Biochemist Sylvy Kornberg performed important research in the quest to understand how DNA gets copied (a process that’s required before each cell splitting so that each cell gets a complete genetic instruction manual). She’s often mentioned in passing as a mother and wife (mother to Nobel laureate Roger Kornberg and wife of Nobel laureate Arthur Kornberg) – but there was so much more to this amazing woman’s life. The fact that she didn’t have a Wikipedia page sent the bumbling biochemist into a rage, so she began a research and editing rampage! 

Although this post might include some Korn-y puns, Sylvy Kornberg deserves some serious recognition. So I hope you’ll take a minute to read more about her – and the other countless under-appreciated scientists around the world throughout history who, although “in the background” and/or overshadowed, are no less vital to the generation and sharing of scientific knowledge. So, in today’s post I want to give thanks and recognition to Sylvy and her research (which I will tell you about) as well as to reflect more generally on how science is told and remembered – and how you can help keep stories from being forgotten (ANYONE can create/edit/expand Wikipedia articles).

One of the first things you’ll find when trying to find out more information about someone related to famous people is that it’s hard to find information about this “less famous” family member because people just want to tell you about the more famous relatives. And don’t get me wrong, I think that Roger Kornberg, with his work on RNA polymerase & transcription and Arthur Kornberg, with his work on DNA polymerase and replication (work to which he credits Sylvy with helping him greatly on) deserve recognition. They contributed greatly to biochemistry and they did and found really amazing stuff!

In fact, it wasn’t until I was reading about some of that amazing stuff in that “For the Love of Enzymes” book by Arthur Kornberg that @iubmb president-elect Alexandra Newton gave me, soaking up all the amazing experiments and discoveries on the path to understanding DNA copying (replication), that I even learned that Arthur had a biochemist wife whom he worked with – I sadly had never heard of the name “Sylvy Kornberg” – if I heard “Kornberg” I might ask “Arthur or Roger?” but not “Arthur or Roger or Sylvy?”

And it turns out I was far from alone. In 2017, the magazine “The Scientist” was trying to ID an “unidentified woman” in a picture with another scientist that appeared in an article about cancer research (she was actually described in the caption as a “pharmacy technician”), so they put out a call for help through social media – and got a response from another of Sylvy’s sons, Kenneth (who bucked the family trend and became an architect – but one who designs lab spaces…) saying, basically, “hey, that’s my mom!”

The Scientist wrote a follow-up article about Sylvy (which helped me learn more) but she still didn’t have a Wikipedia page, so I decided to change that. Here’s a brief snippet of what you’ll find there about her life (and I encourage you to check out the full Wikipedia page for more – and go ahead and contribute while you’re there!). And after a quick bio I will describe some of her key research contributions, which involve discovering and characterizing a protein that was inhibiting the replication of DNA they were trying to study and one that was making long chains of phosphate (polyphosphate, or PolyP). 

Sylvy was born Sylvia Ruth Levy in Rochester, New York in 1917, the eldest of 3 children. Her parents were Jewish refugees from Latvia and Belarus who worked in factories their whole lives and didn’t have the opportunity to pursue a secondary education. Sylvy did have an opportunity, and she took it, enrolling at the University of Rochester where, ironically, she listed “chemistry and general science” as her least favorite subjects. She’d quickly change her tune, falling in love with biochemistry to the point where she was one of the few female students to commute to the mens’ college to take advanced biology and chemistry courses. She went on to earn a master’s degree in biochemistry (also from the University of Rochester). 

During this time, she met her future husband, Arthur Kornberg (he was a medical student there), but they didn’t really get to know each other until they met again in Bethesda, Maryland where Sylvy had taken a research position at the National Cancer Institutes and Arthur the National Institutes of Health. They got married in 1943 and between 1947 & 1950, they had 3 sons: Roger, Thomas, and Kenneth. Sylvy took time off from the lab during this time, but she continued to edit science books from home. She then returned to the lab when Kenneth was 3. 

When they moved to St. Louis, Missouri so that Arthur could take a position as chair of the microbiology department, Sylvy was right there with him in the lab. And she was there too when they relocated to Stanford University in 1959. After a couple years at Stanford, she retired – but continued to review and edit manuscripts from home – and then went back for a couple years to study the anti-cancer drug bleomycin’s effects on DNA replication. But her work and life were soon and tragically taken over by a rare neurodegenerative disease related to ALS, and she died in 1986, at the age of 69.

Much of Sylvy’s most significant work was carried out during their time at Washington University. They were trying to find out what enzymes (biological reaction speeder-uppers) were responsible for copying DNA. DNA is the biochemical language our genetic information is stored in. It’s made up of 4 nucleotide letters – A, T, C, & G, which have a generic sugar-phosphate part that allows them to link together to form chains (this linking is called DNA polymerization) as well as unique nitrogenous base parts (often just called “bases”) that stick off from the generic backbone. These bases are kinda like puzzle pieces that fit one (but only one) of the other bases sticking off from other strands – A pairs with T, and C matches up to G. So double-stranded DNA (its normal state in our cells) can be “unzipped” and each single strand used as a template to copy the second strand. And in this way, cells can replicate their DNA before they split in 2 (which they need to do to make more cells to make more you!)

Processes like these get help from reaction speeder-uppers (catalysts) called enzymes. Enzymes are often proteins, sometimes protein-RNA combos, or just RNA alone. They mediate biochemical reactions by doing things like bringing together reactant molecules in an optimal environment and holding them still (and in the right orientation) long enough to react. Because each reaction is different – there are differently-shaped molecules to hold & different conditions those molecules like – different enzymes are required to carry out different steps. more here: http://bit.ly/2r7x40l 

The Kornbergs and their colleagues were trying to figure out what enzymes were required for DNA copying (which was made especially difficult since they didn’t even know what the steps were!) Their basic strategy was a biochemical “process of elimination” – starting with a whole cell extract (the stuff that comes spilling out of cells when you break them open (lyse them) & taking away proteins until the mix was unable to copy DNA (which they could measure by adding radioactively-labelled letters and seeing how much of it got added into chains).

It wasn’t like they had a list of proteins they could selectively “erase” – they didn’t even know what proteins were in there – instead they used a technique of selective precipitation. Different proteins (because they have different combos of protein letters (amino acids) which themselves have different properties) react differently to different concentrations of salt. Increase the salt enough and proteins will “crash out” – the salt gets them to come out of solution as a clumpy “precipitate” – but the amount of salt a protein can withstand will differ from protein to protein. more here: http://bit.ly/2PEpwgf 

So what they did was add a bit of salt (usually ammonium sulfate) – see if the mix still had DNA copying power – if yes, add a bit more – test again – and keep doing this over and over until the DNA copying power was lost – and then they’d redissolve the precipitated stuff and see if they could find what was in there that the DNA copying needed. 

They were having some difficulties because they were being enzymatically “tricked” – even when they had all the necessary ingredients for DNA copying, copying wasn’t happening – because they had an “extra ingredient” – a “contaminating” enzyme was acting as an inhibitor by chewing up one of the DNA letters (the G) in a “weird way” – chopping off the “energy money” part, the triphosphate, and Sylvy discovered and characterized the culprit contaminant.

“Phosphate” is the chemical “nickname” for a phosphorus atom (P) surrounded by 4 oxygen atoms (Os) -> so, “PO4” and, depending on whether those Os are also linked to other things, the phopshate will have various negative charges (ranging from -3 to -1). Like charges don’t like to be next to each other, so when you put phosphates next to each other, they’ll repel, so in order to keep them linked up, phosphate-phosphate bonds have a role akin to clamping a spring together. And when they “give up” – that is, when these bonds are broken, energy is released because that clamping energy is no longer needed. And, when carefully captured, this energy can be used to do things like offset the energy cost of linking together DNA letters. So phosphate-phosphate bonds can be considered a form of “energy storage” more here: http://bit.ly/2WiPOpg 

When they’re just floating around the cell waiting to be added, DNA letters usually exist in a high-energy  “triphosphate” state – the sugar-base combo is called a nucleoside, so we call these nucleoside triphosphates (NTPs). When they link up, they kick off 2 of those phosphates (this PPi molecule is called pyrophosphate – and if you’re wondering about that little “i” it stands for “inorganic” because these free-floating phosphates aren’t attached to a carbon-containing thing) to give you a phosphodiester linkage in which there’s a single phosphate between the 2 sugars of the 2 letters. So,

DNA chain + NTP -> 1 letter longer DNA chain + PPi)

But, in their experiments with the polymerase, they were consistently finding in their reactions free “tripolyphosphate” – which was weird – because they’d only expect to see these 3-in-a-row phosphates if they were attached to a nucleoside. The kicked off stuff should be that pyrophosphate (PPi) and the further breakdown products of that PPi, orthophosphate (Pi). 

What could be the source of this PPPi? Sylvy set her sights on answering this plight! In a 1957 paper she’s first author on, she characterizes this enzyme, which catalyzes the reaction:

deoxyguanosine triphosphate (dGTP) -> deoxyguanosine + tripolyphosphate 

By figuring out what was going on that was keeping the polymerization reaction from going on, she helped the team get over a roadblock on the path to replication results. As Robert Lehman, who was a postdoc in the lab at the time and is now a professor emeritus at Stanford, puts it “We were having a major problem with inhibitors of the replication reaction, and she solved the problem.” And, In For the Love of Enzymes, which Arthur dedicated, “in memory of Sylvy, my great discovery,” Arthur writes that Sylvy “contributed significantly to the science surrounding the discovery of DNA polymerase.” 

Sylvy also worked on an enzyme that makes other “weird” phosphate products – long chains of phosphates called polyphosphate, or “PolyP.” Through that selective precipitation technique she was able to isolate and characterize an enzyme that can take ATP and add one of its phosphates (its end one) onto a long chain of phosphates (not nucleoside phosphates – just the phosphates) (weird, right?!)

so, ATP + phosphate chain -> ADP + one longer phosphate chain

It turns out a lot of microorganisms make PolyP chains hundreds of phosphates long, and scientists are still trying to figure out exactly why – it probably has multiple functions including helping to regulate gene expression, storing metal cations like iron (Fe2+) (PolyP’s negativity makes it well-suited for this), and acting as an energy source (lots of high-energy bonds). Humans use polyP too, but not such long ones – instead, we have shorter, 60-100 phosphate-long chains that are stored in our blood platelets and released to help out with blood clotting. 

Her discovery of polyphosphate kinase was only the second type of enzymatic polymerization (molecule-link-upping) ever discovered. And I’m so glad I “discovered” her story – and I really want more people to be able to discover and share such stories of overshadowed scientists – so I encourage you to get involved with Wikipedia editing. ANYONE can edit Wikipedia. I got inspired by Dr. Jess Wade, who’s published almost 300 articles on female scientists in a year! 👉 https://bit.ly/2Lh8X8B

I saw her work on Twitter & got inspired so, last March, I started creating, expanding, & improving Wikipedia articles on #womeninscience and other things. And you, yes YOU can help! You don’t have to create whole new articles (though you certainly can!). Many deserving scientists have articles that are just “stubs” (few sentences) or way too short for what they deserve. Others have articles that are OK, but need copy editing. Every bit helps!

This post is part of my weekly “broadcasts from the bench” for The International Union of Biochemistry and Molecular Biology (@theIUBMB). Be sure to follow the IUBMB if you’re interested in biochemistry! They’re a really great international organization for biochemistry.

more on topics mentioned (& others) #365DaysOfScience All (with topics listed) 👉 http://bit.ly/2OllAB0

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