Barbara McClintock’s Contributions to Biology
By Jake Rubens
How a series of classic experiments 70 years ago led to Tessera
We are honored to launch Tessera Therapeutics close to the 118th anniversary of Barbara McClintock’s birth. McClintock’s contributions to genetics, as well as her intellectual tenacity, agility, and rigor, are an inspiration to everyone at Tessera. She is the only woman to have won an unshared Nobel Prize in Physiology or Medicine and was recognized as one of America’s most important scientists in 2005 when the United States Postal Service issued a stamp in her honor, along with the mathematician John von Neumann, physicist Josiah Willard Gibbs, and physicist Richard Feynman.
Twenty years before Watson and Crick described the structure of DNA, McClintock observed for the first time that genes are physically located on chromosomes, launching the field of cytogenetics. Her cytogenetic techniques enabled scientists to observe the arrangement of genes and served as a bridge from Thomas Hunt Morgan’s genetic-linkage maps to the genome sequencing that scientists routinely conduct today.
Through corn breeding and cytogenetics, McClintock made remarkable inferences about the laws of genetics. Early in her career she elucidated the function of telomeres and centromeres and proved the existence of homologous recombination. Later, she proposed two ideas about how the same genotype can produce different phenotypes that today are entire fields unto themselves: genetic regulation and epigenetics.
It’s McClintock’s two seminal contributions to genome engineering that are the most relevant to Tessera’s science. First, in 1932, McClintock observed that dividing cells fuse together chromosomes with double-stranded breaks as the result of an insult, such as irradiation. This same phenomenon underlies today’s gene editing technology: Cells alter DNA at the location of a double-stranded break made by a nuclease, such as CRISPR. However, McClintock knew that a different mode of genetic rearrangement was necessary to explain the non-Mendelian inheritance of certain corn traits.
She hypothesized the existence of programmed non-homologous genetic transposition. Painstakingly, over six years at Cold Spring Harbor Laboratory, McClintock conducted corn breeding experiments that revealed specific genes to be moving to new locations in the genome. She published her discovery of mobile genetic elements (MGEs) in 1950, but it wasn’t until decades later that her research was widely appreciated. Today, we recognize that MGEs are the most abundant and ubiquitous genes in the world. They are found across the entire animal kingdom, and also make up a large percentage of the genomes of archaea, bacteria, and plants. In fact, by most measures MGEs make up about 50% of our own DNA, meaning that 1.5 billion nucleotides of our genome code for mobile elements. To put that in perspective, the protein-coding genes that we think of as the workhorses of life make up only 2–3% of our genome.
McClintock did not understand how MGEs worked when she discovered them, and in retrospect their prevalence is unsurprising. MGEs code for the machinery to move or copy themselves into a new location in the genome, and they have been selected over billions of years for their ability to replicate. Thus, these genes follow different evolutionary rules than whole genomes. The theory of the evolution of individual genes was popularized by Richard Dawkins’s The Selfish Gene (Oxford University Press, 1976), which argued that our genomes are not only unitary evolutionary entities but, like villages, are composed of thousands of inhabitants, each vying for its own survival.
The field of biology continues to elucidate the diversity of MGEs, building upon the first MGE species discovered by McClintock. MGEs replicate through DNA and RNA intermediates. The intermediate can be linear or circular, double- or single-stranded; MGEs can transpose, retrotranspose, and recombine; copy and paste or cut and paste; and integrate specifically into certain DNA sequences, semi-randomly into genomic regions, or randomly into any location in the genome. Perhaps most interestingly, MGEs efficiently alter genomes with minimal reliance upon (indeed, often in spite of) other genes in the cell.
At Tessera Therapeutics, we are creating a new genome engineering technology that we call Gene Writing, based upon engineered and synthetic MGEs. By harnessing evolution’s greatest genomic architect to alter the genome, we hope Gene Writing will enable us to pioneer a new field of genetic medicine and cure severe diseases. As we publicly set out on our mission, we are proud and grateful to be standing on the shoulders of Barbara McClintock, one of science’s tallest giants.