Conversations with Laureates
Marshall Nirenberg talks with Richard M. Cohen, former CBS News Senior Producer, about his life in science and research.
Nirenberg: I came [here] in 1957, so I have been here for 41 years. I came as a postdoctoral fellow and never left. This is a wonderful Institution. I just think it is terrific.
Cohen: Now some would suggest that the freedom you enjoyed 40 years ago isn't here in the same way today.
Nirenberg: I can only speak for myself and maybe the people that I know. I think the freedom is the same. I mean I haven't seen any change in freedom. I'm in the Heart Institute and we work on Drosophila nervous system...development of the nervous system, so you know I don't think there has ever been any pressure that I am aware of, that I can see, on me at least, to do the kind of work related to the Institute, per se. But in some other Institutes, that is not true. There is a pressure to do work related to the Institute. That, I think, is a bad idea.
Cohen: And do you need to be more certain of outcome today than you might have been 40 years ago?
Nirenberg: That is an extremely good question. In the real world you have to produce, and I think that all scientists...that science now is more competitive...much more competitive than it was 40 years ago. It is competitive for young people to try to get positions, and also to try to get funding for their research And it is too competitive. There is pressure to definitely produce. You don't know when you go into a project—you have high hopes—but you don't know if it is going to work or not, or you don't know how well it is going to work. So the only way you can find out is to do it, to jump in with both feet and start. And sometimes it works out and sometimes it doesn't.
Yes, that is a really good question because when I started here at NIH I did something extremely risky. I changed fields. From my first job, Gordon Tompkins offered me a job in his group as an independent investigator, and I decided to change fields, to go into protein synthesis and nucleic acids—what would be termed molecular biology today. And I had no experience in either protein synthesis or nucleic acids at the time. For a person taking their first position, [they're] supposed to hit the deck running and to show that they are productive and that they are really competent. I wouldn't advise anybody today to do anything like this. To take a risk like that is very, very risky because it was... protein synthesis was one of the hottest fields in biochemistry and the best people in the world were working on protein synthesis, so for somebody totally inexperienced, working by himself, what chance does a person like that have to find anything? I don't think you can do anything like that today.
Also it is a lucky thing I did it at the NIH because I could never have gotten funding for it anyplace else, [having] no experience in the field. So at the NIH you do whatever you want to do, and you can change directions at a moment's notice if you want to.
Cohen: But that sort of begs a question in my mind which is, does that mean that science was freer and better 40 years ago?
Nirenberg: Yes, I think that the pressure now to produce is a very bad thing. I think that the really risky, maybe far-out projects that might be done, people won't do now because they are afraid [that] if it fails it is the end of their career.
Cohen: But to what do you attribute that? What is the change?
Nirenberg: Competition for funds. Competition for positions. Competition has increased markedly. There aren't enough funds for everybody and there aren't enough positions really for... well, there are enough positions for really good people, but for people who may be highly competent but not really exceptional, it is sometimes hard for them to find positions.
Cohen: Let me ask you about what might be another contrast between now and then. When you got into your seminal work on RNA, messenger RNA, scientists around you put down their work and joined you.
Nirenberg: That is absolutely right. That was fantastic.
Cohen: But I had the notion, and perhaps I am wrong, of science today being very proprietary, and I am not sure that I could see what happened then, happening now.
Nirenberg: That may well be true, but this was really such an exciting discovery that people were really interested in doing it and helping with it. That was a wonderful thing. I mean, Bob Martin, who is an investigator here at the NIH, stopped the work he was doing and joined me in doing the work. That was terrific. That was just a marvelous thing, and also other people at the NIH helped in different ways. Leon Heppel, for example. At that time there were only [about] eight nucleic acid biochemists in the world—really experienced people—and he was one of them. He suggested a number of things that were a tremendous help to us in our work. He is a fantastic individual and was a tremendous help to us.
Cohen: You were young men then, and it must have been very exciting working at the bench in that era.
Nirenberg: Oh, it was fantastically exciting. Yes, it was a wonderful... I must say it was a terrific experience to have a wonderful problem that is going well. There were so many discoveries because...in deciphering the genetic code there are 64 codons and 20 amino acids...and so there were lots of discoveries to make, for all of the codons had to be deciphered, and we ran through everything twice. First deciphering base compositions, and then base sequences. So, it took about five years to do this, and working flat out doing it. And there were a lot of people who participated, postdoctoral fellows that came to the lab, and everybody was excited by the problem.
Cohen: How would you explain to a non-scientist the role and importance of RNA as the go-between, as it were, between DNA and amino acids?
Nirenberg: The DNA is transcribed into RNA, which is a related sequence that is a long strand. It has four kinds of letters and they are in different sequences. And the sequence of the letters in RNA determines the sequence of the letters or amino acids in proteins. So it is a logical code. Three letters in RNA correspond to one letter in protein, one amino acid residue in protein.
Cohen: But it is no accident that it is called messenger RNA, right?
Nirenberg: That term didn't exist at the time we were doing it. I called it template RNA at the time. I think that the term messenger was given by somebody at the Pasteur Institute. I am not positive where it first originated.
Cohen: But it is a message from DNA delivered to the protein, right?
Nirenberg: It is a transcript in a related language, a different language than DNA, but related, and that is the template for the synthesis of protein. It contains the information for the order of amino acids to be incorporated into a long chain of proteins.
Cohen: Doesn't RNA explain why an ear is an ear and a foot is a foot?
Nirenberg: No.
Cohen: Doesn't it tell the protein what the DNA wants the protein to know?
Nirenberg: Yes, yes. The message is encoded in DNA. You inherit DNA from your parents, but you rewrite pieces of DNA into RNA, and only a few parts of the DNA actually encodes protein...is the information for the sequences of protein. So a lot of it is regulatory. Regions in DNA that contain information for where and when that protein is to be expressed. But RNA is the transcript from DNA that directly encodes the information for protein synthesis.
Cohen: I have read a couple of references to the work that won the prize in 1968, and they said you cracked the genetic code. Is that the right verb?
Nirenberg: That is exactly right.
Cohen: Explain that to me.
Nirenberg: We found that we could take a synthetic polynucleotide, poly-U, which contained only one kind of letter [or nucleotide]. It is a long sequence of the same letter, U-U-U-U, and on hundreds of U's linked together. And that directed the synthesis of protein that contained only one kind of amino acid, phenylalanine, in a long sequence of phenylalanines. So we got poly-phenylalanine synthesis. It was clear that a sequence of U's in RNA corresponded to the amino acid, phenylalanine, in protein. That cracked the code because it was the first time that one could decipher...the first codon was deciphered. And it provided a simple experimental approach that gave us the base compositions of other codons for every other amino acid, by making synthetic RNA's with different kinds of bases, or combinations of bases. We determined the base composition of the other codons, but not the sequence.
Cohen: Is that what Francis Crick meant by "information flow"?
Nirenberg: Yes, the information flows from DNA to RNA to protein. Yes. But it did crack the code because it enabled us to decipher the rest of the code and we got the sequences of nucleotide sequences of the codons. Three letters in RNA correspond to one amino acid in protein.
Cohen: Explain if you will, in terms that I can understand, about nucleotides.
Nirenberg: Nucleotides. A nucleotide is a letter. There are four kinds of nucleotides in RNA: T, C, A, and G. And there are four kinds of letters in DNA, too, that are very similar chemically, but slightly different. They have slightly different sugars and slightly different bases. The DNA is in every cell in the body...or most cells in the body. All the information is encoded to synthesize all of the proteins that you need. We now know that in the human genome there are about 30,000 genes...something like that. Which is far fewer than I thought that would be present. And that is what you inherit from your parents...the information that tells you how to synthesize proteins and when and where to express those proteins. Different tissues express different proteins.
Cohen: But are they encoded in the nucleotide?
Nirenberg: In the nucleotide sequence. It is like a necklace composed of four different kinds of beads. And the order of the beads determines the order of the amino acids in protein.
Cohen: Now explain transcription.
Nirenberg: Transcription is when you copy DNA into RNA. That is transcription. Translation is when you copy RNA and translate it into protein.
Cohen: And that is what this process is all about.
Nirenberg: That is what the process is all about. This was the first time anybody really showed that messenger RNA existed biochemically. We could take messenger RNA, add it to our extracts from bacteria, and the machinery of the cell would synthesize...I mean, we could program the machinery to make the protein that we wanted just by...you know, they would follow the instructions.
Cohen: Is the work in that area done now?
Nirenberg: The work on the code is done. Yes.
Cohen: Can that be manipulated?
Nirenberg: The code? Yes, it can be. And there are some dialects that have been discovered. Mitochondria had a dialect, slight dialect. Some organisms had dialects, and then there are interesting phenomena that people don't know that much about still, like RNA editing, the mechanism for changing a single base in a single position in a messenger RNA molecule.
Cohen: Tell me more about that. I am not sure I understand what you meant.
Nirenberg: Just like you edit a message, there are molecular machines that will change one letter for another letter at a particular place inside a message, only on a particular message, and it has biological consequences. Things like that are being studied now, and are a really interesting phenomena. Frame shifting. If you read three bases at a time, like this, that is the normal way of reading. But there are certain situations, like reading the Maloney leukemia virus RNA, where you need to have frame shifting. You need to skip a base in order to come out right, and that has interesting biological consequences as well. If you don't skip the base it doesn't make the virus. It is necessary.
Cohen: The genome project may be relatively new, but genetic research isn't, is it?
Nirenberg: Oh, genetic research has been ever since Mendel. You know it is more than 140 years old. Now we are working on Drosophila on the nervous system and asking the question, "How do you build a nervous system?" and using Drosophila embryos. Now that the human genome has been sequenced, the mouse genome has been sequenced, the Drosophila genome has been sequenced, as well. There are [something] like 14,000 genes in Drosophila. How you make a complicated fly with only 14,000 genes is remarkable.
Cohen: Where do you hope that takes you?
Nirenberg: Well, there are two real systems in biology that involve information transfer, encoding information, retrieval of information. The major systems, really, are the genes and the nervous system. I mean, that was the logical progression [for] why I went into the nervous system, because at the time I went into it, it was a black box as far as I was concerned. I didn't know how you make a complicated computer like the brain or spinal cord.
Cohen: But if you are talking about central nervous systems, isn't that part of brain science?
Nirenberg: Sure.
Cohen: That is the frontier, isn't it?
Nirenberg: That is what we are working on.
Cohen: Isn't that where the next big discoveries are going to be?
Nirenberg: I think so. I think that there is an enormous amount that is not known about the nervous system; but as I said, what is known, the basic strategy of how it is done, how you make part of the Drosophila's central nervous system is known. You do it by making orthogonal concentration gradients...that proteins that regulate other genes generate diversity in cell type and determines...gives the nucleus an internal molecular address in the embryo. And this determines the initial cell type that develops, because you have a dynamically changing induction-repression of gene regulators. The set of gene regulators that are expressed determines the cell type.
Cohen: In layman's terms, what do you think we are going to know in the foreseeable future that we don't know now about the brain and the nervous system?
Nirenberg: Oh my goodness. That is a hard question to answer. One of the things I would really like to know is how you assemble a nervous system. How it really is assembled, all the way through. I think that tremendous strides are being made right now in understanding some of the mechanisms for axon pathfinding. How does a cell extend a long process, find the correct synaptic partner, and make a synapse? The synapse is where the information transfer occurs from one cell to another.
Cohen: So are you talking about, just so I understand, brain impulses?
Nirenberg: Brain impulses.
Cohen: To the body.
Nirenberg: To the body and to other neurons, to process information. To muscle cells, to have movement. The nervous system is like a leaky plumbing system where neurons secrete chemicals on other neurons at specific places. That excites or depresses the neurons, the other cells that receive the information. But how do you make this wiring? How do you wire the thing together so it works in the proper way?
Tremendous strides are being made right now in understanding the mechanisms of finding the correct path, and we still don't understand how the neuron will find the right synaptic partner and make a synapse—which is a connection. This is a functional connection where it groups chemicals on the other cell, and excites it or depresses it.
Cohen: This is pretty basic research
Nirenberg: Very basic. Yes. But if you knew that, and we surely will know this in the coming years, you can begin to repair broken nervous systems, maybe. If you break the spinal cord or cut neurons, in mammals at least, there is some regeneration but not that much. So you can have permanent defects in a person if you cut the spinal cord. The person can't walk. If you knew how these connections formed in molecular terms, you could maybe repair these defects.
Cohen: Do you have any sense of time frame?
Nirenberg: It is hard to make predictions. Years ago, in the 60s, I made a public prediction. And when I was struck with the ease with which we could program cell extracts to synthesize protein, I had made a prediction that it would take 25 years before we would be able to do this with intact mammalian cells. And it would take 25 years to do this in man. I was very lucky; it did take 25 years before the first experiments were done, but that [accurate prediction] was just a matter of luck. I think it is very hard to predict. I think these things are 10 or 20 years ahead. Maybe longer. The nervous system is very, very complicated, and in Drosophila a third of the genes are expressed in the nervous system. Nobody even knows the function of most of these genes, even though the genome has been sequenced and the genes have been discovered. Most genes have unknown functions. So there is an enormous amount of work to do. It will take years and years and years.
Cohen: Science knows less about the brain, doesn't it, than any area?
Nirenberg: Yes, yes. That is absolutely true because the brain is so complicated. The nervous system is so complicated. It is the most complicated organ in the body.
Cohen: It sounds like you like what you do for a living.
Nirenberg: Oh I love it. I really like it yes, yes.
Cohen: Did you always want to be a scientist?
Nirenberg: At one time I wanted to be a doctor, but I was always interested in nature and I was fortunate enough...when I was about 11, my parents moved to Orlando, Florida—this was before Disneyland. It was a natural paradise, and I was thrilled to learn about birds and all the wildlife down there. As a matter of fact, when I was a kid of 13, I collected spiders for the American Museum of Natural History in New York. I had always been interested in nature, and I think the interest in science has just grown out of the interest in nature.