lateral moves

We're back on our home turf, after making our way across all three US time zones (some more than once) in the past two-and-a-half weeks. My internal clock has no idea what time it's supposed to be. And there's been nonexistent blogging here at the cocktail party over the last week as I've struggled to catch up with everything that piled up in my absence.

Among other news, I returned to find that Frink Tank has declared itself suspended in a persistent vegetative state, hinting at some deep dark conspiracy. Jen-Luc Piquant is tres desole at the loss of one of the most irreverent science-minded blogs out there. Yet she is ecstatic to note the return to the blogosphere of that unrepentant miscreant, professor of dangeral studies Michael Berube (our fellow French-Canadian), who retired his eponymous blog earlier this year, and is now hanging his hat at Crooked Timber. (Hah! Future Spouse predicted Berube wouldn't be able to stay away!) Such a mishmash of conflicting feelings -- Jen-Luc's Cyber-Gallic soul doesn't know quite what to make of all the happy/sad permutations, ergo, she has taken refuge in the cool, emotionally detached objectivity of her crackpot scientific research.

While we're all eagerly awaiting Berube's first pithy offering at his new bloggy home, check out this intriguing article by Lindsay Borthwick in the current issue of Seed about a serious challenge to long-held assumptions about "silent" genetic mutations. Basically, silent gene mutations, while plentiful throughout the human genome, have long been believed to have no impact on the amino acid sequence of proteins -- since the late 1960s. Amino acids, for those like me who don't regularly follow genetic research, are the fundamental building blocks of proteins. Adding amino acids one by one to a growing protein chain causes it to elongate, until the protein begins folding. And how it folds determines its biologically active function. (I think.) 

However, last December, a team of scientists at the National Institutes of Health -- led by Chava Kimchi-Sarfaty -- published a paper in Science reporting that the silent mutations occurred more frequently than usual in one particular gene (multidrug resistance, or MDR1), commonly found in human cancer cells; in fact, it's what makes cancer cells resistant to chemotherapy drugs. The gene variant that had a particular kind of silent mutation enhanced this resistance even more. Further investigation revealed that these mutations were slowing down the process of protein manufacturing.

This is relevant because, per Borthwick's article: "[T]he folding of a protein into its three-dimensional shape is partially speed-dependent, [so] these mutations were able to alter the structure -- and biological function -- of the protein without changing its basic building blocks." They call the mechanism "translational pausing." The upshot is that the long-accepted theory of neutral molecular evolution is likely wrong. The mutations in question might be "silent" to the casual scientific observer, but they are potentially quite deadly. Furthermore, the NIH researchers also found some 40 other examples of silent mutations that can change the way a gene is spliced, thereby causing diseases like cystic fibrosis or connective-tissue disorders.

The SEED article ties in nicely with some belated news from the APS March Meeting held in Denver a couple of weeks ago, namely, the role that something called horizontal gene transfer might play in the evolutionary process. One of the things that puzzles scientists is that, per that all-important fossil record, single-celled life forms first appeared about 3.5 billion years ago, with another 2.5 billion years passing before multi-celled organisms finally made their debut on the scene. Here's the thing: it took just 1 billion years -- give or take a few -- for every other conceivable form of life to evolve: plants, mammals, birds, insects, reptiles and any other terrestrial species.

That's a pretty significant increase in the rate of evolutionary development, and scientists have been baffled about why this is so. The standard mechanisms are point mutations -- "random changes in single nucleotides on the DNA chain, or genome" -- and recombination, which occurs when the genetic sequences of a set of parents are recombined ("sexual selection"). But models that simply take into account these two common mechanisms really don't explain the sudden rapid acceleration of evolutionary rates indicated by the fossil record.

Enter Rice University physicist-turned-bioengineer Michael Deem, who has a penchant for adapting mathematical models from physics to the mutation and evolution of the flu virus, among other research. Lateral moves across the traditional boundaries between scientific disciplines can be difficult, since different fields use widely different terminology, and often employ vastly different approaches, but the potential payoffs are huge. For instance, Deem says he has now developed "the first exact solution of a mathematical model of evolution that accounts for this cross-species genetic exchange." He attributes the phenomenon to horizontal gene transfer (HGT), in which the DNA from one species is introduced into another.

The notion was first broached some 50 years, but only recently have scientists started taking it seriously, particularly in light of the increase in drug-resistant bacteria, and the surfacing of evidence of a specific protein used by bacteria to trade genes. And Deem found that by accounting for HGT -- in addition to point mutations and sexual recombination -- his model can demonstrate how HGT increases the rate of evolution by spreading favorable mutations across populations.

So it is indeed possible to swap entire sets of genetic code, including the genes that allow bacteria to develop resistance to antibiotics -- and, in fairness, for the human immune system to continually adapt to invasive species, an attribute Deem has traced to an HGT insertion that occurred some 400 million years ago. In fact, he thinks a significant portion of our DNA was donated by viruses and bacteria that infected our ancestors over lots and lots of generations.  "Life clearly evolved to store genetic information in a modular form, and to accept useful modules of genetic information from other species," says Deem.

I wrote about Deem's prior work on flu vaccines -- notably, the use of nuclear spin glass modeling to better predict which strain of the flu virus was likely to dominate in any given year -- a few months ago here, particularly the notion of "original antigenic sin." See, the antibodies produced by the body's immune system to fight exposure to the flu virus become part of the body's "memory" so that it can fight off future exposure the same flu strain. The problem is, those same antibodies end up suppressing the creation of new antibodies when the body is exposed to a new strain of the flu. The phenomenon has also been observed in dengue fever and HIV, among other viruses, and the latter was the topic of the second paper Deem presented at the Denver meeting.

HIV is an especially difficult virus to eradicate, in part because the thing mutates so quickly after initial infection, producing several different virus strains. It's an ingenious "divide and conquer" strategy, according to Deem: the human immune system responds to viral infection by producing antibodies to ward off any given strain, but it tends to only focus on a single strain; the rest just run rampant. So the body defeats itself thanks to in-fighting among its own T-cells, and the end result is full-blown AIDS.

T-cell competition takes two forms, per Deem's computer models: original antigenic sin (described above, and also known as "deceptive imprinting"), and something called immunudominance, which occurs when several viral strains simultaneously infect a single person. The cells that respond to each strain compete until one emerges the victor. "Once the immune system chooses a winning set of T-cells, it has a natural tendency to go with those cells when it's confronted  by new strains of the same disease in the future," Deem is quoted in the Rice press release. "For HIV, which mutates rapidly, this is an Achilles' heel. We found a direct correlation between the level of competition among T-cells and the rate at which the virus escaped."

That's what makes the HIV virus so deadly. But Deem thinks it also suggests a potential new strategy for a more effective HIV vaccine. It's been difficult to develop such a thing because of how quickly the virus mutates. Deem thinks that inoculating someone at various points on the body against different strains simultaneously could all but eliminate competition among T-cells, so that the HIV will be trapped in a permanently latent state, never raging out of control to develop into full-blown AIDS.

How is this possible? You may well ask. There are lymph nodes scattered throughout the body, responsible for producing those all-important T-cells, but it takes four or five days before any T-cells produced therein to leave the node and spread throughout the body. Simultaneous inoculation would mean that each different node would select for a different strain, with no single T-cell emerging as dominant, because immunodominance doesn't have time to kick in. It's ingenious; now we just need to develop effective HIV vaccines. In the meantime, Deem hopes to test his multi-vaccination scheme on the spread of dengue fever.

Many years ago, I lost a close friend to AIDS, one among millions of gay men who died in droves in the first wave of infections that hit the US. If only we'd had access to an HIV vaccine then; alas, he didn't even have access to some of the better drug therapies available today to keep the disease under control. And the pain of watching a loved one slowly waste away with disease isn't limited to those with full-blown AIDS; we are mortal beings, so death and dying is universal; our mortality is the ultimate incurable disease, an inescapable fact of the human condition. The only variant is how we shuffle off this mortal coil. One of my oldest and dearest friends is currently holding vigil at her mother's bedside as cancer practically eats the unfortunate woman alive. Listening to her describe what her mother and family are going through, I find that words -- usually my trustiest allies -- fail me. There is simply no way to respond to this kind of pain, except silent commiseration and support; anything else just comes off seeming trite and insincere.

I bring up the unwelcome specter of human mortality not to end on a "downer" note, but because it's on my mind at present, and because it's a very real, brutal reminder of why the work of Deem and others like him is so damned important. It's easy to forget that the seemingly cold, objective realm of science also has a profoundly human face -- perhaps more visible when it comes to human health, but  no less present even in something as abstract as computer modeling. Like genes that move horizontally across species, scientists like Deem who move across traditional disciplinary boundaries can bring useful ideas and mechanisms to bear on well-worn knotty problems. Ideally, that lateral "cross-species" exchange leads to better survival strategies, and longer, healthier human lives.

Comments

[Matt Heavner]

Thanks for the great blog, but "all three US time zones"?!?

There are more than three US time zones, you know that, right? :)

[Jennifer Ouellette]

*sigh* Oh okay, All three CONTINENTAL U.S. time zones. :) But really, if DC can't have statehood, why should Hawaii and Alaska? Not that I'm bitter...

[Roger]

I thought there were four time zones in the forty-eight contiguous states. Eastern, Central, Mountain, and West? Am I wrong?

But then I delight in finding unimportant errors. In other people, of course, never in myself.

[Jennifer Ouellette]

Nope, you're right, but like I said, I'm all discombobulated and no longer know what time it is. Anywhere. :)

[TBB]

Roger, I like pointing out others' mistakes, too - don't we all? ;-)

So, what is West time? There are four time zones in the continental US, then Hawaii and Alaska:
http://wwp.greenwichmeantime.com/time-zone/usa/

Mountain Time states:
http://wwp.mountain-standard-time.com/

[TBB]

Roger, OK, I guess you're calling Pacific Time "West." It is called Pacific, though. :-)

[Matt "pedantic" Heavner]

Hmm.. Can you tell me again what continent Alaska is on? :)

Maybe conterminus or contiguous (Roger got it) is what you mean?

To be totally pedantic, Alaska actually still spans three time zones:

"Alaska", "Aleutian/Hawaii", and the town of Hyder (55.9 N, -130 E) which uses a Canadian phone exchange (so there's a trivia question--Alaska actually has two phone area codes!) and "Pacific" time. Hyder is very isolated from the rest of AK and very tied to the Canadian town of Stewart (all the kids in Hyder go to school in Stewart).

Sounds like you need an Alaska vacation to recover from all the crazy conferences you've been attending/covering.

[Stephen Uitti]

When it's my time, i want to go peacefully in my sleep like my Uncle. Not screeming in terror like his passengers.

[cheralyn]

I won't join in on the time zone debate, but will just say that I enjoyed reading this article. HGT is a particularly fascinating idea to ruminate over.

[theoreticalminimum]

I know the following remark might potentially frustrate you to some nontrivial extent, but my rigorous study and appreciation of French are to blame for my sometimes glaring, but sincerely unpretentious, pedantry. "tres desole" should instead be "très désolée".

[TBB]

No, it's just that Jen-Luc has masculine tendencies and tends to project those qualities for her male admirers...I mean, readers. Cela me desole...

(Someone needs to show me how to use foreign fonts properly.)

There should be a Nitpicker Award! However, when nitpicking, it would be nice to see people offer some back-up link/explanation/reason.

Jennifer, your last paragraph was far from a "downer." In fact, sometimes it takes personal experience for some people to *really* get the importance or significance of scientific research (say, with stem cells or such). I wish it didn't take that kind of firsthand experience, but alas it often appears to. :-/

[TBB]

...and I know about the preposition, too. ;-)

[Roger]

Pacific, not West, oops. I should have known that I lived on the West Coast in the Pacific Time Zone; I grew up in the Midwest in the Central Time Zone; I've visited the East Coast in the Eastern Time Zone; I now live in the foothills of the Rockies in the Mountain Time Zone and have friends in all four of the time zones for the 48 continguous states. And one of these days I'll know what I'm talking about.