Saturday, February 13, 2010

Better psychoactive drugs

Careful choice of organisms yields faster drug screening

One of the lesser-appreciated aspects of biology is the momentous choice of research subject. Most biology is justified in medical terms, i.e., better understanding of ourselves as the target organism (I am speaking of molecular biology, mostly, not ecology and systematics). Yet that target is dauntingly difficult to work with. Generation times on the order of 25 years, enormous size, prone to high-maintenance living standards, and capable of organized political resistance to intrusive investigation, to say nothing of euthanization at the end of an experiment. No, something else needs to be done!

Fortunately, there have been plenty of questions amenable to biological investigation without resorting to inhumane methods. Many studies use cells isolated from humans, either taken recently and quickly amplified to large numbers, or developed from cancers which render those cells immortal for laboratory work. These unquestioning and docile research subjects are useful for cell-centric questions, like how the nucleus talks to the mitochondrion. But how brains work? That question is not going to answered in such a lab.

The unity of life allows us to go farther afield, however, and use other systems and organisms to answer significant questions. Bacteria and viruses were long the darlings of molecular biology, back when DNA was a novelty, and the most basic questions were being asked, like how any kind of living metabolism works, how proteins are strung together, how DNA controls protein production, and how simple cells orchestrate division. Bacteria are easy to grow, genetically simple, and a treasure trove of molecular information and tools- especially the many enzymes that have become standard in the field, like DNA polymerases, ligases, and cutting & trimming enzymes.

Yet with rising ambition, more complicated questions were asked, like how the golgi apparatus works, or the actin cytoskeleton. Bacteria don't have either of these internal structures, so other organisms were consulted- the simplest ones to have such (eukaryotic) structures but still be easy to work with. Baker's yeast fit this bill, leading to a rich research field that still is making great contributions to biology. And so it goes. Q: animal development, including simple brain development? A: fruit flies and nematode worms. Q: neuron, synapse, and reflex functions? A: The large sea-snail Aplysia. Q: plant-specific molecular biology and genetics? A: the mustard weed, Arabidopsis.

Lately, a small fish has become a popular- the zebrafish, Danio rerio. One of its benefits is that it is highly transparent, so its development is easy to watch. Also, as a vertebrate, it is much more closely related to the most important organism of all time (us) than are the other developmental models (fruit flies and nematode worms), while being much easier to grow and study than mice and rats. It represents a nice mean between ease of use and proximity to humans, for many questions.

One of those questions is how the vertebrate brain works, and how to efficiently isolate drugs that act on it. The current paper uses the moderate scale possible in zebrafish labs to screen for such psychoactive drugs, focusing on a relatively simple metric- activity measurements such as the sleep/wake cycle.

The general paradigm for creating psychoactive drugs has been hit-and-miss. Usually, someone happened across an interesting effect serendipitously while tasting/testing a drug for some other use in humans. (Prozac is an example, where the incidental antidepressant effect of some antihistamines led to this class of drugs. Another example is LSD, which was based on the known medically active compounds of ergot mold.)

Otherwise - and this is called the "rational" approach - a protein like a transporter for neurotransmitters is demonstrated to be important for brain function, and expressed in laboratory cells whose activity is then used to screen for drugs that alter the action of that protein/enzyme/transporter, after which that drug is tried on whole organisms, working up to humans if sufficiently promising. The only examples of this kind of drug would be those in already-established classes of chemicals, such as hunts for new SSRIs/Prozac, where, once the mechanism and target were understood, more drugs could be developed against the same target. I don't think any truly novel classes of psychoactive drugs have ever been developed in this way, since the theoretical connection between molecules and brain functions remains rather indirect at best. This method has been used with great success against HIV, however.

Drug screening is a painful, laborious process, often starting with hundreds of thousands of miscellaneous compounds (derived either from obscure natural sources, or chemically synthesized in programs aiming at maximal diversity and appropriate-ness as drugs). Each is thrown at some cell or organism that has been engineered to test for a disease (cancer cells, for instance), or just watched carefully for interesting effects.

Here, the researchers looked for interesting effects of a battery of compounds on fish embryos grown in a large system of isolated wells, ten per drug treatment. They were able to screen 4,000 compounds (mostly already-recognized drugs) by computerized monitoring of each well, looking for sleep-wake behaviors. (Whether this approach can discover new hallucinogens is not at all clear!).

You can just barely see one fish in each of the square wells.

Graph of one drug's effect on sleeping (black bars) and waking activity (white bars) showing dramatic effects on waking activity, while much less on sleeping. Sounds rather unpleasant for the fish, actually. This drug binds to glutamate neurotransmitter receptorsThe y-axis is measured activity- red, drug treatment; blue, controls with no drug.

What they found were new chemicals that affect sleep and wake cycles and general activity, inferring previously unknown pathways and perhaps leading to novel drugs- possibly a super-Ambien or super-amphetamine. They also show that this is an efficient way to characterize the mode of action of unknown chemicals, by comparing them through various assays with a panel of known drugs. If the patterns match, it is likely that the unknown drug works in the similar pathway, which may in turn tell us where its target protein fits biologically, if its role is unknown.

This group, based at Harvard, appears very well plugged into the pharmaceutical industry, indicating that this work is, in all probability, a demonstration of principle for a new biotech company that may use this set of methods to achieve a golden mean between rapid and broad drug screening, and screening for interesting properties that are medically relevant to us.

Graph showing that two chemical analogs of podocarpatriene-3-one (related to chemicals from the Neem tree used in ayurvedic practice) make the fish quite restless, taking far longer than control fish (DMSO) to quiet down after lights are turned off, which they term rest latency.

  • Basics of modern monetary theory, from Mitchell, also here. Lengthy, but cogent. Includes the following quote from Abba Lerner, about the reticence of Keynesians:
"The scholars who understand it hesitate to speak out boldly for fear that the people will not understand. The people, who understand it quite easily, also fear to speak out while they wait for the scholars to speak out first. The difference between our present situation and that of the story is that it is not an emperor but the people who are periodically made to go naked and hungry and insecure and discontented – a ready prey to less timid organizers of discontent for the destruction of civilization."
  • Some notes on the 'Hockey stick" climate warming controversy.
  • People are happy to have best-of-science near-term weather reports, but long-term weather/climate reports? Not so much!
  • William Mitchell quote of the week, speaking of government deficit terrorists and balanced budgetistas:
"... the use of the term “sound financial management” is an ideological construction which means at worst balanced budgets over the business cycles and maintaining a buffer of unemployed so that wage shares are low (profit shares are high) and inflation is low.
Meanwhile, the more important policy goal of full employment has been subjugated and unemployment used to further the free market ambitions which ultimately are designed to redistribute national income away from workers into the hands of capital. Along the way, the dominance of financial capital has somewhat usurped this process with deadly results as we are witnessing now."

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