Monday, December 31, 2007

Breakthrough of the Year

I'm ripping off Science Magazine here, but since it's New Years Eve I want to do some sort of wrap up of science in 2007. I just happen to agree with them that this is the most important achievement in science this year, but they got it out first.

Anyway, Science announced their 2007 Breakthrough of the Year in this weeks issue (article written by Elizabeth Pennisi). The winner was sort of a culmination of technological advancements over the past few years coupled to a long-standing goal in the field of human genomics. It is best described as the assessment of human genetic variation.

First, let's take a step back. The sequencing of the human genome several years ago was a major achievement for human medicine, but not necessarily for the reasons that most people think. What the sequence of the human genome actually is has always been a common area of confusion within the public. "What does it actually mean? We always hear that our genes make us who we are. I'm very different from any other human, so it follows that my genes must have some differences, right? So then, how can there be one single sequenced human genome?" Great questions. Let me try and clarify a little, it will help to point out why this was such a major breakthrough.

There are indeed some major genetic differences between all humans. The fact remains though, that when you look across a population (at every human being for example), there is what we call a consensus sequence for the genes in our cells. There are approximately 3,000,000,000 base pairs in every one of our cells. A majority of those bases, however, are exactly the same from person to person. In fact, it is estimated that there are only 15,000,000 base pairs that differ consistently from person to person. If you think about it, that is only 5% of the 3,000,000,000 total bases. So we can sequence a mixture of DNA from several people (this was how it was originally done) and get a very good idea of the concensus sequence of the human genome. Additionally, it is really just a compilation of those 15,000,000 differing base pairs [we call them SNPs (Small Nuclear Polymorphisms)] which make us individuals. If you do the math, that leads to a possible 50,625,000,000,000,000,000,000,000,000 (i.e. 50,625 billion-trillion-trillion) individuals with at least one differing base pair. That is just a number and not very meaningful, but you can see how the magnitude of it makes sense considering there is some 6,000,000,000 people in the world. That means that less than 0.000000000000000012% of the possible combinations of SNPs are being used today (man I hope my numbers are right, I did a lot of rounding and simplified things by ignoring insertions/deletions and other complicating factors).

To be clear, try not to put too much stock into these numbers. I am just using them to illustrate a point which will hopefully become apparent at the end of this paragraph. The 250,625 billion-trillion-trillion number does not actually represent the potential number of individuals, and there are two contrasting reasons for this: 
  1. People probably need a minimum number of distinct SNPs in order to actually appear distinct. I couldn't even guess what this number is, but it would decrease that 50,625 billion-trillion-trillion number by some significant factor.
  2. Our appearance is dependent on the amount of the given gene that is expressed (i.e. the amount of the gene product that is present in our cells), which also has a genetic component to it, but I don't want to drag out here. This complicating factor would increase the number of potential individuals, mitigating to some extent the logic in point 1. 
The main issue here, which I hope to get across, is that we can be, and are, very different from each other while still having mostly identical DNA.  In fact, the most recent study shows that any given individual shares 99.5% of her/his DNA with any other person.

Ok, moving on. Hopefully I have answered the first part of my own hypothetical question. The original human genome sequence was a consensus type of study that generalized most of the sequence features in our genomes. Now, in order to make the human genome useful, we need to be able to sequence the genomes of individuals. And that is exactly what Science (and me too) dubbed the breakthrough of the year. We are finally starting to see some progress in this important area. We are finally able to look at our own DNA sequence, and because we can compare it to other people's sequences, we can learn how the differences affect our appearances (and more importantly our health!). The studies that are geared towards understanding these relationships are called Genome-wide association studies, and there have been more than a dozen of them this year.

The first individual genome sequenced was that of J. Craig Venter, of the institute bearing his name (JCVI).  This is no surprise since he was the person who privately funded one of the two original sequencing projects in the late '90s.  It took about 4 years, and was finally published this fall.  In any case it was a huge accomplishment, and as sequencing technologies become cheaper, better and faster we are going to see this become commonplace.  Already there are companies set up to sequence the genomes of individuals (although we should be wary of these claims until the companies have shown they are reliable), and the more sequences we have from individuals, the more data we have for the Genome-wide association studies, and the more we will know about how our genes affect disease and other traits.  Exciting, no?

From a scientific perspective, this was a fascinating study because it actually showed that we are even more different than we ever expected.  Until the Venter study, it was believed that we shared 99.9% of our DNA with all other humans.  We now estimate it to be closer to 99.5%.  You may think "hell, both are very high numbers so what's the diff?"  Well, it means we were off by a factor of 5 before, so it just goes to show that we have ton of work to do in this field.  I think that we are finally starting to see the results from the human genome project that we were expecting all along.

DS

Wednesday, December 19, 2007

Whale Ancestors

I was going to write something about this Nature paper which fills in some of the questions about the ancestors of whales. However, PZ Meyers beat me to it. It's pretty fascinating, but oh well. I have another idea, which I'll write about in a few hours.

DS

Monday, December 17, 2007

Whoo

Well, my posting has been sporadic to say the least. What can I say, I'm still working this thing into my schedule, which is cramped.

Today I'd like to discuss a common misconception about evolution. You can get this information anywhere, and there are clearly more established blogs which I have directed you to in the past. Also, check out this good site for all of your argumentative needs. But I specifically want to address one very depressing error, which I read this evening in a salon.com article. The article discusses the "new atheists" (whatever that means) and has this sentence at the end of the opening paragraph:

"How can a person of faith reconcile the apparently random, meaningless process of evolution with belief in God?"

This is utter bull-plop! Bull-plop I say! There is not a single statement that more accurately predicts that the person making the statement knows absolutely nothing about the topic of evolution. And if you know not about a topic, you are hardly in position to write an article about it. Granted, the article was not specifically about evolution, but who are we kidding here? Evolution is at the heart of this debate.

Anyway, back on point. Evolution is not random. Let me say that again. Evolution is not random. Ok. That was unnecessary, but, whatever. Random events, aka mutations, clearly play a major role in evolution. However, the beauty of evolutionary theory is that natural selection chooses favorable outcomes, and discards negative ones. This is the exact opposite of evolution. So many people think that if a single designer is not involved it must therefore be random. It is not random. Do not say that it is random. It is not. I hope I have made this clear.

Friday, November 30, 2007

Nuclear Pore Complex Structure

This is just mind-blowing. In the link is a pretty decent explanation of the research, as well as links to the papers and a video interview with two of the (many) authors.

The nuclear pore complex (NPC) is the gatekeeper of the nucleus. Eukaryotic cells (including the cells that make up humans and other higher organisms) contain a nucleus which contains the cell's genome. The nuclear envelope is the barrier which encases the genome, however it has to be selective in what it keeps in or out. In other words it has to somehow let in specific molecules that are necessary for a huge number of nuclear processes, and allow other molecules to exit. The way it does this is through NPCs. NPCs poke big holes in the nucleus, but act as the gatekeepers of these holes. They prevent molecules from entering or exiting the nucleus unless they have a ticket, er, actually, that is, unless they are associated with transport proteins.

Anyway, the NPC is too big to get a crystal structure, but still sub-microscopic enough that it is hard to make out the fine details like where specific components are. This study was a real tour de force because it compiled molecular restraints from biochemical and proteomic experiments into a program that generated a most likely conformation of the NPC. It's a thing of beauty too. It's like a donut with spaghetti in the middle. The spaghetti is too thick for large molecules to pass through, while little ones can squeeze through with ease. Additionally, if a molecule is associated with the right transport factor (or if it has a ticket), the spaghetti lets it pass. Donuts and spaghetti! It makes perfect sense!

BizZay

Oh man. Had a busy November with various familial obligations and research objectives to meet. Lots of good stuff going on though. And now I'm home sick on a Friday night. yay. I loved the NOVA special on the Dover schoolboard trials. It's hardly worth talking about since so many others have given their thoughts (like here, and here). Good stuff though. Check out Monkey Girl by Edward Humes if you're interested in more details about that particular ID fiasco. There were lots of fascinating characters and ins-and-outs and what-have-yous during that whole trial. Humes did a fantastic job putting it together in his book. One thing that I did not notice in the NOVA special that was a great point in the book was that judge Jones was quoted as regretting his decision to keep cameras out of the courtroom. He said the scientific evidence was so overwhelming, and was presented in such an organized way that everyone should have been privy to it (my intereperetation of his words). To bad. An oppurtunity missed if you ask me, but it was still a landmark victory for logic and common sense.

Saturday, November 10, 2007

ERV's Translation

OK, here is ERV's 'parentification' of her debate with Michael Behe. If you can't tell I truly enjoy reading her blog, and everyone should check it out regularly. As soon as I get a chance I'll make a list of all of the science blogs that I read daily.

DS

Thursday, November 8, 2007

Yaaaaaaaaaayyyyyy! (yay!)

My first comment. What a rush. And from ERV, one of my favorite science bloggers, too! She previously posted a great 'parentification' of this argument, and has promised to post a second, more detailed one soon. This is nice because I don't have to research all of the details and translate it, and because she is clearly much more of an authority than I on the subject so it will be 100x better that anything I could do. I'll post the link when it arrives.

DS

Monday, November 5, 2007

Might as Well

Even though this helps her not at all (because I have yet to get any readers [I'm a pathetic beast, I am]), I would feel remissed if I did not link to a beautifully worded and elegant article by ERV. She responds to Michael Behe, who I can only describe as detestable at best for his fraudulent claim to be a scientist, all the while misrepresenting bad science and ignoring good science in his quest to debunk evolution. I really don't need to say much about it as she takes care of him so thoroughly that there is nothing left to explain.

I'm a little confused about Behe's motives in all of this. I suspect that he was never a particularly good scientist, knew this, and saw an opening in society as a "scientist"-spokesperson for intelligent design (ID). Pretty shrewd, but his bit is getting old as he seems to just be mailing it in these days. He doesn't even try to make a reasonable argument anymore. He makes it too easy for intelligent bloggers like ERV to tear him apart. I guess it was inevitable all along.

DS

Friday, October 26, 2007

Open Access

Here's an interesting article about open access journals. Basically, Senator Inhofe (R, Oklahoma) tried with all of his might to prevent a bill from being passed which called for open access to government (NIH) funded research. The bill called for all research to be made public no more than 12 months after publication. Seems pretty reasonable, right? If the government (and taxpayers) are paying for something, they should have the right to read it. So why would this guy put so much effort into putting the kibosh on it? Turns out one of his largest campaign donors is Elsevier, which in turn is one of the largest scientific publishers in the world. It's amazing how these things work. Inhofe is one of the most deplorable characters in politics today, and has been for a while. But now I think I'll be boycotting Elsevier journals due to their underhanded ways.

Tuesday, October 9, 2007

Still No Comments... But Nobel Prizes to Discuss!!!

I'm ok with the lack of activity, even though it probably means that nobody has read my first post. Maybe I'll put a little more effort into spreading the word. I guess I should write more as well, but I've been a bit busy for the past week. Anyway, I'm thinkin' I'll post a long one describing one of the winners of the Nobel this year. If you don't know (I'm speaking to the void right now since I have yet to attract any readers) the prize for medicine was awarded yesterday, physics was today, and chemistry will be out tomorrow. If anyone is out there reading, waiting, observing... I'll be happy to parentify* any of the work that lead to one of the prizes. Maybe I'll take a poll. Send comments if you have a preference!

*Parentification is the tentative term that I will use for explaining science in everyday terms. I think it fits because a) I have to do it all the time with my parents b) I don't think my parents are dumb, so it is very different from 'dumbing things down', and c) a famous scientist once said that all scientists should know their material well enough to explain it to their parents (actually he said grandmother, but in this context I take them to be interchangeable), so practicing this will be good for me.

Tuesday, October 2, 2007

A Flip-Book Animation of Translation Initiation

The dynamics of proteins while they go through biological processes fascinates me. Most of biochemistry and related fields involves measuring things indirectly and, after going to great lengths to validate hypotheses, scientists are able to make useful statements about the process at hand. It can however, be difficult to say things definitively about dynamics. Let me explain a little further.

An enzyme is a biological macromolecule that performs a specific chemical reaction within a cell. There are millions of different types of enzymes within each cell, whether we're talking about an individual cell within a human body or a single-celled bacterium. Each of these enzymes is a series of amino acids strung together, and each have evolved a specific amino acid sequence over the millennia which conveys a specific function to each enzyme. Now, typically the activity of (or the chemical reaction specific to) a particular enzyme involves the following: 1) the enzyme binds a substrate (the compound being chemically altered by the specific reaction of the enzyme) 2) the enzyme modifies the substrate 3) the enzyme releases the substrate. Hopefully you can see how this would be important for a cell or an organism. If you have ever wondered how we metabolize food into energy, it's through this process. Frequently there are many enzymes involved, like people working at different steps on an assembly line. Each enzyme binds to the substrate, modifies it into something more useful, and shoves it down the conveyor belt to the next enzyme which follows the same process, and so forth until the substrate is no longer a substrate, but a product which our bodies can utilize (e.g. an amino acid for making new proteins). So, biochemical analysis of a particular enzyme typically gives us the following information about it; we can find out what substrate it binds to, how strongly it binds to it, and what the product is. We can even learn about the specific mechanism the enzyme employs to perform its chemical reaction. This is all extremely important information, but there is something missing. What does the enzyme look like when it is undergoing it's process? Does it change the way it looks, allowing the substrate to bind? Does it change shape again when the product is ready to be released? These are the dynamics of the enzyme. To be fair, biochemistry (with it's long and powerful reach) can tell us a little about these problems and has in the past. The information learned has tended to be hard-fought and (dare I say it?) inferred from indirect evidence.

Now a recent article published in Cell called 'Structured mRNAs Regulate Translation Initiation by Binding to the Platform of the Ribosome' (Marzi et. al. Cell 130, 1019-1031, 2007) shows that this information can be determined directly. The work was a collaborative effort between groups from France and the US, and it visualizes the discrete stages of translation. Translation is the process whereby a message RNA (mRNA) is relayed into a protein. This is how genetic information is carried out within a cell. DNA is "transcribed" into mRNA, which is "translated into a protein. Proteins carry out a bulk of the processes within a cell (they make up enzymes as well as structural molecules that give cells their shape). Anyway, the ribosome is the enzyme that converts mRNA into protein. Follow? I hope so. In this paper, they literally take pictures of the ribosome while it is binding to mRNA. The cool thing that they show is that there can be structural features in the mRNA which prevent it from being translated (think of a tangled ribbon on a cassette tape which will not go into the tape). The ribosome binds to this knotted mRNA, but temporarily shoves it off to the side because it is not in the correct state to be translated. When the mRNA is in the correct state (i.e. unknotted), it moves to the correct region of the ribosome and is translated as normal. The great thing about this paper is that it shows a series of pictures that essentially describes the steps leading up to the translation of a "knotted" mRNA. So we know, with pretty great resolution where the mRNA molecule binds at each stage. It's like watching a movie of a biological process, or more accurately, a flip-book style animation. It's great. They used a technique called cryoEM which I won't get into today (maybe another time, or ask if you're interested), but it's basically the use of a very powerful microscope to look at things that are much, much smaller than the size of a bacterial cell (I'm talking millionths of a millimeter here). They use a clever trick to trap the various stages of the process so they can take these snapshots.

Ok, so why is this important? I guess one can argue for the general utility of a system that shows where substrates are bound to enzymes when they are going through their functional cycle. Drug companies like this kind of information because the drugs that they design are often inhibitors of these processes. Additionally though, translation of mRNA is a fundamental process in all organisms. If we want to ask ourselves "where did we come from?' we need to understand the biological processes that make us who we are. Some processes are specific to humans. Some are specific to vertebrates, and many still are present in all organisms from the simplest bacterium to us. Translation is one of these, and this means that it was probably one of the first processes to evolve and one that is critical to life, as we know it. Therefore understanding the details of such a process is critical to understanding ourselves. Being able to watch a critically important process take place is a major goal of biology. We aren't yet even near a stage where we can point a camera at a region of a cell and watch what happens, but this was a step in that direction.

Monday, October 1, 2007

First... Blog Post... Ever

OK. I'm new to this game, so I'll start small. My goals are simple. I just want to talk about my opinions on various scientific/societal issues that may catch my fancy. As a graduate student I do a pretty hefty amount of reading, and I'm always trying to think of how best to pass this information to the general public in a not-dumbed-down but easy to understand way. Hopefully I can use this as a forum for trying out various styles and techniques for disseminating these all too important and sometimes hard to comprehend issues. And if anybody reads it they can let me know if I'm supplying anything useful. If so, maybe it will evolve into something interesting. If not, I'll kill it, and finish my PhD. Wish me luck!