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Nobel Prize 2015: What the chemistry winners taught us about the fragility of human life

The Nobel press conference at the Royal Swedish Academy in Stockholm.
The Nobel press conference at the Royal Swedish Academy in Stockholm.
(Fredrik Sandberg/TT News Agency via AP)

Early this morning we learned that the 2015 Nobel Prize in Chemistry went to Tomas Lindahl of the Francis Crick Institute, Paul Modrich of Duke University, and Aziz Sancar of University of North Carolina Chapel Hill.

They won for a simple reason: Their scientific discoveries revealed the surprising ways in which our DNA is at once extremely fragile and super resilient.

To understand the significance of the Nobel winners' work, let's start with some basics. Every individual's development traces back to that moment when 23 chromosomes from a sperm combine with 23 chromosomes from an egg. These chromosomes are made up of chemical strands called DNA that carry genetic information — they essentially contain recipes for proteins to produce the wide variety of traits that make us who we are, from the texture of our earwax to the color of our eyes and hair.

As late as the 1960s and '70s, these building blocks of life were believed to be exceptionally stable. How else could DNA be passed down from generation to generation? Scientists surmised that human evolution must have selected for sturdy molecules. After all, if our gene molecules were fragile, no complex organism could possibly survive, right?

Around that time, however, Lindahl began to question the conventional wisdom, asking: "How stable is DNA, really?" As a postdoc student at Princeton and later at the Karolinska Institutet in Stockholm, he carried out a series of experiments showing that DNA molecules, when isolated outside of the cell, actually degraded pretty quickly.


A view of the screen showing the winners of the 2015 Nobel Prize for Chemistry, during a press conference in Stockholm. (AP Photo)

Lindahl's research suggested that DNA can actually sustain quite a bit of damage — but somehow manage to thrive and repair itself. "[DNA] turned out to be photosensitive, temperature sensitive, and all-sorts-of-other-stuff sensitive, and that meant that living cells (1) must have mechanisms to repair DNA damage and (2) must spend a substantial amount of time and energy on them," explained chemist Derek Lowe in a fantastic blog post on the awards.

"The genetic information that governs how human beings are shaped has flowed through our bodies for hundreds of thousands of years," the Nobel Prize Committee said. "It is constantly subjected to assaults from the environment, yet it remains surprisingly intact."

The big question, then, was how DNA gets repaired. Lindahl arrived at part of the answer here: He identified a bacterial enzyme that removes damaged cells. Later on, he also discovered a cellular process — called "base excision repair" — that essentially continuously repairs damaged DNA using a similar enzyme.

Lindahl's co-winner, Aziz Sancar, later built on this work, mapping the mechanism that cells use to repair the most common type of assault — UV damage — a technique called "nucleotide excision repair." Basically, our cells can cut out sections of DNA that are damaged by UV light and replace them with new DNA. Meanwhile, Paul Modrich discovered yet another repair mechanism: Cells can correct replication errors through a process called "mismatch repair."

The upshot of these discoveries is that cells are constantly working to repair DNA damage. "Every day, [these processes] fix thousands of occurrences of DNA damage caused by the sun, cigarette smoke or other genotoxic substances; they continuously counteract spontaneous alterations to DNA and, for each cell division, mismatch repair corrects some thousand mismatches," the Nobel Committee described. "Our genome would collapse without these repair mechanisms."

These discoveries were important in themselves: They completely changed how the scientific community understood the fundamentals of cell biology and DNA. But they could also have more practical applications. The findings laid the groundwork for further research on how these repair mechanisms can fail, bringing about diseases, including cancer, metabolic and neurological disorders, and other problems related to aging. Understanding these weaknesses and defects has already helped to give rise to new medicines, according to the Nobel committee, such as olaparib for advanced ovarian cancer.

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