PAUL CHARLES ZAMECNIK (1913- )

Paul Zamecnik was born in Cleveland, Ohio. He went to Dartmouth College and graduated from Dartmouth Medical School in 1934. Although he trained to be a medical doctor, Zamecnik was always interested in science. He eventually decided to go into research because there was so much to discover. His interest in protein synthesis started with a question. In 1938, as an intern, Zamecnik was doing an autopsy on an obese woman. He wondered why there was fat when there should have been protein and muscle – no one knew the answer.

In 1939, Zamecnik approached Max Bergmann, a protein chemist at the Rockefeller Institute. He was hoping to get a job in Bergmann's lab so he could work on the problem of protein synthesis. Bergmann turned him down because Zamecnik was an M.D, not a Ph.D.

Zamecnik did get a fellowship to work with Kaj Linderstrøm-Lang at the Carlsberg Laboratory in Denmark. Linderstrøm-Lang was a leader in the field of protein chemistry and Zamecnik obtained enough training and experience that Bergmann gave him a job when he came back to the States.

Zamecnik didn't stay at the Rockefeller for long. He was offered a job at the Huntington Laboratory at the Massachusetts General Hospital in Boston. Here, he worked with Fritz Lipmann (1953 Nobel laureate) and used radioactive isotopes to prove that proteins were built from amino acids in a process requiring chemical energy – ATP. Zamecnik then became interested in how protein sequences were specified and to understand that he tried to isolate and identify all the components necessary for protein synthesis.

In 1952, Zamecnik was partially successful in that he made a cell-free extract from rat liver with which he was able to synthesize proteins from amino acids. In 1953, using this system, Zamecnik and Mahlon Hoagland showed that amino acids had to be energized, "activated," by ATP before they were incorporated into a peptide chain. Then in 1956, Hoagland followed up on an observation Zamecnik made earlier. Zamecnik noticed that low molecular weight RNA in the cell-free extract could be associated with radiolabeled amino acids. This led to the identification of tRNA ? the adaptors Francis Crick predicted in his Central Dogma.

In 1956, Zamecnik was appointed head of the Huntington Laboratory. In 1960, his lab developed a cell-free extract from the bacteria E. coli. He shared the preparation method with other scientists. Marshall Nirenberg and Johann Matthaei used the cell-free extract from E. coli to crack the genetic code.

Zamecnik continued to work on tRNA purification and sequencing. Then in 1978, he made another interesting observation. He found that oligonucleotides were able to enter cells. This led to a new area of research and possible therapy. Anti-sense RNA could be used to block the translation of viral messenger RNA. Since 1993, Zamecnik has been on the Board of Directors of a biotech company called Hybridon Inc. that develops therapeutic drugs based on the idea of anti-sense blockers.

Zamecnik still runs a lab at Massachusetts General Hospital and is a Professor Emeritus at Harvard University. He doesn't have any immediate plans for retirement; there are still many things to discover.

MAHLON HOAGLAND (1921- )

Mahlon Hoagland was born in Boston. His father was a research scientist with an interest in neurobiology. His dedication and passion for his work both drew and repelled the younger Hoagland, who learned first-hand what it was like to be a scientist. Hoagland knew fairly early on that he wanted a profession but wasn't sure that he wanted to be a scientist.

Hoagland decided he would be a medical doctor so as not to be in direct competition with his father. He went to college, first Williams College and then transferred to Harvard after a year. World War II had just started and with the need for medical doctors, Hoagland entered medical school even before graduating from college. He found he had the aptitude for being a surgeon ? he was manually adept and anatomy was one of his favorite classes. Unfortunately, three months before graduation, Hoagland was diagnosed with tuberculosis. He was sent to the Trudeau Sanatorium at Saranac Lake ? the same one where Phoebus Levene stayed ? for the classic bed rest cure. Treatment of tuberculosis with antibiotics wasn't available until near the end of his stay and by that time, Hoagland was deemed healthy enough.

In 1947, Hoagland returned to Harvard Medical School to finish his interrupted year. He still wanted to become a surgeon and applied to work as a surgical intern after graduation in 1948. It was soon obvious that he needed a less taxing career; after only weeks, Hoagland reactivated his tuberculosis. Disappointed, Hoagland applied for a postdoctoral position with Dr. Joseph Aub, the director of the Huntington Laboratories at Massachusetts General Hospital.

At Huntington, Hoagland learned to be a scientist. He worked on the effects of beryllium on enzymatic activity and in the process became more interested in biochemistry and the protein synthesis work going on in Paul Zamecnik's lab. Hoagland arranged sabbaticals to learn more about biochemistry with the goal of working in Zamecnik's lab on his return.

In 1953, Hoagland started work in Zamecnik's lab on the problem of amino acid activation. Using Zamecnik's cell-free system, Hoagland worked out the mechanics and published his results in 1955. He then began working on a project that Zamecnik had put on hold. This led to the discovery of tRNA, the adaptor (predicted by Francis Crick) that shuttles amino acids to messenger RNA. The results were published in 1957 and served to connect two fields of science research, biochemistry and molecular biology.

Hoagland spent 1958 at Cambridge University and worked with Francis Crick to try and use tRNA to solve the genetic code. He returned to the U.S. as associate professor of microbiology at Harvard Medical School. In his seven years at Harvard, Hoagland found great satisfaction in teaching and was distressed at the lack of "teachers" among the scientists who were only interested in research. He left Harvard to accept a position at Dartmouth Medical School where he improved the biochemistry curriculum.

In 1970, Hoagland accepted the directorship of the Worcester Foundation, the institute founded by his father. Hoagland was able to attract new researchers and established and strengthened research programs in cell biology, endocrinology, neurobiology, and reproductive biology at Worcester. In 1980, he was successful in recruiting Paul Zamecnik.

Although Hoagland is now retired, he still has a strong interest in education and teaching. Over the years, he has written a number of "non-scholarly" books on the subject of genes and molecular biology. The Way Life Works is being re-edited to be used as a textbook in high school biology classes. Hoagland lives in Vermont with his wife and as a hobby creates art by carving and sculpting wood.

SYDNEY BRENNER (1927- )

Sydney Brenner was born in Germiston, South Africa. At the age of 15, Brenner won a scholarship to the University of the Witwatersrand in South Africa. At the time, the South African university system was underdeveloped and Brenner did a lot of independent research and self-teaching on the subject of molecular biology. When he graduated from Witwatersrand, there was no graduate research program. Brenner applied to and went to Oxford and started graduate work on bacteriophage.

In 1953, Brenner was one of a group invited to Cambridge University to view Watson and Crick's DNA structure. This became the first of many meetings and collaborations Brenner had with Watson, and even more so with Crick.

In 1954, Brenner received his doctorate degree and returned to lecture at the University of the Witwatersrand. By now he was working on the problem of the genetic code and the role of RNA in information transfer. In 1956, Brenner sent a paper to members of the RNA tie club On the Impossibility of All Overlapping Triplet Codes - an elegant proof that used statistics and amino acid protein sequences to show that three nucleotides code for one amino acid. That same year, Francis Crick, who was also interested in the problem of information transfer, helped Brenner get a research position at the Medical Research Council in Cambridge.

In 1957, Brenner, Seymour Benzer, Francis Crick, and Leslie Barnett published a paper in Nature on the fine mapping of mutations in phage. By correlating the genetic mutations with changes in the amino acid sequence, they were able to prove colinearity between the genetic message and the protein product. Brenner then moved onto the problem of how the information was transferred between DNA and protein. In 1960, Brenner, François Jacob, and Matthew Meselson designed and worked on another series of experiments establishing the existence and function of messenger RNA.

In the late 60's, Brenner became interested in the problem of development, especially that of the nervous system. In 1968, having decided against Drosophila melanogaster as too complex, Brenner chose Caenorhabditis elegans as a model organism for study. C. elegans is now a research field onto itself, and in 1998, was the first multi-cellular organism to have its complete genome sequenced.

In the 90's, Brenner chose yet another organism, Fugu rubripes, the Japanese puffer fish. Although it has about as many genes as humans, the puffer fish does not have as much "junk" DNA. Brenner is in charge of the Fugu fish genome sequencing project at the Medical Research Council.

In 1998, with a donation from tobacco giant Phillip Morris, Brenner established and is the director of the Molecular Science Institution (MSI) in Berkeley, California. A non-profit organization, part of the role of the MSI is to process the flood of information from the various genome sequencing projects.

Brenner splits his time between Berkeley and Cambridge. He likes travelling and good wine and writes an opinion column called Loose Ends for the journal Current Biology.

Brenner shared the 2002 Nobel Prize in Physiology or Medicine with colleagues John Sulston and Robert Horvitz. All three made major contributions in the field of developmental biology using the model organism Caenorhabditis elegans.