Concept


DNA was discovered as a major chemical of the nucleus at about the same time Mendel and Darwin published their work. However, during the early 1900's, proteins were considered better candidates as molecules able to transmit large amounts of hereditary information from generation to generation. Although DNA was known to be a very large molecule, it seemed likely that its four chemical components were assembled in a monotonous pattern — like a synthetic polymer. Also, no specific cellular function had yet been found for DNA. Proteins, on the other hand, were important as enzymes and structural components of living cells. Proteins were also known to be polymers of numerous amino acids. These polymers are called polypeptides. Most importantly, the 20 amino acid "alphabet" of proteins potentially could be configured into more unique information-carrying structures than the four-letter alphabet of DNA.

Animation


Hello, I'm Freidrich Miescher. I was interested in the chemistry of cells. In 1869, I began working with white blood cells. White blood cells are the major component of pus from infections. I collected a lot of pus from bandages at the local hospital. I used a salt solution to wash the pus off the bandages. When I added a weak alkaline solution to the cells, the cells lysed and nuclei precipitated out of the solution. From the cell nuclei I isolated a unique chemical substance, which I called nuclein. I found nuclein in every cell type I tested. Chemically, nuclein is high in phosphorus. Therefore, I thought nuclein mainly functioned as the cellular storehouse for the phosphorus atom. In my lifetime, we were not able to show any other clear biological function for nuclein. I'm Phoebus Levene. By the early 1900's, we knew that Miescher's nuclein was a mix of proteins and nucleic acids. There are two kinds of nucleic acids. DNA — deoxyribonucleic acid — is found mainly in the nucleus. RNA — ribonucleic acid — is found mainly in the cytoplasm. Although most of my work was on the chemical nature of DNA, let's first talk about proteins. Proteins are made up of 20 different subunits — amino acids. These amino acids are chemically linked together to form protein chains. With 20 different amino acids to build from, even a small protein can have millions of sequence combinations. Let's take an example where we link just 4 amino acids. Since any one of 20 amino acids can occur at each position, there are 160,000 different possible combinations. Therefore, proteins come in many different shapes and sizes. I believed that this variety made proteins a good candidate as the molecules of heredity. DNA, the molecule that I worked on, has only four different units, called nucleotides. A nucleotide is made up of three elements: phosphate, deoxyribose sugar, and a nitrogenous base. The carbons of the deoxyribose sugar are numbered 1-5. In a nucleotide, the nitrogenous base is always bound to carbon#1, a hydroxyl group (OH) is bound to carbon#3 and the phosphate group is bound to carbon#5. Each of the four nucleotides has its own distinctive nitrogenous base. (cytosine, adenine, thymine, guanine) I figured out that nucleotides are linked by a phosphodiester bond: one phosphate group binds to two sugars through the hydroxyl group on carbon#3 of one sugar and carbon#5 of another sugar. The phosphodiester bonds give the linkage between nucleotides a directionality: from carbon#5 to carbon#3, 5 prime (5') to 3 prime (3'). I thought that nucleotides were found in equal amounts in DNA molecules. So, I proposed that DNA must be a tetranucleotide — a linked series of four where the order was always the same. In 1938, I found that DNA is a much larger molecule than anyone had thought. It made more sense to think of DNA as a polymer, a long-chain molecule made up of repeating units of tetranucleotides. It was hard to see how DNA could be "intelligent" enough to carry hereditary information. In my model, DNA is made up of tetranucleotide blocks; whereas, proteins have an alphabet of 20 amino acids. In my opinion, proteins were a better choice as the nuclear hereditary material.

Gallery


Friedrich Miescher.
1879 picture of the laboratory where Miescher isolated nuclein. The lab was run by Felix Hoppe-Seyler, and located in the vaults of an old castle.
Phoebus Aaron Theodor Levene, 1915.
Levene working in the lab.
(1 of 4) Levene's laboratory at the Rockefeller Institute, 1922. Levene had a large lab space; note the type of equipment used at the time.
(2 of 4) Levene's laboratory at the Rockefeller Institute, 1922.
(3 of 4) Levene's laboratory at the Rockefeller Institute.
(4 of 4) Levene's laboratory at the Rockefeller Institute--used for distillation purposes.

Audio/Video


Audio Glossary

Base pair, Chromosome, Deoxyribonucleic acid (DNA), Genome, Nucleotide

Video Interviews

Thomas Sakmar

Thomas Sakmar is a professor at Rockefeller University. His lab works on the role of several proteins involved in photochemistry, specifically how protein structure is related to function. Dr. Sakmar has a personal interest in the work done by Phoebus Levene.

Clip 1 (2:14)
Comments on some of the prevailing theories of the time and Phoebus Levene's basic hypothesis.

Clip 2 (1:30)
Phoebus Levene's contributions -- the distinction between DNA and RNA.

Clip 3 (0:55)
The work of Erwin Chargaff and how it contributed to the downfall of Levene's tetranucleotide theory.

Clip 4 (2:00)
Did Levene's tetranucleotide theory affect the development of ideas in the field of nucleic acid research?

Biography


 

In 1869, Friedrich Miescher isolated "nuclein," DNA with associated proteins, from cell nuclei. He was the first to identify DNA as a distinct molecule. Phoebus Levene was an organic chemist in the early 1900's. He is perhaps best known for his incorrect tetranucleotide hypothesis of DNA.

FRIEDRICH MIESCHER (1844-1895)

Friedrich (Fritz) Miescher was born in Basel, Switzerland. The Miescher family was well-respected and part of the intellectual elite in Basel. Friedrich's father was a physician and taught pathological anatomy; Friedrich's uncle, Wilhelm His, was a well-known embryologist.

Miescher was an excellent student despite his shyness and a hearing handicap. Miescher initially wanted to be a priest, but his father opposed the idea and Miescher entered medical school. When he graduated in 1868, Miescher ruled out specialties where patient interactions were necessary because of his hearing problem. He decided to base his career on medical research. He went to the University of Tübingen to study under Felix Hoppe-Seyler in the newly established faculty of natural science.

Hoppe-Seyler's laboratory was one of the first in Germany to focus on tissue chemistry. At a time when scientists were still debating the concept of "cell," Hoppe-Seyler and his lab were isolating the molecules that made up cells. Miescher was given the task of researching the composition of lymphoid cells -- white blood cells.

These cells were difficult to extract from the lymph glands, but they were found in great quantities in the pus from infections. Miescher collected bandages from a nearby clinic and washed off the pus. He experimented and isolated a new molecule - nuclein - from the cell nucleus. He determined that nuclein was made up of hydrogen, oxygen, nitrogen and phosphorus and there was an unique ratio of phosphorus to nitrogen. He was able to isolate nuclein from other cells and later used salmon sperm (as opposed to pus) as a source.

Although Miescher did most of his work in 1869, his paper on nuclein wasn't published until 1871. Nuclein was such a unique molecule that Hoppe-Seyler was skeptical and wanted to confirm Miescher's results before publication.

Miescher continued to work on nuclein for the rest of his career. He also examined the metabolic changes that occur in salmon when they spawn. In 1872, Miescher was appointed the professor of physiology at the University of Basel, a position previously held by his father and then his uncle. The appointment meant more funds and equipment for research, but it also meant that Miescher had to teach. Although he put in a lot of time and effort, Miescher was not a good teacher. His shyness and preoccupation with his research made it difficult for him to relate to his students. He was a perfectionist and a workaholic, and often worked very long hours to do the nuclein isolations.

It would be years before the role of nucleic acids were recognized. Miescher, himself, believed that proteins were the molecules of heredity. However, Miescher laid the groundwork for the molecular discoveries that followed. Miescher died in 1895 from tuberculosis.

PHOEBUS AARON THEODOR LEVENE (1869-1940)

Phoebus Levene was born in Sagor in Russia. He grew up in St. Petersburg and studied medicine at the Imperial Military Medical Academy. As a student he worked in the laboratory of his organic chemistry professor where he likely developed an interest in biochemistry.

In 1891, because of growing anti-Semitism in Russia, Levene and his family emigrated to the U.S. They arrived on the symbolic day of July 4. Levene went back to Russia almost immediately to finish his medical degree, but by 1892, he was in New York and practicing medicine on the Lower East Side.

Levene did not give up research. He enrolled as a special student at Columbia University and he split his time between his medical practice and research in the department of physiology. By 1894, he began publishing papers on the chemical structure of sugars. Two years later, Levene received his first appointment as an Associate in the Pathological Institute of the New York State Hospitals. Unfortunately, around this time, Levene contracted tuberculosis and was forced to take time off to recuperate.

Levene used the time between 1896 and 1905 to regain his health and to work with a number of well-known chemists, including Albrecht Kossel and Emil Fischer, the nucleic acid and protein experts of the time. In 1905, Levene was hired by the newly established Rockefeller Institute of Medical Research to head the biochemical laboratory. Levene did most of his nucleic acid work at the Rockefeller and stayed there until his death.

Levene was a cultured man, an art lover and a collector. The walls of his house were lined with either prints and paintings or overflowing bookshelves. Levene was extremely well-read and was fluent in Russian, English, French and German. He also spoke passable Spanish and Italian. His experience, knowledge and his generosity made him a favorite with colleagues and friends. He was also said to be a great teacher, enthusiastic and supportive.

Although mostly remembered now for his incorrect tetranucleotide theory of DNA, Levene published over 700 original papers and articles on the chemical structures of many biochemicals. Levene died in 1940, before the true significance of DNA became clear.

Factoid

Links


 

Links

The Friedrich Miescher Institute

Located in Basel, Switzerland, the FMI was founded in 1970 and named in honor of Friedrich Miescher.

Bibliography

  • Davidson, J.N., 1965, The Biochemistry of the Nucleic Acids, John Wiley & Sons, Inc., New York.

  • Dunn, L.C., 1991, A Short History of Genetics: The Development of Some of the Main Lines of Thought: 1864-1939, Iowa State University Press, Ames.

  • Griffiths, Anthony, et. al., 1996, An Introduction to Genetic Analysis, W. H. Freeman and Company, New York.

  • Judson, Horace Freeland, 1979, The Eighth Day of Creation: Makers of the Revolution in Biology, Simon and Schuster, New York.

  • Lagerkvist, Ulf, 1998, DNA Pioneers and Their Legacy, Yale University Press, New Haven.

  • Morange, Michel, 1998, A History of Molecular Biology, Harvard University Press, Cambridge, Massachusetts.

  • Olby, Robert, 1974, The Path to the Double Helix: The Discovery of DNA, Dover Publications, Inc., New York.

  • Portugal, Franklin H., and Cohen, Jack S., 1977, A Century of DNA: A History of the Structure and Function of the Genetic Substance, The Massachusetts Institute of Technology, U. S. A.

  • Slyke, Donald, and Jacobs, Walter, 1943, Biographical Memoir of Phoebus Aaron Theodor Levene, National Academy of Sciences, Biographical Memoirs, 23: 75-87.

  • Watson, James D., 1987, Molecular Biology of the Gene, The Benjamin/Cummings Publishing Company, Inc., Menlo Park, California.

Glossary


Base pair - Two bases which form a "rung of the DNA ladder." A DNA nucleotide is made of a molecule of sugar, a molecule of phosphoric acid, and a molecule called a base. The bases are the "letters" that spell out the genetic code. In DNA, the code letters are A, T, G, and C, which stand for the chemicals adenine, thymine, guanine, and cytosine, respectively. In base pairing, adenine always pairs with thymine, and guanine always pairs with cytosine.
Chromosome - One of the threadlike "packages" of genes and other DNA in the nucleus of a cell. Different kinds of organisms have different numbers of chromosomes. Humans have 23 pairs of chromosomes, 46 in all: 44 autosomes and two sex chromosomes. Each parent contributes one chromosome to each pair, so children get half of their chromosomes from their mothers and half from their fathers.
Deoxyribonucleic acid (DNA) -
Genome - All the DNA contained in an organism or a cell, which includes both the chromosomes within the nucleus and the DNA in mitochondria.
Nucleotide - One of the structural components, or building blocks, of DNA and RNA. A nucleotide consists of a base (one of four chemicals: adenine, thymine, guanine, and cytosine) plus a molecule of sugar and one of phosphoric acid.

Children resemble their parents.
Genes come in pairs.
Genes don't blend.
Some genes are dominant.
Genetic inheritance follows rules.
Genes are real things.
All cells arise from pre-existing cells.
Sex cells have one set of chromosomes; body cells have two.
Specialized chromosomes determine gender.
Chromosomes carry genes.
Genes get shuffled when chromosomes exchange pieces.
Evolution begins with the inheritance of gene variation.
Mendelian laws apply to human beings.
Mendelian genetics cannot fully explain human health and behavior.
One gene makes one protein.
A gene is made of DNA.
Bacteria and viruses have DNA too.
The DNA molecule is shaped like a twisted ladder.
A half DNA ladder is a template for copying the whole.
RNA is an intermediary between DNA and protein.
DNA words are three letters long.
A gene is a discrete sequence of DNA nucleotides.
The RNA message is sometimes edited.
Some viruses store genetic information in RNA.
RNA was the first genetic molecule.
Mutations are changes in genetic information.
Some types of mutations are automatically repaired.
A chromosome is a package for DNA.
Higher cells incorporate an ancient chromosome.
Some DNA does not encode protein.
Some DNA can jump.
Genes can be turned on and off.
Genes can be moved between species.
DNA responds to signals from outside the cell.
Different genes are active in different kinds of cells.
Master genes control basic body plans.
Development balances cell growth and death.
A genome is an entire set of genes.
Living things share common genes.
DNA is only the starting point for understanding human biology.
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