September 18, 2006

The Movability of Genes

Barbara McClintock, Mutable Loci in Maize, 1948

I often forget just how much research into genetics went on before the structure of DNA was discovered. My education in biology covered the Abbot Gregor Mendel's discovery of dominant and recessive traits, the rediscovery of his work in 1900, and then jumped straight to Watson and Crick. I am not alone in this: many scientists neglected earlier work in the decades after the DNA revolution.

Barbara McClintock is one of the least-known great scientists of the 20th century. Her work on genetics was ground-breaking, from her proof of the link between genetic recombination and chromosomal crossover in 1930 right through to her discoveries about transposable genes in the 1950s. Although well regarded by those of her colleagues who understood her work, many of her discoveries weren't well known until the early 1980s. Indeed, in 1953 she actually stopped publishing her work on gene regulation through sheer frustration with the fuzzy assumptions and dull incomprehension she encountered in geneticists at the time.

Basically, most geneticists started out believing that all genes follow Mendel's simple model: each gene produces one trait, in either a dominant or a recessive form. Genes were known to reside on the chromosomes, those tiny structures in cells which later turned out to be huge bundles of DNA. Most cells contain two copies of each chromosome, and thus two copies of each gene, which also fits Mendel's model.

During sexual reproduction, cells divide differently than they normally do, and sister chromosomes can be observed exchanging parts. As mentioned above, McClintock was the first to show that this "crossover" process causes genetic traits to be exchanged between chromosomes. The consequences of this are useful: if two genes happen to be near each other on the same chromosome, they are much less likely to end up in different offspring. That is, most offspring will have both traits, or neither. If they are far apart, or on different chromosomes, offspring will tend to have one trait and not the other as often as having both or neither.

Using this statistical information, one can map the chromosomes, showing which chromosome each gene is on and where it is relative to other genes. McClintock did this with maize (corn), a plant she studied for most of her career. This is sort of like an early version of gene sequencing. Most geneticists knew about this kind of work, and believed as a result that genes are lined up linearly on chromosomes, and stay in the same position.

McClintock added all kinds of wrinkles to this model. For starters, she discovered a gene on the 9th chromosome of maize whose dominant form frequently caused the chromosome to break at the gene's location. (This was observed with a microscope.) As you can imagine, this caused havoc with the development of the plant. Corn kernels on the same plant often look quite different from each other, in part because chromosome breakage causes large mutations in the different kernels during the lifetime of a single plant.

McClintock then discovered that this gene was controlled by a second gene. When the recessive form of the control gene was present, breakages never happened, no matter whether the breakage gene was dominant or recessive. When the dominant form of the control gene was present, the breakage gene behaved normally. The discovery of genes whose only effect is to control the action of other genes is a major step forward all by itself.

But McClintock didn't stop there. During her detailed study of maize, she noticed that some corn kernel mutations appear in paired patches: one patch with a higher mutation rate than normal, and an adjacent patch with a lower mutation rate than normal. (McClintock was known for her incredible eye for detail. Admittedly, she was using a microscope, but still!) These paired patches, she theorized, must have arisen from a single ancestral cell, early in the growth of the kernel, that divided in such a way that one daughter cell gained something from the other daughter cell. The two neighboring patches then, represent all the descendants of the two daughter cells.

She quickly discovered that the differing mutation rates were governed by the same gene that controlled the breakage gene. The gains and losses appeared at many different strengths, and with time McClintock came to realize that the control gene was composed of a repeating segment of DNA, and the paired patches were being caused when some of the repeated units got moved from one chromosome to its sister. Along the way, she discovered that the breakage gene sometimes moved to a different position on the chromosome!

In short, McClintock destroyed the notion that chromosomes are immutable lists of dominant and recessive traits. It seems they are better understood as collections of genes, many having variable strength, and many of which cause other genes to be activated, deactivated, moved about, and even edited. These phenomenon are not restricted to maize; one estimate has 45% of the human genome composed of transposons (genes known to change location). Bacteria are particularly good at this trick, even going so far as to take genes from other bacteria and incorporate them into their own genome.

In many ways, genetic systems actually resemble incredibly messy, self-modifying computer programs.

September 05, 2006

Nuclear Fission

Otto Hahn and Fritz Strassmann, Concerning the Existence of Alkaline Earth Metals Resulting From Neutron Irradiation of Uranium, 1939

Lise Meitner and Otto Frisch, Disintegration of Uranium by Neutrons: A New Type of Nuclear Reaction, 1939

Do you feel you have a handle on how atoms behave? So did scientists in 1938. They knew that atoms have a nucleus containing positive protons and neutral neutrons of roughly equal mass, orbited by the right number of tiny, negatively charged electrons to make the atom as a whole neutral. They knew that the chemical properties of atoms are determined by the number of electrons in the outer shell, and therefore also by the number of protons in the nucleus. They knew that the positive charges on the protons must repel each other, so there must be a force strong enough at short ranges to overcome that repulsion and bind the nucleus together.

With this model, even radioactivity becomes understandable. Radioactive atoms typically release one of two types of radiation, designated alpha and beta radiation. Alpha particles turn out to be helium nuclei: two protons and two neutrons. Beta particles turn out to be electrons generated as a byproduct when a neutron changes into a proton. So, when an alpha particle is emitted, an atom drops two places on the periodic table, and when a beta particle is emitted, an atom goes up one place on the periodic table. (So, technically, lead could turn into gold if it emitted two alpha particles and a beta particle, but this is extremely unlikely.)

At the experimental level, this was all worked out by chemists as much as anybody else. It was they who separated out pure samples of various radioactive elements, then, after watching the radiation detectors ping for a while, used chemical reactions to separate out and identify new elements produced by radioactive decay. For example, after separating out samples of uranium, chemists ran them through a chemical reaction which precipitates out thorium but leaves uranium in solution, and discovered that the precipitate was radioactive, indicating that some of the uranium decayed into thorium.

After cataloging the nuclear reactions that occur with high enough probabilities for us to observe them in a single lifetime, scientists began firing neutrons (which aren't repelled by positive charge) at normally stable atomic nuclei. This often resulted in atoms emitting alpha or beta particles, or absorbing a neutron to become a new (possibly less stable) isotope. Enrico Fermi soon discovered that firing neutrons at uranium produced some interesting results. For example, one nuclear reaction involved an atom of uranium absorbing a neutron and emitting two beta particles. The resulting element behaved very much like osmium, so Fermi concluded that it belonged in the same column of the periodic table as osmium, but in the same row as uranium: element number 94, now known as plutonium. For this discovery and related work, Fermi was awarded the Nobel Prize in 1938.

Within a year, Otto Hahn and Lise Meitner proved him wrong!

Their discovery began, like so many others, with a puzzling observation. Hahn, a skilled chemist, had determined that either barium or radium had been produced from a sample of uranium bombarded with neutrons. He concluded that this must be radium, which is in the same row as uranium, and proposed that it was created by the absorption of a neutron and the emission of two alpha particles. However, the intermediate, thorium, had not been observed, and neither had the alpha particles. Even worse, he had been firing very slow neutrons, which should not have been able to give enough energy to knock out two alpha particles.

Lise Meitner, a physicist and long-time colaborator of Hahn, realized that the proposed nuclear reactions were highly implausible, and asked Hahn to perform some control experiments. Hahn proceeded to carry out the even more difficult chemisty to separate barium and radium. The result: the mystery element was barium, not radium! Producing barium from uranium by a chain of radioactive decays is about a million times as preposterous as producing radium, and you can tell that Hahn knows it in his paper. ("... which we publish rather hesitantly due to their peculiar results." "... drastic step which goes against all previous experience in nuclear physics.")

Lise Meitner and her nephew Otto Frisch came to the rescue with an explanation. As the number of protons in a nucleus grows, so too does the amount of repulsion that must be overcome by the strong nuclear force. The nucleus also becomes larger, meaning that the strong nuclear force, which weakens rapidly with distance, has less of an effect. The result is that very large atoms, such as uranium, are inherently unstable. With a little nudge from a stray neutron, the nucleus of a uranium atom can be distorted slightly from its normal spherical arrangement, which weakens the effect of the strong nuclear force enough to allow the distortion to grow, and the whole reaction accelerates to the point where the nucleus of the atom splits in two.

These results suddenly caused a reinterpretation of much previous work, including Fermi's. Plutonium can, in fact, be produced from uranium by a chain of decays, but what Fermi detected was actually the splitting of uranium to produce osmium. Hahn alone was awarded the 1944 Nobel Prize for chemistry, in a decision that was much contested. Fermi went on to help produce the world's first nuclear reactor and atomic bomb.