Category Archives: DNA

On Anti-Aging

from reference 2

Throughout your life, your cells are continually replaced. The replacements are newly differentiated stem cells: cells which have somehow come to a decision regarding their fate in your body, and have thus undergone a transformation from a ready-to-become-something state, to a liver cell, a retinal cell, a skin cell, a brain cell (neuron). This further means that your stem cells (and others) are constantly dividing, a process called mitosis. The most fundamental operation in mitotic division is the replication (copying) of DNA. This is a multifaceted operation involving a large cast of molecular players including (amongst others) enzymes, cofactors, and nucleic acid building blocks.

When DNA is replicated, complementary nucleic acid bases are added one by one to each strand of the double helix as it is unwound, resulting in two copies of the original piece of DNA (chromosome). However, this presents a slight problem. The enzyme complex responsible for adding these base pairs (the process is called elongation) requires a bit of RNA at the end of the strand to get started. The solution is that part of the end of the DNA strand is snipped off and replaced with a chunk of RNA as a jumping off point. This would be an issue if these enzymes were chopping off pieces of “important” (functional) DNA; cells have so called “proofreading” mechanisms to look for the kinds of erroneous DNA sequences that would result from trimming parts off the end, which if found in large enough numbers, result in cellular suicide (apoptosis). Instead, and rather ingeniously, there are long sequences that cap the ends of the important parts of DNA called telomeres. The only function of these sequences is to be snipped apart, slowly ground down over time, by replication so that the important stuff in the middle doesn’t get messed with in this process.

Telomeric DNA has been seen as a potential target for anti-aging therapy. The idea is simple: make telomeres longer, the animal lives longer because the animal’s cells can replicate forever without ever being forced to snip “important” DNA during the replication part and ultimately apoptose. Furthermore, there is an enzyme whose job it is to lengthen telomeric DNA called, unsurprisingly, telomerase. Indeed, it is known that increased telomerase activity extends the lifespan of most human cell types in vitro1. Sadly, high telomerase activity is correlated with the development of cancer, and the exploration of its use as an anti-aging therapy has thus been attenuated.

A recent study, published in the journal Cell, however, has explored the possibility of pumping-up telomerase activity in mice2. The authors of this study enhanced telomerase activity in mice who had also been given a number of tumor-suppressing agents (p53, p16, and p19ARF) to render the rodents cancer resistant. This enhancement “improves the fitness of epithelial barriers, particularly the skin and the intestine, and produces a systemic delay in aging accompanied by extension of the median life span.” (See figure, below.) The real significance of this study is that it is the first to demonstrate the ability of enhanced telomerase activity in extending lifespan in vivo, in a living organism.

from reference 2

Cells can only divide so many times before they become inviable (around 53 for humans). This hints at a fundamental limitation to the replication process. One component of this is surely that described herein of telomere shortening. However, there are many other ways that errors can accrue in DNA. On another note, it will be extremely intriguing to see how these sorts of aging stories regarding DNA and cell division relate to those concerning calorie restriction and associated metabolic pathways.

While the enhancement of telomerase activity is a piece of the aging puzzle, we have a long way to go in understanding the finite quality of cell division, and it may truly be inescapable, to say nothing of aging itself.

References:
1. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE. Extension of life-span by introduction of telomerase into normal human cells. Science 279: 349-352, 1998.
2. Tomás-Loba A, Flores I, Fernández-Marcos PJ, Cayuela ML, Maraver A, Tejera A, Borrás C, Matheu A, Klatt P, Flores JM, Viña J, Serrano M, Blasco MA. Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell 135: 609-622, 2008.

On Art from Science

Copyright © 2005 Hunter O’Reilly

Hunter O’Reilly obtained a Ph.D. in genetics from the University of Wisconsin-Madison and graduated cum laude from the University of California, Berkeley. Her abstractions have been shown internationally including galleries in New York, San Francisco, England, Italy, Japan, the Czech Republic, Indiana and Wisconsin.”

“Observations in the laboratory and the world around her inspire the shapes in her abstract oil paintings. Hunter’s abstract art hints at both organic matter at the highest level (human faces) and at the smallest level (single cells). This section includes many images of artwork.”

“O’Reilly teaches biology and art at Loyola University Chicago. She created a course, Biology Through Art, where students have the opportunity to create innovative artworks in a biology laboratory. Students view microorganisms, use DNA as an artistic medium, create music based on DNA sequence and see anatomy as art. The course culminates in students creating their own biological self-portrait.”

More images here.

Life


This is Carl Woese, he’s a biologist. Although I’ve been aware of several of the theories that he has espoused over the years, it wasn’t until recently that I attributed their authorship to this great thinker. Three of the “biggest” ideas that he’s responsible for are: the RNA world hypothesis, the current organization of the tree of life with three domains at the bottom, and the concept that there was a time, before species existed, when Darwinian evolution was not dominant because of the prevalence of horizontal gene transfer. Briefly, the RNA world hypothesis suggests that the most primitive version of life as we know it must have consisted entirely of RNA because RNA can act as both an enzyme (for which we mainly use proteins) and as an information storage molecule (for which we use DNA). The three domain system split the prokaryotes (simple cells having little to no internal membrane structure like bacteria) into two separate groups: bacteria & archaea. As to pre-Darwinian evolution and horizontal gene transfer, well the idea there is that before there were individual species, all the forms of life were so similar that there was massive intermixing of genetic information betwen living organisms such as we do with bits of electronic data today. This is incredible because it’s essentially akin to lizards appropriating wings from birds because they’re an effective way to avoid ground predators (excuse the hyperbole).

This is Gertrude (gerry) Brin and her grandson Colby, another great thinker. In reading Colby’s blog post from today, about his grandmother and life in general, I was reminded of what I think is Woese’s most powerful idea.

As an undergraduate student of Physics and Mathematics just starting to become interested in Neuroscience, and delighted by the fact that I could use my beloved equations to explain the behavior of biological systems, it none the less seemed to me that we would need an entirely new form of Mathematics, spurred by a paradigmatic shift in thinking, to really understand such complex systems as brains and indeed life in general. The best that I could do was to think of life as a temporary reduction in entropy. Perhaps you remember from some physics course that the universe is constantly tending towards an increasing state of disorder (entropy). This is true on a global (all-universe) scale, but smaller scale things such as life defy this. Life forms, temporarily, organize molecules. I’ve never been able to do much more with this idea, but I am fond of it and try to consider its ramifications once in a while.

One of the big problems we’ve had with understanding these very complex systems, is that all of our science has been reductionist for a very long time. We take something we don’t understand (a watch is one classic though not ideal example) and we open it up and look at all the pieces and how they fit and work together, and then we can understand in some way how the watch functions, but only in terms of the smaller pieces. I could say much much more about this, but I think Dr. Woese says it far better in the piece he wrote in Microbiology and Molecular Biology Reviews in 2004. I must also preface the following quote from that work by saying that I was turned on to ALL of this by Freeman Dyson’s fantastic article in the July 19th issue of the New York Review of Books (that link may expire fairly soon, I found it by googling the second paragraph of the text below), which also uses a substantial portion of the quote that follows.

“Let’s stop looking at the organism purely as a molecular machine. The machine metaphor certainly provides insights, but these come at the price of overlooking much of what biology is. Machines are not made of parts that continually turn over, renew. The organism is. Machines are stable and accurate because they are designed and built to be so. The stability of an organism lies in resilience, the homeostatic capacity to reestablish itself. While a machine is a mere collection of parts, some sort of “sense of the whole” inheres in the organism, a quality that becomes particularly apparent in phenomena such as regeneration in amphibians and certain invertebrates and in the homeorhesis exhibited by developing embryos.

If they are not machines, then what are organisms? A metaphor far more to my liking is this. Imagine a child playing in a woodland stream, poking a stick into an eddy in the flowing current, thereby disrupting it. But the eddy quickly reforms. The child disperses it again. Again it reforms, and the fascinating game goes on. There you have it! Organisms are resilient patterns in a turbulent flow—patterns in an energy flow. A simple flow metaphor, of course, fails to capture much of what the organism is. None of our representations of organism capture it in its entirety. But the flow metaphor does begin to show us the organism’s (and biology’s) essence. And it is becoming increasingly clear that to understand living systems in any deep sense, we must come to see them not materialistically, as machines, but as (stable) complex, dynamic organization.”

That last sentence just kills me, we must in some sense abandon our devotion to the material. For what is life about if not interaction.