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Manufacturing Proteins Isn't Easy
CHAPTER 62 Shedding, Splicing and Sterilizing
This past week the remnants of Hurricane Patricia passed through New Jersey, providing us with a small amount of needed rain and relatively mild gusts of wind. Quite a contrast to three years ago the same week when we were hit by Hurricane Sandy and my wife and I spent 11 days in our editor Brian Trumbore's apartment awaiting power to be restored to our home. Can I hope that our weather in November and the coming winter is as benign as our weather has been this summer and fall? One thing I will miss during the winter months is our farmers market on Sundays. "Farmers market" is a broad term inasmuch as we also can buy freshly caught fish from New Jersey waters.
Swordfish is my favorite fish but, in view of all the warnings about swordfish being loaded with mercury compared to other aquatic species, I balance my mercury consumption by purchasing cod or flounder most of the time. Given my concern about mercury, I was intrigued by a news item in the September 21 issue of Chemical and Engineering News (C&EN) about molting elephant seals. The Donald would no doubt say, "Those animals are HUGE!" The article states they can range up to 14 feet in length and weigh 5,000 pounds!
What does this have to do with mercury and fish? Well, it seems that thousands of these elephant seals make a pilgrimage to Ano Nuevo State Park on the California coast near Santa Cruz. Researchers found that the concentration of methyl mercury in the ocean waters in the vicinity spikes after the hordes of elephant seals arrive. While there, the seals molt, shedding copious amounts of skin and hair. It turns out that these huge animals are top of the food chain predators and as such build up mercury, which increases in concentration as you go from the bottom to the top of the animal food chain.
In contrast to huge animals, I was taken by an item concerning microorganisms by Lacy Schley in the October issue of Discover magazine. We're all familiar with accounts of experiments involving the culturing of microorganisms in Petri dishes. These cells are commonly grown in what is known as agar growth media. Agar is a jelly-like substance obtained from algae. According to the article, the standard way to make agar growth media is to mix agar with a phosphate solution and sterilize the mixture by heating it to a high temperature. This has been the procedure for 120 years. Although it's a nourishing solution for the little critters, typically only 0.1 to ten percent of the microorganisms survive in the agar growth media. Why do such a small number of cells survive if the agar is such a good nutrient?
Enter Yoichi Kamagata and his group at Hokkaido University in Japan. They realized that mixing the agar and the phosphate solution and then heating it to a high temperature generates hydrogen peroxide. Hey, I just bought a bottle of hydrogen peroxide to apply to my wound following a visit to my dermatologist. I presume that I'm applying the peroxide to kill bacteria or other bad stuff. Well, Kamagata and company must have thought the same thing. They heated the agar and the phosphate solution separately and then mixed them to form the growth medium. No hydrogen peroxide and, sure enough, ten times as many cells survived. I love the fact that in over a century of using this growth medium nobody thought to do this simple chemistry experiment. Good job, Kamagata!
Well, having discussed a couple of items that I believe I understand, let's turn to another topic related to microscopic stuff that thoroughly befuddles me. As I've said on a number of occasions previously, I often write about complex subjects in the hope of convincing myself that I understand them. Typically, that hope is totally misplaced. So, here I go again, trying to understand the "spliceosome", the subject of an article by Sarah Everts titled "Uncovering the Spliceosome's Secrets" in the October 5 issue of C&EN. I was drawn to the article by the opening paragraphs, which noted that the fruit fly buzzing around that ripe banana has some 23 thousand genes, about the same number of genes we humans have in our DNA. How can it be that, with the same number of genes, we are so obviously more complex than the lowly fruit fly? The answer, according to Everts, is the spliceosome.
OK, I admit that I had never heard of a spliceosome, or if I had, I've certainly forgotten all about it. It seems the spliceosome comes into play when a gene produces a protein. Back in the day, my impression of roughly how this happens was that something called a messenger RNA (mRNA) sidles up to a gene in your DNA and copies the A, C, G and T "letters" (actually, chemical bases) in that gene. The mRNA then carries this information to something called a ribosome, which uses the information to manufacture a specific protein. I vaguely recall reading somewhere that a given gene could supply the code for more than one kind of protein, which seemed strange to me. How can a gene with its particular code of ACGT combinations lead to different end product proteins?
Well, after reading about the spliceosome, I'm more comfortable with this possibility. What is a spliceosome? It's sort of like a pruning machine, in that it lands on the mRNA while it's doing its transcribing of the sequence of the ACGT "letters" in the gene. In transcribing this sequence from the gene, there are portions of the sequence that are important (coding) called exons, and parts that are not important (non-coding) called introns. While the mRNA is doing its job transcribing, the spliceosome is snipping out introns and leaving exons. But the spliceosome may not simply remove introns; it may intentionally rearrange the order of the exons, it may leave out an exon or even include an intron. This tinkering with the final sequence carried by the mRNA to the ribosome means that the ribosome will manufacture different proteins depending on how the spliceosome altered the sequence carried by the mRNA. OK, now I can "understand" how one gene can be responsible for manufacturing different proteins.
A given gene probably has more than one intron and a different spliceosome is needed to remove each of the introns. If you're interested in seeing an animation of how the spliceosome works go to the DNA Learning Center Web site (dnalc.org). The animation shows how the spliceosome splices out the intron to form a loop, bringing the ends of the adjacent exons together, thus cutting loose the introns and joining the exons. Again, if I understand correctly, the spliceosomes are formed more or less on the spot and are huge, consisting of many different compounds getting together and then falling apart after the splicing is done. To me, it's totally mind boggling.
I at first assumed that spliceosomes were unique to animals but then I happened upon two articles in my September 11 issue of Science on the structure of spliceosomes in yeast. The papers are by Yigong Shi and coworkers in China. Shi and his colleagues are cited by Everts in her C&EN article as doing outstanding work on the structure of spliceosomes and I believe it. Looking at the pictures of the structures in the Science articles I have absolutely no idea what they mean! I am totally shocked by the size and complexity of a spliceosome. To give some idea as to why I'm shocked I quote from the abstract of one of the papers in Science: concerning the spliceosome "The atomic model includes 10,574 amino acids from 37 proteins and four RNA molecules with a combined molecular mass of 1.3 megadaltons." That's 1.3 million Daltons. I confess that I had to look up what a Dalton is and I find it's essentially the mass of a proton or a hydrogen atom. At any rate, the spliceosome is big, even HUGE!
All in all, what impresses me most about all this is the complexity of the compounds and the processes that go on in those tiny cells in our body. It makes me wonder how long it took evolution to come up with the spliceosome and how such a complex chemistry evolved with it. The older I get, the more I come to think that the complexity of theoretical physics and such things as dark matter and dark energy pales compared to the complexity of what goes on in our bodies and our brains.
Next column, hopefully, on or about December 1.
Allen F. Bortrum