2009 review [pdf]

I’d like to say a few words about one of the hottest and, in my view, most important areas in biomedicine: autophagy, a process crucial to health, disease, and aging. Autophagy research is expanding rapidly.

In autophagy (“self eating”), cells engulf and digest their own macromolecules and organelles. Autophagy serves two functions: providing critical nutrients in times of scarcity, and recycling damaged cellular structures (2009 review, pdf).

It seems that lab animals and human beings fed ad-libitum do too little autophagic recycling. The resulting accumulation of damaged machinery causes a wide range of functional deficits, and accumulation of damaged mitochondria, in particular, increases the production of reactive oxygen species, accelerating further damage.

In a range of organisms, dietary restriction both induces autophagy and results in wide-ranging health benefits, including the extension of healthy lifespans. Blocking autophagy blocks the most important of these effects. Rapamycin induces autophagy and extends lifespan, as does sirtuin-1. Autophagy again appears to be central to these effects. A recent review article examines genetic interventions that indicate “tight connections between autophagy, health span and aging”.

The importance of vigorous autophagy to human lifespan is an inference, but it’s more than just plausible. Diverse results in humans, mice, and C. elegans: they all fit a pattern of effects that stems from a process as old as eukaryotic cells.

Upregulating autophagy has known, wide-ranging benefits, and more are being discovered at a fast pace. You might enjoy exploring the state of current knowledge with Google Scholar (here’s a search).

Let’s see… a July, 2010 opinion from Trends in Molecular Medicine: “Autophagy as a basis for the health-promoting effects of vitamin D”. That’s a new link to another hot topic.

A benchmark for judging hype:

WSU Researchers Use Super-high Pressures
to Create Super Battery

The researchers created the material on the Pullman campus…The cell contained xenon difluoride (XeF2), a white crystal used to etch silicon conductors, squeezed between two small diamond anvils….The researchers eventually increased the pressure to more than a million atmospheres, comparable to what would be found halfway to the center of the earth….

That’s it: a super-compressed material, not a battery, much less a “Super Battery”. If the material is stable at atmospheric pressure (or anything close), I’ll eat it or breathe the fluorine. This stuff couldn’t even be used in a battery.

As I’ve said, hype like this erodes trust in science and impedes rational choices in research. One way or another, it richly deserves to be stigmatized — how about calling it “deceptive advertising”?

An addendum: By the way, I regard problems like this as primarily institutional and cultural, and I think that placing much blame on any individual would be both unfair and counterproductive.

Why “unfair” to focus blame on individuals?
First, the fundamental problem is with permissive norms and expectations — the actions of people who live down to current standards are more a consequence than a cause. Second, I’m sure that the worst examples of hype emerge thorough multiple stages of exaggeration and confusion, with no standard fact-checking procedure and abysmal standards for what passes for a fact. It’s best to regard responsibility as diffuse, and to not look too closely.

Why “counterproductive” to blame individuals?
I think we’d all benefit from a shift in attitudes that leads decent people to stop doing this, but starting by blaming people for routine behavior would cause needless pain on all sides, making it far more comfortable to instead do nothing. All that’s needed — or appropriate — today is turning up the general level of criticism to make hype less fun, profitable, and acceptable.

For example, people who join in grumbling about deceptive hype at lunch are less likely to produce it when they get back to the office. Progress through griping — what could be more fun?

An influential study of diet and health has been exploded here. The data and the conclusions don’t just disagree, they aren’t even on speaking terms.

Soon after Earth’s life first touched the Moon, NASA promised to make spaceflight routine and inexpensive, and I began studying the prospects for space as a genuine frontier.

Geologists had analyzed the new, hard-won lunar samples, and I read up on the results in the local college library. Not nice: almost no carbon, nitrogen, or hydrogen, and no obvious promise of a decent mineral ore. Asteroids, by contrast, had been delivering samples for free in the form of meteorites, year after year. Much nicer: Lots of carbon, nitrogen, and hydrogen, along with nickel-alloy steel, a substantial dash of platinum metals, and (of course) a little or a lot of everything else.

I summarized the case for bypassing the Moon in favor of asteroids in a 1983 advocacy piece written partly about resources and engineering, and partly about cognitive biases favoring the Moon.

The biases held, though, and the Groundhog vision has been Back to the Moon!— until recently, culminating in last week’s Presidential statement announcing a plan to

…abandon another landing on the moon, and develop new technologies to send astronauts to an asteroid by 2025….

New York Times, 3 June 2010

In terms of relative priorities, I like it.

In 2007, the area of Arctic sea ice reached a record low. By comparison, here’s the current story:

   National Snow and Ice Data Center

Looks low by about 4 standard deviations. (Yes, too much geophysics & climate…)

The GOCE satellite flies extraordinarily low and it thrusts constantly to compensate for air drag while making exquisite measurements of the gravitational gradient. The just-released result is a map of the geoid — the gravitational equipotential surface of the Earth — shown below as a delta from an idealized ellipsoid. GOCE can measure the geoid with an accuracy of 1 – 2 cm vertically, with 100 km spatial resolution.

This has many uses. For example, if Earth’s ocean were quiescent, its shape would track the geoid, and the discrepancies from this ideal shape are informative. Changes in the geoid over time can track the movement of magma under the Yellowstone caldera and the depletion of groundwater in India. The BBC has a story, and the European Space Agency has more information, including a slick video of the mission.

A BBC news story includes a high-resolution version.

• GOCE on a Mission of Gravity
• Mission of Gravity, Part 2
• Space data lost to whale-oil shortage

How do you see whether critical valves in a blowout protector are open or closed, a mile deep in the sea and through inches of steel?

Gamma-ray imaging, as suggested by Secretary of Energy Steven Chu:

Atlantic: How is it that you know enough about gamma rays and oil spill technology to be helpful? I wasn’t aware that that was an area you’d worked in before you were secretary?

Oil spills were not something I’ve worked on, but I do know about gamma rays.

Atlantic: How?

Because I’m a physicist. [...]

(Exclusive: How Steven Chu Used Gamma Rays to Save the Planet)

Steven Chu has used the leverage of his brain and Nobel-Prize credentials to manage Lawrence Berkeley National Laboratory and now the Department of Energy, doing his best to direct them toward solutions to the energy problems of the 21st Century. As a matter of enjoyment (rather than duty), I think he’d rather be doing research, which he hasn’t left, e.g., see “A precision measurement of the gravitational redshift by the interference of matter waves”.

The connotations of “bureaucrat” don’t really apply.

Irrational drug design (aka high-throughput screening) parallels other areas of data-driven science: it abandons the methodology of traditional hypothesis-driven science — which demands a focus on specific predictions — and pursues instead the weak and humble hypothesis that looking in a general area will find something. As I discussed here, genomics and synoptic sky surveys are classic examples.

High-throughput screening for drug discovery differs from these examples in that the areas studied are real only in an abstract sense, consisting of regions of molecular-structure-space that nature hasn’t filled. And indeed, making and testing millions of drug-like molecules often turns up interesting results, in both a practical and a scientific sense.

A few of the 1000s of new anti-malarial drug candidates.

Two papers in Nature (here and here) turned this method on malaria, finding thousands of candidate drugs, defined as molecules that inhibit the growth of malaria parasites by 80% or more at concentrations in the micromolar range. The hit rates were, respectively, ~1,100/310,000 and ~13,500/2,000,000.

Many of these candidates are unlike any now in use (different structures, different mechanisms of action) and crucially, these often evade mechanisms of resistance to existing drugs — a problem that threatens to restore malaria to its previous level of deadliness across much of Africa and South Asia.

Promise beyond malaria

In our household, small risks of malaria arise only when traveling to these regions. A footnote to the search for new malaria drugs, however, indicates the potential for finding treatments for scourges of the older populations of temperate zones: the disorders of protein hyperphosphorylation that underlie the leading dementias, including Alzheimer’s disease.

These result from imbalances in the activity of enzymes that add and remove phosphate groups to alter the activity of proteins. Kinases do the addition side of this, and they are diverse and specific. Many of the candidate drugs discovered in the studies reported in Nature are thought to work by inhibiting specific kinases in malaria organisms. Molecules with similar discrimination in modulating the activity of specific kinases in human cells could provide leverage in a treating a range of human diseases, including those that can steal the mind.

• The Data Explosion and the Scientific Method