During a three-month test across eight hospitals, several continents, and almost 4,000 patients, a new technology reduced serious surgical complications by 36% and deaths by almost 50% — in raw numbers, over 150 cases of severe harm and nearly 30 patient deaths.

This performance was demonstrated in the spring of 2008 with the prototype version of the technology, applied indiscriminately to surgeries of all kinds — a prototype without the specialized features that would improve performance in (for example) abdominal, cardiac, or neurosurgical procedures.

The surgeon who spearheaded the development and deployment of this technology should, in my view, be the leading candidate for the next Nobel Prize in Medicine. He has earned it, and awarding the Nobel Prize for this accomplishment would speed the adoption of a technology proved to save lives in settings that range from leading surgical centers in the US and UK to a remote hospital in Tanzania.

The prototype hardware consists of a sheet that lists 19 carefully engineered steps. The first step after sign-in — proved by testing to be crucial — is a pause in which the members of the surgical team simply introduce themselves to one another by name.

The Checklist Manifesto:
How to Get Things Right

The name of this innovative surgeon is Gul Gawande, and he’s told the story of the technology in an excellent and many-faceted book, The Checklist Manifesto.

It’s a good read that offers concrete and compelling insights into why buildings stand and aircraft seldom fall out of the sky. Ultimately, it’s about cognition, complexity, knowledge-sharing, and team coordination, all vividly illustrated with stories of surgery gone wrong (and right) and extended in surprising directions with tales of success that range from methodical heroism in modern aviation to methodical investment in high-tech venture capital.

I had planned to skim the book, but after picking it up yesterday I read it cover to cover.

A carefully engineered checklist is a high-value medical technology by any measure you choose. It averts injury, saves lives, saves money, improves morale, and reduces staff turnover. It costs virtually nothing. Only inertia holds it back, and what the humble checklist needs most now is an infusion of glamor and excitement. A Nobel Prize for Dr. Gawande would do more than recognize accomplishment: It would give a boost to a critical technology that could save your life.

Compared to small molecules, nanoparticles offer more physical scope for functional engineering, and according to a report in Science, more than 50 companies are pressing forward to exploit this for cancer diagnosis and treatment. Nearly a dozen nanoparticle-based medicines are reportedly in clinical trials, and lab research suggests a road to programmable control of cellular functions.

Nanoparticles make good delivery vehicles for molecular cargo in vivo. The have distinct surfaces and interiors, and this makes it possible separately engineer for solubility, immunological compatibility, targeting and penetration of cells, and controlled release of compounds that, when simply injected, are ineffective or horribly toxic.

Not just size and surface properties matter: Shape makes a difference (cylinders penetrate cells better than spheres), and even mechanical stiffness is important — soft particles can remain in circulation for almost 100 hours, where rigid particles are cleared in 1/50 the time.

Looking forward

The advantages of nanoscale engineering for biomedicine will increase in concert with increasing capabilities in molecular and supramolecular engineering. There’s a continuum of prospective technologies that stretches from macromolecular conjugation and liposome encapsulation of drugs, through applications of current-generation multifunctional liposomes and nanoparticles, to medical interventions based on particles that undergo differential activation in response to weighted molecular sensing inputs and threshold measurements, evaluated by Boolean logic*. And then more, and more beyond that.

(* Programmable intracellular Boolean logic has already been demonstrated: see below.)

The wonders of siRNA and the role of nanoparticles

Keep a keen eye on advances in small interfering RNA (siRNA) technology: By modulating protein expression, siRNA therapeutics promise to provide remarkably flexible and specific control of cellular processes. RNA molecules have have short half-lives in circulation and don’t readily enter cells, but engineered nanoparticles promise to overcome this obstacle. (Recent research abstract & pdf; recent review abstract & pdf.)

Biocompatible molecular Boolean logic has already been demonstrated, with RNA as the basis:

“A universal RNAi-based logic evaluator
that operates in mammalian cells”

Abstract, Nature Biotechnology:
…The encoding rules, combined with a specific arrangement of the siRNA targets in a synthetic gene network, allow direct evaluation of any Boolean expression in standard forms using siRNAs and indirect evaluation using endogenous inputs. We demonstrate direct evaluation of expressions with up to five logic variables. Implementation of the encoding rules through sensory up- and down-regulatory links between the inputs and siRNA mediators will allow arbitrary Boolean decision-making using these inputs.

PDF here.

Abstract:
Antioxidants inhibit basal autophagy and block the induction of autophagy by calorie restriction and other means. Because this effect inhibits the central mechanism of cell repair, it helps explain why dietary antioxidants have failed to deliver their expected benefits to health and longevity. The nature of the effect suggests prudent modifications to popular supplementation regimens.

“Imagine this program could keep you young…”
(© 1999)
… but it won’t …

The puzzle:
Dietary antioxidant trials
show little benefit

A paper published a few weeks ago may help answer a long-standing question in aging research: Why have treatments that protect cells from oxidative damage produced so little net benefit?

It seems reasonable to expect benefits from increasing antioxidant protection in cells. Reactive oxygen species (ROS) damage cell components — especially mitochondria — and elevated ROS levels can shorten life, causing cancer, heart disease, neurological damage, etc. Dietary interventions successfully reduce ROS levels, hence the damage caused by oxidative stress, by increasing antioxidant activity in cells (for example, by elevating levels of antioxidants like vitamin E, superoxide dismutase, and α-lipoic acid).

Surprisingly, though, the well-studied dietary antioxidants have delivered little, no, or negative benefit in reducing age-related disease and mortality. Consider this review, “Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention: Systematic Review and Meta-analysis” (JAMA, 2007):

In 47 low-bias trials with 180 938 participants, the antioxidant supplements significantly increased mortality….beta carotene…, vitamin A…, and vitamin E…, singly or combined, significantly increased mortality. Vitamin C and selenium had no significant effect on mortality.”

In each case, something is offsetting the benefits of ROS protection, yet these interventions have nothing in common but ROS protection itself. Stranger still, that something seems to result in the accumulation of ROS damage. But how can reducing the rate of damage fail to reduce the accumulation of damage?

There’s a relevant mathematical truism:

The bad news:
Antioxidants down-regulate autophagy (damn.)

Autophagy removes cell components — including ROS-damaged proteins and organelles — by engulfing and digesting them, producing wastes and recycled nutrients. It’s ongoing, tightly regulated, and as I discussed in “Autophagy: Why you should eat yourself”. it’s essential to life and health,

Upregulating autophagy has metabolic costs (burns scarce calories) but has extraordinarily wide-ranging benefits. Interventions that extend healthy lifespan in animal models include calorie restriction, resveratrol, spermidine, and rapamycin, and in each operates, at least in part, through autophagy. Upregulating autophagy has positive effects in models of several specific neurodegenerative diseases, too, as I discussed in “Trehalose, autophagy, and brain repair”.

Interventions that increase production of ROS induce increased autophagy in response. As one might expect, antioxidants that reduce ROS have the opposite effect, because they reduce this inducer. There are, however, other inducers that don’t work by increasing ROS, including rapamycin and the inexpensive wonder-sugar, trehalose.

The surprising, nasty part of this story is reported in a big new paper, “Antioxidants can inhibit basal autophagy and enhance neurodegeneration in models of polyglutamine disease” (in Human Molecular Genetics, 1 September 2010). The paper has a lot of content, but in outline:

All tested antioxidants blocked autophagy induction, and all autophagy inducers were subject to being blocked. This included rapamycin and trehalose, which have nothing to do with oxidation and ROS levels, and it includes calorie restriction, too.

With caveats regarding the antioxidant doses used and the limitations of both in-vitro experiments and animal models, it seems that:

• Life-extending interventions induce autophagy.
• Strong antioxidant interventions block this effect.

In short: Slowing damage interferes with repairing damage.

Possible directions

This result suggests lines of research, but perhaps also directions for prudent modification of (still) popular antioxidant supplementation regimens.

Levels of antioxidants

One response is to give more credence to the negative results of antioxidant trials, because evidence for a mechanism always reinforces evidence for a result, and in this instance, the nature of the mechanism also suggests that the negative results can be generalized. This shift in the balance of the evidence tends to discourage antioxidant consumption, at the margin.

But which antioxidants, and to what extent? Although “antioxidants” may share a name, their effects differ, as do people, their aims, and their states of health. Vitamin E is not interchangeable with cocoa powder (in fact, nothing is interchangeable with cocoa powder…[slurp, return cup to table]…). Context matters, too: for example, antioxidants can have a strong positive effect on the immediate, postprandial response of the vascular system when consumed with a meal.

Timing of antioxidants

A second, compatible, direction of response might be to try shift the balance of cost and benefit associated with dietary antioxidants.

The key is that a brief interval with intensified autophagy could potentially induce a lot of repair, while forgoing supplementary antioxidants during that interval would sacrifice at most a small increment of benefit (a fraction of whatever the cumulative benefit might be).

In other words, sometimes remove the blocking agent.

How much good might upregulated autophagy do, and how quickly? Research noted in this review — “Towards an Understanding of the Anti-Aging Mechanism of Caloric Restriction” [pdf] (in Current Aging Science, 2008) — suggests surprising potential:

Recent data show that the acute stimulation of autophagy by the injection of an antilipolytic* drug can rescue older liver cells [in rats fasted for a day] from the age-related accumulation of oxidative damage of mtDNA in less than 6 hours [as indicated by levels of the marker 8-hydroxy-2-deoxyguanosine]

A strong stimulus evidently changes not just the rate of autophagy, but also the targets.

[*Addendum: Antilipolytics (for example, Acipimox high-dose niacin) inhibit fat metabolism.]

Research in autophagy is exploding. I’ve seldom explored a literature where so many of the important papers are less than a year old.

What I’ve written here is just a sample of some of the recent information, together with a few ideas about what some new information may mean for an old puzzle and some practical questions. I’m sure that there are further insights (and corrections) that can be extracted from the literature in place today, and I look forward to seeing that literature itself become half-obsolete next year.

Meanwhile, please don’t inhibit autophagy in your cells (at least not all the time), and consider giving them a healthful autophagy-inducing kick from time to time. The current state-of-the-art advice (Nature Cell Biology, September 2010) is basically simple: Fast.

See also:

• Autophagy: Why you should eat yourself
• Trehalose, autophagy, and brain repair