Criticism. Essay. Fiction. Science. Weather.
Take a moment to think about seeing; it is not a mindless process. Seeing is a series of complex calculations carried out by the brain that transform the information produced by two source inputs into color, discrete objects, distance, movement. But after we learn how to use it, our vision becomes preprogrammed to notice certain things, and ignore others. Take a minute or two to look at a leaved tree and you might just see what Annie Dillard means when she describes "the tree with the lights in it" in her classic Pilgrim at Tinker Creek
. Even at its most diligent though, seeing can only describe the surface; more probing is required for understanding. Scientists are still in the seeing stage in the field of genetics. Even with the complete genome sequences of a growing smorgasbord of organisms at hand, we still have only a fragmentary understanding of how it all fits together to make a living thing live. We've seen the cast shot, but haven't yet seen the movie.
Knowing a protein's amino acid sequence--the information that is contained within the code of a gene--is a woefully deficient way of finding out what that protein actually does. Even though the shape a protein will take is dictated by this sequence, the world's fastest computers and greatest minds have found it exceedingly difficult to determine protein shape from sequence, not to mention what task that protein might perform. The Human Genome Project was centered around the process of constructing; compiling the four letters of the genetic code into a magnificent string of order, creating a description of every gene in the body. However, the next step in genetics is surely one of destruction. When you get right down to it, breaking something is a pretty direct way of learning how it ticks.
Geneticist's current understanding of genes is similar to the knowledge of a car mechanic who has never actually looked inside a car. This fictional (and no doubt unemployed) mechanic has a list of all the components of the car, and a short description of what each one looks like, but having never opened up the genuine article, he has no idea how all the parts work or how they fit together to make the functioning vehicle. The best way for our mechanic to learn about the components is for him to start breaking them, one by one, to see how the part fits into the puzzle of a driving automobile.
This is essentially one of the ways by which geneticists are elucidating the functions of genes. To get a true sense of the difficulty involved in the geneticist's task however, imagine if the car mechanic had to systematically break each car part without being able to open the hood, or touch the car at all. He could still accomplish his task, but he would need a random way to break only one part at a time from the inside, and then some other method of finding out which part had been broken in order to asses its function. It's not particularly surprising that randomness is at the base of this strategy; it's a concept that lies at the foundation of many aspects of science: the movement of an electron around the nucleus of an atom, the motion of gas particles in a container, the mutational force driving the evolution of organisms.
Geneticists are most successful when they co-opt existing genetic mechanisms and use them as their dissection tools. If you're interested in throwing random wrenches into the genome, transposons are your best bet. In the presence of the right enzyme, these short pieces of DNA insert themselves into other genes, thus deleting their function. Transposons are not laboratory creations, they actually exist in a number of different organisms and are potentially the smallest unit indicative of the ultimate purpose of DNA: to spread itself as efficiently as possible (what else are living beings, than a way to spread As, Ts, Gs and Cs?)
Until now, transposons have only been used in the Drosophila--a favorite among the cohort of laboratory animals and cursed among those with 20 pounds of fresh peaches in their kitchens. By using these elements to introduce and catalog the effects of random deletions in the fruit fly genome, geneticists have been able to make leaps in understanding the function of fly genes. The human genome, however, has nearly 4 times as many genes as the fly, leaving a large gap in the knowledge to be gleaned from this winged creature. Scientists have tried to use the P-element--the transposon tool of the fruit fly--in mammalian organisms, but have had little success.
This week, researches at Yale have published the first successful use of the transposon technique in mice. Their success comes at the hands of piggyBac a transposable genetic element originally found in the cabbage looper moth. Their procedure works in the same way as the fruit fly method: by inserting piggyBac into mouse embryos, researches can produce mice that have the transposable element integrated into the same DNA sequence in all of the offspring's cells. If the element disrupts a gene, it will make it nonfunctional and more often than not produce a specific alteration in the mouse's appearance or behavior. Mice lacking single genes are called knockout mice and have already been crucial in determining the genetic basis of diseases like diabetes, obesity and cancer. Most importantly, piggyBac has a small genetically engineered enhancement--the inclusion of a fluorescent protein to highlight both if the offspring mice have an inserted copy of the transposon and to pinpoint which specific gene the element is disabling. The metaphorical car mechanic has both the tool to break single parts from the inside and the beacon to tell him which unique part has been broken.
Although the whole technique is still in its developmental stages, the finding represents a significant step in the field of mammalian genetics, one that will ever further the understanding of gene function. Many in the field of genetics were taken by surprise at the ultimate superficiality of the genetic code in the grand scheme of organism function. Its almost as if they thought learning individual words would tell them the whole story. That they could decipher the soul of a book without understanding sentence structure and paragraph organization, let alone flow, themes or allegory. Its these supra-concepts that will continue to hone our understanding of living bodies, including our own. Its hard to blame the eager geneticist; the field has moved so quickly over the past 30 years that there has been little time for reflection, but we should continue to watch for the hubris and naiveté in marveling that it could all be so simple.