Arthur Kornberg

Notes on a great biochemist.

One thing that has made America great is our biomedical research establishment. Over the second half of the 20th century, the US created a uniquely effective set of funding institutions, and grew a large cadre of scientists who have led the world in the adventure of figuring out what makes us tick. Biology, at the molecular level, is an alien technology, based on chemistry, yes, but otherwise utterly unlike to any technology we have developed or been previously familiar with. It has taken decades to get to our current incomplete level of knowledge, and it will take decades more to unravel such complex processes as the detailed genetics of early development, or of schizophrenia, or the nature of consciousness.

Yes, it has led to biotechnology and growing prospects for improved medicine. But the historical significance of this epoch lies in the knowledge gained, of finding and exploring a vast and ancient new world. One of the leading scientists of the early days of enzymology and molecular biology was Arthur Kornberg, whom I learned from through his textbook on DNA replication. It was a model of clarity and focus, filled with apt illustrations. It was the rare textbook that didn't try to cover everything, and thus could treat its proper subject with loving care and detail.

The cover depicts a micrograph of replicating viral DNA, the new duplex forming in a loop in the middle, and much of the DNA covered with proteins that help the process along.

Kornberg was the subject of both an autobiography and a biography / hagiography. The latter was written by a fellow scientist, but steers only gingerly into the science, sticking mostly to the story of Kornberg's life, times, and relationships. And what science there is is rather biased. For example, several years after the Watson-Crick model of DNA came out, Kornberg's lab developed a compositional assay for their short snippets of replicated DNA made in the test tube, and deduced that replication was anti-parallel. That is, one DNA strand of the duplex runs in one direction, chemically speaking, while the other strand runs in the opposite direction. This is portrayed as a discovery, for which Crick was very grateful in correspondence. But the Watson-Crick model had already posited the anti-parallel nature of DNA as an intrinsic property, and the model had been richly supported by that point, so Kornberg's work was at best confirmatory. Crick was just being polite.

An interesting side-light is that this epoch in biochemistry and molecular biology was substantially enabled by the scientific and technological breakthroughs of the Manhattan project and nuclear physics. It was isotopes like phosphorous-32 and sulphur-35 that allowed far more sensitive assays for nucleic acids than ever before, allowing tiny amounts of enzyme to be tracked down. DNA sequencing began with ladders of size-selected nucleic acids digested chemically from longer molecules and visualized by X-ray film thanks to radioactive P-32 enzymatically attached to the ends.

Early days, Arthur (right) and his wife Sylvie, who played a central, though unheralded, role in his laboratory and work.

One irony of the story is that Kornberg was so stuck in his system that he was resistant to the new fields it gave birth to, i.e. molecular biology. In his prime, he ran a factory of a lab, indeed a whole department, (first at Washington University, St Louis, then at Stanford), devoted to finding and characterizing the enzymes of nucleic acid synthesis and particularly DNA replication. These groups purified enzymes on a massive scale from E. coli cells, which were broken open, filtered, and then passed over various charge-selective and size-selective media, in extensive multi-step protocols to come out at the end with more or less pure single proteins or complexes of proteins. Some of these enzymes turned out to be extremely useful in biotechnology, for the cutting, copying, ligating, repairing of DNA, etc. As time went on, scientists realized that enzymology, while an important part of understanding how things work in cells, is usefully supplemented by the many methods of genetics and cell biology, which resulted in a hybrid field called molecular biology.

For example, Kornberg's Nobel prize was won, and name was made, on DNA polymerase I from E. coli. This enzyme replicates DNA, but not very well. It tends to fall off a lot. Some years later, another lab created a mutant E. coli strain that lacked the gene encoding this enzyme. And lo and behold, the cells were fine. They reproduced and replicated their DNA. It turned out that E. coli encodes five DNA polymerases, of which DNA polymerase I is among the least important- a repair enzyme that finishes gaps and other problems in the duplex, leaving the bulk of replication to other, far more ornate enzyme complexes. It was genetics that provided the critical clues in this story, showing how an integrated and diverse approach to research questions provides more productive answers.

Master of his realm, in later years, with fruit-themed computer.

Kornberg ran a family-style system in his departments. He had drawn most of its members (at Stanford) from among his own post-docs and students. It had communistic, but also authoritarian, elements. Space was shared, reagents were shared, even funding was shared- something unheard of today. At the same time, Kornberg had the last word on everything and was a ferocious micromanager. Researchers who wanted to make a name for themselves and build their own empires had to leave. But Kornberg picked well, and many of his colleagues had very influential careers, especially Paul Berg, a pioneer of recombinant DNA methods. Kornberg's strong dedication to his field and his system- his sense of meaning and purpose- was a precondition of success, communicating itself to all around him and fostering an unquestioned work ethic and community ethic. The Stanford department was legendary in its day, and inspired many other researchers to become enzymologists and use the laborious methods of protein purification to get their hands on the very gears and cogs of life.

• Steve McCarroll on contemporary biochemistry.
• Reformation and enlightenment as coincidences.
• Failure to deal with white collar crime may have led to a white collar criminal in the White House.
• Racism, yes.
• Who could have expected any better?
• The Chicago school, now for banking regulation?
• How much of military spending is waste, even on its own terms?
• Secular stagnation? Hogwash. Response, Wiki page. Response.
• MeToo and Kavanaugh. And perjury.