New Year, same me – but who is me? I’m Bri! At least to people who know me in person where in my day to day life I’m a biochemistry grad student at CSHL… On here I like to go by “the bumbling biochemist” – some of you might be surprised to learn that I’m a natural introvert. I think this is one of the reasons my mind is so strangely creative – I spend a lot of time thinking and entertaining my brain (I think it might stem from a lot of time out time as a kid for being a bit stubbornly explorative (think car-door opening on the freeway, climbing out of grocery carts, etc.…) But anyways, I find that sticking on a lab coat cape and distancing myself a little bit helps me turn on the extroversion and give me the confidence I need to help teach people about biochemistry. 

And that’s what I’m here to do. And I’m so grateful that the International Union of Biochemistry and Molecular Biology (IUBMB) helps give me a platform to do so as their Student Ambassador. So today I want to tell you more about me, the IUBMB president-elect Dr. Alexandra Newton (a biochem prof at UC San Diego) and how we’ve been working together and will continue working together in this new year to share the joy of biochemistry!

Words cannot describe just how much I love biochemistry – and words cannot adequately describe what biochemistry even is – as scientists we can classify “types of science” based on the types of things we study and the methods we use – study living things? We’ll call you a biologist – wait, you’re studying those things at the cellular level? We’ll call you a cell biologist. Oh, *sub-cell* level? Like individual molecules? We’ll call you a molecular biologist. How they work at the mechanistic level? We’ll call you a biochemist. 

And that’s just “biology!” But nature doesn’t have such classifications – everything is interconnected – the same chemical processes that powered dinosaurs power you – and you might even have some of the same exact atoms (basic units of elements like carbon and oxygen) they did. And those atoms can be joined up in different ways to give you sugar or fat or protein – or rocks. Science basically rocks!

Speaking of words – if you follow me (thanks by the way!) you know (and if you’re new to my posts you’ll quickly learn) I tend to take some liberty with word conventions, ditching jargon when possible so that understanding by anyone is possible. 

When I do this, it’s not because I’m trying to dumb down anything – in fact, it’s quite the opposite. Just because you don’t have the vocabulary to follow along with something doesn’t mean you don’t have the capability to understand it. As scientists, we often use vocabulary that makes things easier for us (like formal chemical names that describe what’s in different molecules, making them easy to compare and predict how they’ll react – dihydrogen monoxide – must have 2 hydrogens and an oxygen! Since oxygen is much more electronegative, you have a polar molecule capable of extensive hydrogen bonding.) 

Did you get lost? Basically, “water’s sticky” because oxygen hogs the negatively-charged electrons it shares with the hydrogens, so it’s partly negative, the H’s are partly positive, and partial charges attract. As a result, raindrops are drop-shaped, water climbs up the walls of straws, and insects can walk on water!

In my grad school interviews, one of the questions I was asked a lot was whether my parents are scientists – nope (at least not officially – my mom did lead some pretty rad film canister baking soda/vinegar rocket launches!). And part of my inspiration for starting the bumbling biochemist was to help explain my work to them. Because I think it’s so cool and unfair that I have all this knowledge thanks to being privileged to a great education. So I want to give back and give forward. 

So I was so thrilled when Dr. Alexandra Newton, President Elect of the International Union of Biochemistry and Molecular Biology (IUBMB) asked me to be their first Student Ambassador – it’s one of those crazy serendipity things – I ran into her in the hotel lobby at last year’s ASBMB (American Society of Biochemistry and Molecular Biology) meetings. It was early in my bumbling days and I was still kinda shy about it – I hadn’t really told my PI (lab-head) Dr. Leemor Joshua-Tor) about it because I was afraid she’d disapprove and/or think it a detraction from my research (thankfully since she found out she has been nothing but supportive – and my research is going great (going to get to present at 2 conferences this coming year!!!!!)- which funding from IUBMB so thank you again!)

But anyways, I ran into Dr. Newton in the hotel lobby and she recognized me from social media and came up to me and told me that she really admired what I was doing and that I was doing a great job – it was just a really brief conversation but it was seriously life-changing for me. At first because it validated what I was doing – serious scientists took me seriously despite my seeming silliness! And later because it led to our collaboration. More on that here in an article by CSHL http://bit.ly/2Qn9HtV 

We didn’t have a lot of time to talk then – but since then we’ve gotten to know each other a lot better – and she’s super awesome! So I wanted you all to get to know her better too – so I interviewed her and below you’ll find her answers to my questions – but first, she insisted that I answer some of her questions…

Who are you? 

I’m the bumbling biochemist, aka Bri, aka that weird PhD student you’ll find rocking a lab coat cape in the lab of Dr. Leemor Joshua-Tor at Cold Spring Harbor Laboratory (CSHL) where I’m a student in the WSBS graduate program. 

How and when did you get interested in biochemistry?

Pretty sure it had something to do with that first gasp of oxygen I took… But of course I didn’t have the words to describe it – but, like I mentioned before, just because you don’t have words to describe something doesn’t mean you can’t appreciate and admire it!

In terms of a more formal interest – in undergrad I thought I wanted to become a medical doctor – so I did a summer research project in a biochemistry lab – gotta get those extracurricular experiences to shiny up the resume, right? Little did I know just how much I’d like the research. So much so that I switched to the PhD path and have never regretted it!

What is your favorite amino acid (protein letter)?

Ooh – what a tough question! They’re all so cool for different reasons – and we need them all! (even though some are called non-essential – that just means we need to eat them “pre-made” because our bodies can’t make them from other molecules). But I guess if I *had* to choose it’d be Histidine (His, H). 

Why?

It’s sooooo versatile! Depending on the pH (a measure of acidity) it can be positively-charged or neutral. And that’s because it can give and take protons (which are what pH is a measure of). By doing so it can make other molecules more or less reactive, so it’s often crucial to the activity of enzymes (reaction mediators/speed-uppers). Plus (no pun intended) the positive charge can help it bind negatively-charged things, and it’s electron-rich ring can form cool interactions with other ringed things (like DNA & RNA letters) through “base stacking” and shows up nicely in x-ray crystallography!

Was it love at first sight? If not, how’d it win you over?

At first site it was more like confused admiration – I would seen it drawn with a plus or a minus and didn’t know what was going on! Turns out, His is the only amino acid that is present in both positive and negative forms at normal body pH (without help).

What’s your favorite thing about life in the lab?

I love the variety of things you get to do and the freedom to explore the things that interest you – it’s an extreme privilege that I try not to take for granted!

What’s your least favorite thing about life in the lab?

THE COLD ROOM!!!!!!!!

What’s the experiment you are most proud of?

I can’t tell you the details of the experiment I’m really most proud of – yet! – because it’s a work in progress that’s not at the progressed-enough point for publicly pronouncing… But in undergrad I made a homology model of a protein I was studying – basically I took the x-ray crystallography – determined structure of one protein (a peptide-cutter called neurolysin) and used it to model the structure of the rat version of that protein – and I made (what I thought was) a pretty figure of it – and then I printed it out as a giant poster that my mom has hanging up in my room at her house!

How do you explain what you do to your family?

I write posts that they at least read the first few sentences of – and look at the pictures – still hoping some day they’ll read on… 

But if they want the gist – I study a process by which our bodies (and those of all sorts of critters) regulate what proteins get made when through a process called RNA interference (RNAi). Basically, if your cell wants to make a protein it first has to make RNA copies of the DNA recipes, and RNAi is a way to use short pieces of RNA to direct a silencing-complex to destroy specific recipe copies to prevent their corresponding proteins from being made. 

What do you want to be when you grow up?

I would *love* to be a professor at a small primarily-undergraduate college. I feel like undergrads are a really under-appreciated and under-serviced group. A lot of science information is either written in super technical talk for “experts” or super vague talk for the “general public” – and I found this to be a big problem in undergrad, which was part of my inspiration for going bumbly. And it always warms my heart to get feedback from undergrads that they find my posts helpful! I would love to be able to teach undergrads in person in the classroom and hands-on in the lab – walking them through their first gels, their first protein purifications….

What do you like to do outside the lab?

I’m a big fan of puzzles – both of the jigsaw and crossword varieties. And random crafting. I also enjoy hiking.

What advice do you have to:

general public– chemicals are cool! just because something has a chemical name doesn’t mean it’s bad. Dihydrogen monoxide is just water (so never believe marketers who tell you their product is chemical free!). Yes, some chemicals can be harmful, but that doesn’t mean all of them are bad. Instead of using chemophobia to sell products, I dream that someday, chemistry education will be more valued…

under undergrad students – don’t play dumb. being geeky is awesome and passion can get you far – it’s cool to love school!

undergrad students – don’t be afraid to ask questions in class (or office hours)

Grad students – don’t be afraid to ask questions in seminar or at poster sessions, etc.

Now it’s *my* turn to ask the questions! Let’s turn the mic and talk to Dr. Newton – about herself, her favorite amino acid, Serine, and the protein she studies, PKC. 

Who are you? 

I’m a professor at the University of California, San Diego, who is passionate about biochemistry and honored to be the President Elect of the IUBMB.

What is PKC – what does it do and how does it do it? 

PKC (protein kinase C) is an enzyme that relays information received at the cell surface  throughout the cell.  It is normally ‘off’, but when certain signals (e.g. hormones, neurotransmitters) cause levels of Ca2+ and a lipid called diacylglycerol to increase,  PKC is turned  “on”.  When it is “on”,  it catalyzes the covalent addition of phosphate (from ATP) to the -OH group of serine.  This changes the function of the protein.  

Why does PKC love serine?

It loves Serine for a really elegant reason: it has a Met (large, hydrophobic residue) in its active site that precludes binding of its larger cousin, Thr, which simply wouldn’t fit as well.  Kinases that phosphorylate Thr have b-branched aliphatic residues like Val or Ile at this position.  In kinase jargon, this residue (which is a switch to determine whether petite Ser or bigger Thr is phosphorylated) is called the “DFG+1” site because it is  the residue right after a highly conserved Asp-Phe-Gly motif important for kinase integrity.  

Why – other than its relationship to PKC – do you love serine?

Serine packs a lot of functionality into a relatively small size. And by accepting phosphate, it can completely alter the function of a protein – turn it on or off, relocate it to a different part of the cell, target it for degradation, and much more.  My left earring has the sequence Phe-Ser-Phe, a key phosphorylation site we identified on PKC (and left is Leu-Thr-Pro, another key phosphorylation site). What is there not to love about Serine?

When did you first meet PKC? Was it love at first sight? If not, how’d it win you over?

My first encounter with PKC was not so good: we met in a cold, gloomy room on the 5th floor of Barker Hall at UC Berkeley – the cold room belonging to the lab of renowned biochemist Dan Koshland, my postdoctoral advisor – and PKC, I was told, was in the brains of the 80 rats in front of us.  I was told it was our job to purify it. (untagged, and not abundant, this meant 5 days in the cold room, which we can see from above is also the Bumbling Biochemist’s least favorite place to hang out in the lab).

[bumbling biochemist interjection: I’m shivering just thinking about it!)

BUT my second encounter was a dream. I got to measure the activity of the PKC we had just purified.  I was hooked – this invisible protein was able to take Mg2+ and 32P-ATP and, in a highly-controlled manner that depended also on the addition of Ca2+ and lipid, add phosphates one at a time on to Ser residues of the substrate histone, obeying text-book perfect Michaelis Menten kinetics.  Every time I assayed it, day/night/whenever it had the exact same specific activity of about 5 reactions per second per molecule of PKC!!!!!  And I could withhold Ca2+ and lipid and it would ignore me, and not phosphorylate anything, or I could give it Ca2+ and lipid and it would phosphorylate away.  How can you not love that?  And I could titrate increasing lipid and get these beautiful sigmoidal activation curves because its binding of lipid is higher cooperative.  

What’s your favorite thing about PKC?

How incredibly complex and elegant its regulation is.  There are an abundance of mechanisms that tune its activity to be ‘just right’ in the cell.  And if something goes wrong and there is too much activity, we have found that drives degenerative diseases like Alzheimer’s Disease.  And if there is not enough activity, that is associated with survival diseases like cancer.  

What’s your least favorite thing about PKC?

It’s a bit sensitive to not being treated well….

[bumbling biochemist interjection: can you really blame it?]

What’s the PKC discovery that you’re most proud of?

The most thrilling one was listening to a sequence being read out loud to me over the phone and not being able to hold back my excitement.  We had used proteases as molecular scissors to assay conformational changes of PKC.  We knew that when PKC was active (Ca2+ and lipid bound), the protease Arg-C (molecular scissors that cleave on the C-terminal side of Arg) would cut a piece off one end of PKC.  We did N-terminal peptide sequencing to see where the cut was and the sequence being read off the phone by the peptide sequencing lab was F-A-R-K-G-A-L…..well, that happens to be the beginning of pseudo substrate segment, a stretch of amino acid that had been proposed to bind the active site to keep the enzyme ‘off’.  We showed that when Ca2+ and lipid bind, this segment moves away from the kinase core and PKC is now ‘on’ and can bind substrates and phosphorylate them.  I have a necklace with that sequence.

[bumbling biochemist interjection: you can see it in the pics!]

What’s one of the favorite papers you’ve had published? I kind of like our recent Mol Cell – the cover shows PKC as an armadillo grabbing on to the tennis ball which represents phosphate at the Phe-Ser-Phe motif on my earring.  I like the paper because it uses biochemistry to unveil a mechanism that is disease relevant.

http://newtonlab.ucsd.edu/documents/Baffi%20et%20al.%202019.pdf

What’s the one thing you most still want to know about PKC?

What it looks like 🙂

What are you up to now?

We are using our three decade knowledge base of PKC to figure out how to bring its levels down to normal in disease.

What do you like to do outside the lab?

I’m mom to a professional ballerina – last weekend I caught 6 Nutcracker performances of hers; and my son is an engineering student at Berkeley (not far from where I met PKC), so we have lots of nerdy conversations together.  I have many interests – including taking ballet, reading novels in French, photography, classical music, and crazy fun traveling adventures around the world with my family.

What advice do you have to…

general public? Understanding how proteins work is essential to cure disease

under undergrad students? Follow your passion

undergrad students? Follow your passion

grad students? Follow your passion

overgrad scientists? Follow your passion

[bumbling biochemist interjection: I think I’m sensing a trend here….]

How did you become involved in IUBMB? What do you love about it? What do you hope to see from it in the future?

I’ve been very involved with ASBMB all my career, and at one meeting I was asked to represent ASBMB at an IUBMB Congress in Brazil.  I started doing more for IUBMB and was happy to be nominated to be President Elect not only because I am passionate about biochemistry and training the next generation, but also because I have a fairly international upbringing and speak four languages.  I love how the IUBMB unites biochemists from 79 countries all over the world and provides training and fellowship opportunities, funds meetings, runs journals, and much more.  I hope the future will bring more and more education and research opportunities to students in under developed countries.  I also really enjoy working with a certain Bumbling Biochemist to leverage social media to engage biochemistry students all around the world.

[bumbling biochemist interjection: aww! I really enjoy working with you too! and am sooo glad we met and grateful that you’ve given me the opportunity to work with you and a platform to help share the joy of biochemistry with the world!]

That’s it for this special edition of my Bri*fing’s from the Bench! Be sure to follow along for a weekly does of biochemistry fun!

more on kinases: http://bit.ly/2lOgXSN 

more on enzymes & that Michaelis-Menten stuff Dr. Newton was talking about: http://bit.ly/2NCNYeU 

more on all sorts of stuff on my blog www.thebumblingbiochemist.com 

more on topics mentioned (& others) #366DaysOfScience All (with topics listed) 👉 http://bit.ly/2OllAB0

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