Historical perspectives
The discovery of DNA and RNA
Why was Bergmann's discovery of an unusual nucleoside in a living system so important? Let's go back in time to the early nineteenth century. By then, it was known that cells contained nucleic acids: long-chain polymers of nucleotides. (A nucleotide is a nucleoside plus a phosphate group.) Nucleotides, the building blocks of the nucleic acids, were known to consist of a sugar and a nitrogen-containing base and a phosphate group. Later it was found that the sugar of the nucleoside was always either ribose or deoxyribose, thus giving two forms of the polymers: RNA and DNA. That DNA carries genetic information was proven by Oswald Avery in 1943.
In 1953, Watson and Crick described the structure of DNA as a double helix that can self-replicate. (If you are interested in more on this topic, see A Science Odyssey site and the ba-education magazine.) With all this interest in nucleosides and nucleic acids, it is not so surprising that the nucleosides that Bergmann discovered in the sponges tickled the curiousity of scientists: Why would a living system contain free nucleosides that consisted of a sugar that was slightly different from the sugars in RNA and DNA? What could be their purpose?
The discovery of chemotherapy agents
The 1930s saw the first syntheses of chemical compounds designed to be effective antibiotics. This was a huge advance in medicine. Chemists discovered these effective antibiotics by synthesizing and testing hundreds of compounds to see if any of them could inhibit the growth of bacteria. The discovery of the antibiotics known as sulfa drugs is credited to Paul Ehrlich, who is widely regarded as the father of chemotherapy.
Today many of us immediately associate the word "chemotherapy" with drugs used to kill cancer cells, while the word originated with antibiotics and still means any type of chemical used in therapy.
Ehrlich's strategy was to synthesize dye-like compounds to try as antibiotics. He reasoned that since many dyes have a special affinity for staining bacteria, these dyes might also possess a special toxicity for bacteria. He was successful, in fact, the sulfa drugs that he discovered helped the Allied war effort: these drugs were poured into gaping wounds of soldiers in World War II.
Medical researchers noted the success of antibiotics in curing many medical problems and figured that it might natually follow that they would find compounds that could selectively kill cancer cells. The National Cancer Institute (NCI) was formed in 1937, and at that time, no such compounds had yet been found. Cancer was still being treated with the age-old method of surgery and the newer technology of radiation. (See The NCI is Founded, 1930-1950.)
By the late 1940s, some chemicals were found that did have an effect against cancer. Malignant (cancer) cell lines were successfully kept alive in tissue culture, a way of keeping mammalian cells living in Petrie dishes. This provided a good method to screen potential drugs effectiveness against cancer cell lines. Promising drugs were then tried in animal studies, and finally in human trials. Initial successes using these methods encouraged the search for more and better drug treatments. In 1955 Congress appropriated funds for a national effort, and NCI undertook a National Chemotherapy program devoted to testing chemicals that might be effective against cancer. (See Molecular Biology Comes of Age, 1952-1971.)
Nucleoside analogues as chemotherapy
As outlined above, two areas of research progressing in the middle decades of the twentieth century were:
The study of how DNA is replicated as cells divide.
The design of chemicals to be used as anti-cancer agents.
Some of the scientists put these two together and used the tactic of designing or finding compounds that interfered with the replication of DNA, theorizing that such compounds would stop a cell from dividing. Since cancer cells are cells that are growing out of control, stopping these cells from dividing should be good. Perhaps fiddling with the building blocks of DNA - the nucleosides - would lead to compounds that stopped DNA synthesis in its tracks.
The first efforts to design nucleoside-changed anti-cancer drugs focused on changing the base part of the nucleoside, leaving the sugar (deoxyribose) intact. Then spongothymidine was discovered: marine sponges contained nucleosides with a modified sugar instead of a modified base. This led medical researchers to design nucleosides with changed sugar moieties. One such nucleoside was prepared by changing the sugar of cytosine (another nucleoside) to the very same sugar found in the sponges, creating the compound cytosine arabinoside, also known as cytarabine or ara C.
The earliest work on ara C and spongonucleosides in general is reported in an interesting article written by Seymour Cohen in 1963. His paper is discussed in the next section.