Posted on behalf of Retread

This post is pretty philosophic, but it discusses some issues raised by the previous post that shouldn’t be ignored. Future posts will be far more chemical.

Do we have any hope of constructing a nice chain of causality for what happens when we throw epidermal growth factor (EGF) at a Hela cell (described in the last post) — e.g., the EGF receptor activates kinases 1 through N, each of which phosphorylates substrates (some of which are other kinases) which eventually phosphorylate the 924 sites on the 2,244 proteins (and in the correct temporal order to boot). I don’t think there are enough researchers to do it, or labs to hold them. Even worse, if the results were available, I don’t think our minds are strong enough to grasp them.

A big stumbling block would be the multiple degrees of feedback present even with something as simple as phosphorylation and dephosphorylation. Simple ideas of causality and control vanish with feedback (see two posts back — “The Decline of Master Gland…”). Causality is inherently a linear, sequential idea. Even chaos theory is basically causal, although predictability goes out the window.

That’s not to say our brains don’t do incredibly complex things such as just recognizing people. You never see anyone at exactly the same angle, under the same light, with the same background. People are usually moving, attired differently, etc., etc… Yet our brains in some way compute an invariant that computer science can only dream about permitting instant recognition. As people move about and you interact with them, zillions of new sensory inputs must be absorbed, transformed and matched to the same invariant. Since we do all this unconsciously, we don’t think anything of it.

Yet we don’t do very well predicting events where feedback is involved (like the stock market where most people lose). Perhaps the next step up in human intelligence is the ability to perceive the various forms of multiloop feedback, the way we recognize faces and people.

Could our brains change that fast? Possibly. Consider the man’s best friend vs. the chimp. [Science vol. 298 pp. 1634–1636 (2002)] Chimpanzees are terrible at picking up human cues as to where food is hidden, even when the cues are as obvious as pointing to the food container. Even chimps that eventually perform well, take dozens of trials or more to learn what the cues mean. I find this surprising.

However, puppies (raised with no contact with humans) do much better at this than chimps — anyone owning a dog knows they can read us like a book. Wolf cubs don’t do better than the chimps, even cubs raised by humans. This implies that during the process of domestication, dogs have been selected for a set of cognitive and social abilities that allow them to communicate with us. Domestication has only gone on for 10,000–15,000 years (the dawn of agriculture). I find it absolutely incredible that we could have changed the dog’s brain in what is basically a microsecond in evolutionary time. Yet we did. Hopefully our brains are as plastic.

Not to be too depressed by this. There clearly are single chains of causality in the cell and chokepoints which we can find and modify. Consider Gleevec. Success stories like this provide employment for legions of chemists.

The virus does not infect the population gradually, but in a stop-start fashion, say London researchers.

Ed Yong

In the late 1990s, the number of Londoners with HIV doubled within about seven years. Using molecular forensics, researchers from London’s Chelsea and Westminster Hospital and the University of Edinburgh now understand how the virus spread so quickly.

In a study published in PLoS Medicine, Fraser Lewis and Gareth Hughes found that the epidemic proceeded in a stop-start fashion rather than a gradual one. The virus spread quickly over just a few years within tightly knit clusters of sexual contacts and more slowly between these clusters. A significant number of people passed on the virus within just six months of becoming infected themselves.

This study breaks new ground in viral tracking. Previously, the spread of sexually transmitted disease was monitored using interviews to map networks of sexual contacts. This approach doesn’t work for HIV because people remain infected for a long time and the risk of transmission during any single sexual encounter is low.

To understand how the virus spreads, Lewis and Hughes combined the patterns gleaned from sexual contact networks with information about the genetic relatedness of viruses sampled from different individuals. They call this new approach ‘molecular phylodynamics’.

“This approach has been used at a larger-scale to estimate when HIV was originally transmitted to humans,” says Andrew Leigh Brown, who led the research. “We applied it to a much larger sample to bring the timescale down to a matter of a few years.”

HIV is well suited to this method because it goes through frequent genetic changes to outfox the immune system, and doctors routinely capture genetic data to choose the best medications for individual patients. Using this data, Lewis and Hughes compared two viral gene sequences in samples from over 2,000 patients who attended London’s largest HIV clinic, the Chelsea and Westminster Hospital, between 1997 and 2003.

They found 402 sequences that closely matched at least one other in the group. These came from patients who grouped into six tightly knit clusters of ten or more people who carried genetically similar viruses, along with several smaller groups. Lewis and Hughes worked out dated family trees for these viral strains to show that the majority of transmissions within the clusters took place between 1995 and 2000, which matches the time period when the number of infected people doubled.

One in four cases of infection happened within six months of the original partner becoming infected themselves, which suggests that transmission during the earliest stages of infection is an important driver of the HIV epidemic.

While these patterns are specific to London, they are likely to apply elsewhere in the UK. “We have a much larger study underway, where we’re looking at ten times as many people from all over the UK,” says Brown. Already, his team has started to find several large clusters that, as in London, include about a quarter of patients.

Brown says, “This study shows that HIV epidemics are structured in a way which means that targeted safe-sex interventions would be very effective. Messages could be targeted to places where people are likely to meet for sex, which could include virtual locations as the Internet becomes increasingly popular.” Such interventions are sorely needed. The levels of HIV infection in the UK have increased further since the epidemic of the late 1990s and remain high, with over 7,000 new diagnoses reported in 2006.