taken hold yet. They were really two separate worlds.

N&N: So it was your discovery that later led to the understanding that DNA is the common denominator, the secret code that runs through every living thing from a microscopic bug to a human being?

McCarty: That’s right. Today we know that the DNA code is universal. The DNA code in a bacterium is really like the DNA code in a mammalian cell and their differences are due to outward appearance rather than to the internal mechanisms that guide the growth and development of the organism.

N&N: Did you know you were on the threshold of something so significant at the time?

McCarty: Yes. This was a very special and exciting time. It was even fulfilling before we knew, for sure, that the transforming substance was DNA. Even with the ups and downs that came from experiments that didn’t work, the disappointments were trivial compared to the general feeling of excitement — the idea that you were putting in this material that was able to make a change in the organism which was permanent. It didn’t take long to feel that it was probably taking place at the genetic level. This meant I had the opportunity, very early in my scientific career, to work on as exciting a project as possible.

N&N: I understand that many of your experiments focused on isolating the transforming substance by eliminating possible candidates?

McCarty: Yes, Avery and MacLeod had been trying to eliminate possible causes of transformation, such as RNA and protein, for several years. The first set of experiments I did used the enzyme that René Dubos had first derived in the early years with Avery to attack the polysaccharide, showing that it did nothing to hurt the transforming activity. We undertook many different kinds of experiments to be sure that we weren’t being fooled. Interestingly enough, they didn’t know that DNA was in their extracts until January of 1941, six months before I arrived.

N&N: So the 1944 paper was really a cumulative product?

McCarty: Yes, it reported results for the first time from experiments that went back as far as 1934.

N&N: When you finally put the paper together did you feel “we’ve done it, this long pursuit has finally paid off?”

McCarty: There is no question that we felt that this was the answer. It made so much sense, since it was known that DNA was an important component of the chromosome in higher cells. All you had to do was accept the idea that it was wrong to say that DNAs are all alike. On the basis of our work, Irwin Chargaff immediately turned to analyzing nucleic acids and showed quite clearly they were far from all alike. And then the structural work by James Watson and Francis Crick opened the way for many of the following modern developments.

N&N: What does it feel like to have been one of the three people who essentially laid the foundation for the modern biological age?

McCarty: Well, I’ve taken pride in having been there and been involved with this discovery. I’ve also taken a lot of pleasure in watching the developments that followed because I discontinued this work and got into a more disease-oriented problem in 1946.

N&N: Could this tremendous new power you unleashed one day be used for sinister ends? What about human cloning?

McCarty: Well, I really don’t worry much about that. The potential for misuse is there, but I don’t see that as a reasonable excuse for the human race to remain ignorant the rest of its existence. Some controls may have to be imposed on human cloning, but I think it will be as manageable as most other technologies that have arrived.

N&N: How do you feel about the enormous advances such as the Human Genome Project and gene therapy spawned by your work?

McCarty: It has been exhilarating to watch it all come along. The ability to first sequence DNA, and then to clone it, have become such powerful tools in biology. And it doesn’t much matter what one is doing in biology — whether it is immunology, developmental biology, embryology, plant science or neurobiology. Everybody is using these tools. And it is now being used more and more for medical problems. It is helping us understand and devise treatments for diseases such as atherosclerosis and heart disease.

N&N: So in the sense that you started by looking for a way to treat pneumonia, one could say that your work is coming back full circle?

McCarty: Yes, I think it already has to some degree. For example, I have an anemia and one of the new synthetic products that’s been helping me is erythropoietin. So I am taking a recombinant DNA product for my health. In a sense, I am being treated by one of the fruits of this research myself.

Reprinted from News&Notes, November 12, 1993