As I sit here in a lecture by RNA legend, Victor Ambros, and his fascination with lin-41/lin-4, I thought this might be a fitting time to launch our new series on the wonders of the RNA World. As you may recall, The Brain Institute of America (The BIoA) wanted to memorialize Dr. Thomas A. Steitz in the only way it knew how to, and that was to discuss the amazing power of RNA, and how novel discoveries in RNA biochemistry continually leads to new breakthroughs in the biomedical field.
Before we talk briefly about our RNA hit list, number 10 of which is CRISPR-Cas9 because CRISPR-Cas9 is getting a little old in my opinion, let us stop! And let us remember Dr. Thomas Steitz for all of his great work on the ribosome! It surprises me to this day that many think the ribosome is solely a bunch of proteins that make other types of proteins for animal cells to function. Yet if you think about it. How could that be? How could protein make more protein directly from DNA or itself? In fact I think this concept of protein accumulation is the basis for Alzheimers disease, so that is not a normal cellular function… No my friends the ribosome is really just a beast of an RNA enzyme, (kinda like Henry Philip “Hank” McCoy from the X-men series). While the ribosome certainly isn’t blue, it definitely is responsible for generating all of your proteins in your body that make up your skin, your hair, and your toes (just to name of few parts). That’s pretty beast.
Anyway’s, the discovery of ribosomal RNA (rRNA), and noting rRNAs ability to fold to form secondary structures revealed that the catalytic core of the ribosome was RNA.
But wait, how can an RNA have catalytic activity? Well simply an enzyme is just something that takes compound A and coverts it to product B. So in this regard the ribosome operates just like a protein enzyme.
Substrate(s) + Enzyme = Product
A + Enz = B
In more detail —>
amino acid(s) + ribosome = protein chain
(substrate) + (enzyme) = (product)
So how did Dr. Steitz and others determine the core structure of the ribosome is really RNA. Well, it’s all about the structure! Dr. Steitz had in general, and at least I believe a special gift. There are just certain scientists that are born with a particular form of genius. Structural biology is a tough field. You grow compounds in a solution and form the solution into crystals (like those kits where you have your kids grow quartz crystals in the dark). Then scientists use some fancy instrumentation to determine the shapes of the substrates within those crystals. Now if finding the structure of the ribosome solution wasn’t a tough enough challenge, Dr. Steitz’s team went on to solve the structure of glutaminyl-tRNA synthetase, as well as the initial structures of HIV reverse transcriptase (just to name a few).
Dr. Steitz was truly a structure biologist superstar!
And why does this matter? Well if I know the structure of an entity, I can then go a step further and see what binds to it, what regulates it, and what I most care about, how to detect it or drug it.
Now before I go into more details on this (see part 2 in our next blog series). I have to stop, because I read a fascinating story regarding Dr. Steitz’s time at Cambridge, prior to all that Yale discovery stuff. This youngDr. Steitz got a project from his mentor Dr. Brian Hartley. “Go… and study the structure of hexokinase” (the enzyme that phosphorylates hexoses or 6 carbon sugars present in DNA/RNA). Yikes! How to do that?
Well Dr. Steitz proposed in a grant application to the NIH that he would use a certain instrument called an x-ray diffractometer to solve the structure of hexokinase. Of course his NIH application was denied because the NIH experts said this particular device would never work for the intended application. But what does the NIH know, right?
The BIoA just posted on Instagram that Raymond Damadian developed an MRI from NMR technology… So why couldn’t Dr. Steitz tweak current technology to solve a new series of complex structures?
So when the NIH told Dr. Steitz this approach wouldn’t work, did he listen… Not so much. Years later in an interview session, Dr. Steitz revealed that despite criticism from the experts he had already went ahead and used a diffractometer to solve the structure of hexokinase.
And I think that anecdote sums up the type of individual Dr. Steitz was. So I will end part 1 of this blog series on the following theme. Sometimes we forget as scientist’s that to make great breakthroughs we just need to move forward and not listen to others. Dr. Steitz made great discoveries because he knew both himself and/or his group had the skills to answer certain questions, and I believe he just went with his gut on developing approaches to answer scientific questions. And that’s why the BIoA loves Dr. Steitz.
Dr. Steitz is probably one of the most humblest scientists that made so many amazing discoveries in the RNA world, and because of this path of illumination, his legacy will be best honored by all of us academic folk only through our ability to do great science, by working together as an effective team, and to remember that humble perseverance will always pay off in the end.
So here’s to you Dr. Steitz. Let us now continue the RNA journey and drill down a bit more regarding ribosome biology.
Up next – Part 2, the Ribosome