The opening of the contemporary era of genetics—triggered by the historic discovery that genes are made of DNA—was achieved 50 years ago this year by Maclyn McCarty and his Rockefeller Hospital colleagues, Oswald Avery and Colin MacLeod. This pivotal discovery of the 20th century led the way for stunning revelations in DNA technology, most dramatically in 1953 with Watson and Crick's defining of DNA's double helix configuration. The reverberations continue today, dominating large sectors of biomedical science and biotechnology, and have established the centrality of genetics in biological thought.
In the 1940s, DNA was an unlikely candidate for biological specificity since a homogenous sample of DNA appropriate for chemical analysis was not available. But Avery had done much earlier work with pneumococcal pneumonia and extensive studies with the pneumococcal cell itself. The Avery Lab was the only place where attempts were being made to identify the substance involved in cellular transformation. Then, in early 1940, with MacLeod and McCarty, Avery began the slow, painstaking work that culminated in the historic chemical characterization that the transforming substance—the manner in which the pneumococcus controlled the formation of its capsule—was a highly polymerized viscous form of deoxyribonucleic acid.
Their work was meticulous and exacting. The 1944 paper, in fact, has been called a model of factual statement and analysis. In the next ten years alone, the paper was cited almost 300 times in other work and very frequently cited by indirection.
Confirmation of their findings came quickly and other researchers around the world began extending knowledge of DNA. McCarty himself went on to purify a DNase from beef pancreas and showed that the enzyme efficiently inactivated the transforming principle, something that depolymerases for protein, RNA, and polysaccharide had previously failed to do.
But perhaps most important, their work opened the door to a new age of understanding genetics and an era of inquiry into the most basic issues of fundamental biological science. As Sir Peter Medawar said, it was "the most interesting and portentous biological experiment of the 20th century."
To Maclyn McCarty, for his seminal and historic investigation which revealed that DNA is the chemical substance of heredity, and for ushering in a new era of contemporary genetics, this 1994 Albert Lasker Special Achievement Award is given.
Dr. Maclyn McCarty's September 3, 1998, conversation with Bradie Metheny, publisher of Washington Fax, provides a personal glimpse into the life of Dr. Oswald Avery.
Metheny: I would like you to give me a bit of a personal glimpse of Dr. Avery, as an individual, as a man, and some of his philosophy. And I do have one question on the science. He was into pneumococcus. How did he get from that to the transforming principles of DNA?
McCarty: That all came from the pneumococcus. The whole story is a pneumococcal story.
Metheny: I see. Was that easily recognized by everybody else?
McCarty: Well, no. Actually, it represented a phenomenon called "transformation of pneumococcal types" that was discovered in England by a man named Griffith. At the time it came out—it was reported back in 1928—Avery had been working with pneumococcus for a number of years, and it was a phenomenon that surprised him. As a matter of fact, they might have been skeptical if they didn't have a high respect for Dr. Griffith. But they did repeat it in their laboratory. It was also confirmed in a laboratory in Germany in the Salk Institute by another man who was a pneumococcal expert.
So it was there. The explanation for it and what was happening was not known, and as time went on, Avery became focused on the fact that it probably would be important to find out the nature of this substance that was responsible for transformation. You could extract the substance from one type of pneumococcus, and with the material that you extracted, you could proceed in culture and get a different type of pneumococcus to make the material that was made by the first type.
As one thought about it after working with it for a long time, it was clear that it had the features of the transfer of genetic information. Avery's idea was that we ought to stick with it and try to find out what it was. Nobody else pursued that course.
Metheny: And that was DNA.
McCarty: And that was DNA.
Metheny: Wasn't there a bit of debate whether it was protein that was the basis for life?
McCarty: It wasn't so much a debate, it was because of some partly false information that had come earlier and some of the work on DNA that [indicated it] existed in the nucleus of all cells, of mammalian cells and plant cells. It seemed to be so relatively simple. In other words, it only had four components, four nucleotides, in comparison with proteins, which had 20 different amino acids and could be...you know, you could just have an infinite number of different combinations of those.
The whole idea was that the people who generally would think about the nature of genes, just felt that it couldn't be DNA. But if it was anything that we knew about already, if it were a substance that we had identified, it had to be a protein.
It was not until '44 that the final result that this was DNA was obtained and published. I had come there [the Rockefeller Institute] to work with it a few years earlier.
Metheny: How did you get to be associated with Dr. Avery?
McCarty: I had been interested in getting into research. I had finished medical school and actually got some training in pediatrics, so that I had practical training. The year before, 1940, I had come to New York to New York University with a laboratory man called William Tillett. Tillett was the head of medicine at NYU at that time, the first full-time head of medicine. But he had worked earlier for some eight or nine years during the 20s in the Avery lab.
Toward the end of the year I was with him at NYU. He suggested I apply for a National Research Council fellowship and continue [with him]. They gave me the fellowship, but they said they wanted me to broaden my training and suggested I go to the Rockefeller Institute. Well, Avery was a good friend of Tillett's; he knew him well. So in the face of that he called Avery and got him to agree to take me on with the fellowship. It happened to be at just the time, as Tillett knew, that MacLeod, who had been working with Avery that last year in '40 and '41—he had been working on the transforming problem with Avery—MacLeod was going to NYU as the head of microbiology. He was leaving July 1st, so I just came and sort of took his place in the job.
Metheny: How would you describe Avery?
McCarty: He was a small man, as you've probably heard. He was probably 5'2" or 3", something like that, and weighed about 100 pounds at the max. He dressed quite formally, actually, with the shirts with the stiff collars, always suits, always dressed well in the laboratory—of course he replaced it with a laboratory coat in the lab. He had a fairly large head, somewhat out of proportion with his small body, and he started losing hair early enough so that he had a fairly high dome, which gave him quite a distinct appearance. He used a pince-nez instead of ordinary glasses, which also was a feature of his appearance.
He was very pleasant, and I think he was a man who did very well in his relationships with other people. He did have occasions when he was depressed. Some of this came from the illness that he had, hyperthyroidism, that actually interfered with his doing work in the lab because he had a tremor, and couldn't maintain a sterile bacterial field. This happened, started, in '34, and it took a while until he had a subtotal thyroidectomy and got back in business. But for quite a while he had a period of being depressed and not very...not his usual self in the lab.
You don't know the book by Renee Dubos on him, do you? It's actually a book—he called it "The Professor, The Institute and DNA"—about the Rockefeller, and Avery, and then the work on DNA.
He was famous, of course. He was with Avery for years. But he wrote a lot, and that's the reason he's well-known, I think. He also did some very nice work, of course. But, the point I want to make is that he reveals all this in the book, and there was probably a quite marked change in Avery's apparent personality in his more adult years.
He was the son of a Baptist minister that came from Canada to New York when Avery was about seven. Avery had that kind of background: he went to Colgate which was a Baptist school, I think, and was remarkably attracted to oratory. He actually shared the prize in oratory in his senior year with Harry Emerson Fosdick, who became one of the famous ministers in New York City.
So he had this flair for public speaking, but in later years he lost this, and he lost interest in it. He didn't care a lot for making public speeches and was reluctant actually to get involved in it. The first year I was with him he happened to be president of the Society of American Bacteriologists, so he had to give the presidential address at a meeting held in Baltimore between Christmas and New Year's. This was the first talk I ever heard him give, but it was one of the very few in the remaining years.
Dr. MacLeod and I, after we had finished writing up the work in the fall of 1943 on the DNA, persuaded him that he really had to give a talk at the staff meeting of the institute on the topic because it had been a long time since he had talked before this group at all because of his reluctance to talk. He did that in December of '43, but that's the last time I heard him give a talk of any kind in public...it's the last one that I knew about or he let people know about.
Metheny: What were his interests?
McCarty: Actually, he was a bachelor, and his interests were pretty much devoted to the laboratory. He had an apartment with one of his early colleagues at Rockefeller, who was also a bachelor. They shared a lot of their conversations and this kind of thing, but he would be in the lab even weekends quite frequently, and I think his primary concerns were really the research he got involved in. He came to the Rockefeller in 1913 as the bacteriologist of the hospital, and it was not long before the work on pneumococcus was his primary work, since that was the study the director of the hospital had already started. The hospital was then three years old, and it had only been started in 1910. So that was something he got into, and it was pretty much his life, I think.
Metheny: Is his brother still alive—was it Roy?
McCarty: No, I believe Roy's daughter is all that remains of the family, directly. He was a bacteriologist also. He was the head of bacteriology at a medical school in Nashville, Tennessee. When Avery retired when he left Rockefeller in '48, that's four years after they—we—published the paper, he went to live in Knoxville near Roy.
Metheny: Was he surprised that he, or did he think about the fact that he did not get a Nobel Prize?
McCarty: Well, he never talked about it. Obviously, others did. He had been nominated for the prize for earlier work. He and Michael Heidelberger, who came on with him as a biochemist, worked out the nature of the substance they called the "specific soluble substance" of pneumococcus, which they later showed was part of the capsule of the cell. It surrounded the cell itself, this capsule which contained the polysaccharide. The polysaccharide was an important antigen because it was the thing that determined type specificity. That got involved, of course, in the transformation business as well. But it was the first evidence for polysaccharides being antigens and making antibodies, since immunity to the polysaccharides was the thing that would protect a patient.
This work was cited or proposed for the prize much earlier before the transformation work in the DNA. Then, after our work was published, people were skeptical, not everybody, but there were those....One individual, most importantly, kept promoting the idea that you couldn't be sure that protein wasn't involved, because it wouldn't take very much protein...if we probably had one percent or less protein in our product...but his idea was that it wouldn't take much.
Because these doubts were widely expressed, the Nobel Prize people said...actually it was written up some years later in one of their volumes...they said because of these doubts they had waited, and it was not until later work from another source that the doubts were largely disposed. But Avery lived until 1955, so they didn't get around to doing it even after these doubts were gone.
Metheny: As I understand it, the Royal Academy was really the one who gave him recognition for the DNA work. Is that correct?
McCarty: Yes. They weren't the only [ones]. There were a number of people as well, and it was not too much longer after that other organizations did, of course. They awarded him a medal of the Royal Society, the Copley Medal, which he did not go over to England to get. He didn't. He hadn't traveled for some years, and he didn't go. They actually delivered the medal to him. The citation of the medal, which was written by the head of the Academy, I guess, did cite the fact that it was, it looked like the gened solution, in other words the transforming substance, looked like the gened solution, so it was recognized.
At the level of other scientists, for example, there were a number who actually didn't doubt it. One evident one was Erwin Chargaff...he's still alive....he was at Columbia University. He changed his whole line of work to work on DNA, and [his] was the work that really showed that they weren't all alike, that they were not so simple. They had quite diverse different compositions.
So that was going on, and of course, there were other people who were working in areas that were continuing the studies because they were convinced of it. And Hodgkiss, who followed us right at Rockefeller—he had been there before I came but not working in this area—extended the work by showing that a lot of other traits (other than just this polysaccharide, that's type specificity) could be transferred by DNA extracted from the organism. In other words, he showed that it was, that there were many other possibilities for genetic change, different kinds of genetic changes in the organism.
Metheny: What do you remember most about Dr. Avery, personally?
McCarty: You know, I worked very closely with him because we were alone, the two of us, on this project for the last three years of the work before it was published. We got along, I think, extremely well. There were a lot of disappointments, and things didn't always work, as you know. I have written about this a bit, but in his, in the kind of enthusiasm he had for the whole thing, he would even survive the bad stages when things didn't go well.
It was a lovely kind of experimentation because we set up experiments one day, we would have racks of test tubes which had variables on the thing we were working on, then you could put these in an incubator overnight after the organisms were put in. In the morning, you could have an answer as to whether the transformation occurred in the tubes or not just by looking at them. But you could also then continue, as we always did, and do some plating out to get the final answer.
So we had this routine: it was a sort of 24-hour cycle of experiments. On the basis of the results of one day's experiments, we could sit down together and decide what the next step was. And working with it that way was very illuminating. I learned a lot from it.
Metheny: How old were you at this time?
McCarty: I was 30 when I came there.
Metheny: And how old was he?
McCarty: He was in his 64th year. Retirement in those days was at 65, so he stayed on after that, of course. He stayed until 1948, but you didn't have to retire in the sense of leaving.
Metheny: Did he teach?
McCarty: We didn't have students. The teaching he had done was before he had come to Rockefeller. He was at a laboratory in Brooklyn called the Hopelyn Laboratory, and he taught there a bit, but that's where he got the name "professor," actually.
The name "professor" wasn't used at Rockefeller in those days. The head, the top position, was "member." There were "members" and "associate members" and so forth. It wasn't until the 60s that we became called the Rockefeller University and had graduate students. So there were none of those. The kind of teaching that he did was for people like me, post-docs that came in, and he had a wonderful set of more-or-less fixed talks that got to be known in the laboratory as the "Red Seal records." It came from the phonograph records...
His Red Seal records would review the development of a given problem in the laboratory with phraseology that...you often heard it more than once. The phraseology was something he had worked out, and he used it. It wasn't memorized, but it was repeated quite frequently. As a matter of fact, what he would do....a lot of people worked in the lab over the years....he became quite well known...he would not put them on a problem, he would not say, well, this is what you're going to do. He would talk...to get them fully understanding what had been done in the laboratory and what the developments were like, so the people would get their own focus from this and decide to do something. He really just generated the interest that would get them started on their own problem. This is how I first heard about transformation, with one of these Red Seal records in the first few weeks I was there at the Rockefeller.
Metheny: That's marvelous. Let me just take a second to say thank you for all your help on this thing. Is there anything that I have not asked that you might be able to tell me?
McCarty: Obviously, there are many aspects that I don't have anything [about] on the top of my head at the moment. You may sometime want to see the Dubos book. It was actually published by the Rockefeller University Press, so I think it is still available there, as far as I know. In 1976 is when it came out. My book was later, you see, '85.
Metheny: Thank you, again. It's been a real pleasure for me, and it's a real honor to talk with you.