Editor’s Note: Professor Louis Chow was selected as one of the recipients of Caltech’s 2024 Distinguished Alumni Awards for her pioneering research using electron microscopy to determine genome organization and RNA transcription, which led to the Nobel Prize-winning discovery of split genes and RNA splicing, one of the most important breakthroughs in molecular biology, as well as for research that has opened doors to improved diagnosis and treatment of human papillomaviruses. We reproduce this article to congratulate and to show our respect for her.
You might have heard about the molecular imaging technique cryo-electron microscopy (cryo-EM) because of the 2017 Nobel Prize in Physics. This WiSE Wednesday we’d like to tell you another story involving a Nobel Prize and electron microscopy (though not the cryo kind). In many ways, this story has striking resemblance to a more well-known story of a woman being denied a share of a Nobel Prize for her work. You might know the story of how Rosalind Franklin got the “pictures” of DNA used to solve its structure that earned James Watson and Francis Crick the Nobel Prize. But did you know that Louise Chow took the images that led to her collaborator, Richard Roberts winning the Nobel Prize in Physiology of Medicine in 1993 for the discovery of RNA splicing?
Louise Chow was born in Hunan Province, China and got an undergraduate degree in Agricultural Chemistry from National Taiwan University before moving to the United States to pursue a graduate degree in Chemistry from the California Institute of Technology. Her thesis work involved developing techniques to use electron microscopy to visualize gene organization in bacteria and bacteriophages (you might remember “phages” from last week’s profile of Martha Chase).
After graduating, she took a post-doctoral position at the University of California, San Francisco (UCSF), and then joined Cold Spring Harbor Laboratory (CSHL) in 1975 with her husband and fellow scientist Thomas Broker. It was here at CSHL that she performed the groundbreaking work that undoubtedly was crucial to “Robert’s” discovery of splicing, and for which many people believe she deserved a share of the Nobel Prize.
In order to make a protein, the DNA in genes is first copied into an RNA intermediary called messenger RNA (mRNA). Initially, this RNA contains “extra segments” called introns between the “exons” that actually code for the protein. RNA splicing is the process by which the introns are removed to make mature mRNA that can be translated into functional protein. Chow and Roberts working at CSHL and Phillip Sharp and his team working at MIT independently discovered this process in 1977. Using electron microscopy methods she’d been perfecting for years, Chow set up the experiments and took images that directly showed splicing taking place.
The finding was revolutionary, and an eventual Nobel Prize was almost a given. But whom to award it to? It was agreed that Roberts & Sharp would share pieces, and many people felt that Chow also deserved a share. But, the argument went, if they gave Chow a piece, wouldn’t they have to give Susan Berget, the electron microscopist working with Sharp, a share? And you can’t split a Nobel 4-way, so the men deciding whom to nominate decided to exclude Chow rather than incite controversy over why they chose to award one woman but not the other.
Chow and her husband (and vocal advocate) Thomas Broker left CSHL in 1984, continuing their collaborative work on human papillomaviruses (HPV) at the University of Rochester School of Medicine in 1984 and later (1993) at the University of Alabama at Birmingham (UAB). One of Chow’s major breakthroughs in this HPV research was developing a way to produce large amounts of the virus in the lab and study its replication process in tissue cultures. In addition to her work in the lab, she is an Associate Editor of Virology and a member of an NIH advisory committee that reviews gene therapy protocols. She was elected to the National Academy of Sciences in 2012.
I had the great privilege of hearing Chow talk when she came to CSHL for a meeting honoring the 40th anniversary of the splicing discovery. I can’t give her the Nobel Prize she deserves, but I award her this WiSE Wednesday profile.
A Letter From Professor Chow
Dear Vivien, Lily, Sherry and friends,
Thank you for your email. It was a real surprise to hear from you. I had no knowledge of the cshlwise.org, nor the website story.
I am grateful that you all try to tell the history concerning the discovery of RNA splicing. Since 1977, CSHL never acknowledges our EM contribution, crucial to the discovery.
The story as told by the web posting is largely correct. What is not widely known is that Roberts came to us to propose a collaboration to test his hypothesis to explain the many anomalous biochemical results concerning the adenovirus late RNAs observed by several CSHL research units, including his and our labs. At the time, we had extensive experience in mapping Ad RNAs by EM.
The Roberts hypothesis goes as follows. Adenovirus employs part or the whole of a small abundant Ad virus-encoded RNA, called VA RNA, as a primer to transcribe the Ad late RNAs by elongation. “Priming and elongation” has been observed in flu RNAs and has been proposed by others a mechanism to regulated transcription in high eukaryotes.
We designed the experiments (that were never done before) and conducted the experiments with some of the material supplied by Roberts lab. The EM results immediately revealed that Ad late mRNA were generated by RNA splicing, as well as by utilizing alternative RNA splicing and alternative polyA sites. VA RNA has nothing to do with the genesis of Ad late RNAs. Further extensive experimentations followed to map the RNA leaders. Then history and facts were altered by Roberts in his successful campaign for the Nobel Prize.
By coincidence, I am going back to Caltech next week for my first official event, 51 years after I received my PHD. I was selected by Caltech as one of four recipients of Distinguished Alumni Awards of 2024.
It was a completely surprise; out of the blue I was notified by an email. The Selection Committee cited my EM contribution to the discovery of RNA splicing as well our research on human papillomaviruses in the last 40 some years.
Again, thank you all for contacting me.
Warm Regards,
Louise
Professor Emerita
Biochemistry and Molecular Genetics
University of Alabama at Alabama
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