Monday, January 12, 2004

What does oxygen teach us about being careful in interpreting psychiatric research?

MARGINALIA  (in American Scientist Online)

The Story of O
Roald Hoffmann

Everything in oxygen chemistry seemed more or less in place: Up there, in the stratosphere, there were oxygen atoms, O2 molecules and ozone, O3, as well as ions derived from these and a bit of active OH, all in a dance of creation and destruction.

Meanwhile, within our bodies, normal O2 served us well. There was even a place, under enzyme supervision, for the somewhat nasty relatives hydrogen peroxide (H2O2 and its deprotonated form, O2 2-) and superoxide (O2 - and its protonated alter ego, HOO●), whose chemistry may generate the harmful hydroxyl radical ●OH. Of course, there's also water everywhere. And here and there singlet dioxygen, a more reactive and excited state of normal diatomic oxygen.

A nice, neatly compartmentalized world: ozone for atmospheric chemists, but not biologists, who had plenty of more complicated molecules to worry about.

So they thought...

I love articles like this.  The article by Roald Hoffman, in American Scientist, describes new findings regarding the various forms that oxygen takes in the human body.  Of particular interest is the discovery that the human immune system has mastered oxygen chemistry, to produce a variety of unusual forms of oxygen.  The following excerpt describes the salient details:

In the past three years, Scripps Research Institute chemists and biochemists have dramatically revised this picture. Richard learner, Albert exchanger and Paul Wentworth, Jr., collaborating with several groups, first discovered that all antibodies could produce hydrogen peroxide. More recently, they have found that antibodies appear to catalogs the generation of ozone! The overall reaction (unbalanced, and obscuring many intermediate steps) is

H2O + 1O2 H2O3 O3 + H2O2 + O2

This reaction includes many of oxygen's protean molecular manifestations: Aside from the familiar water, hydrogen peroxide, excited singlet and normal ground state oxygen, it contains the unusual HOOOH molecule. Dihydrogen-trioxide was proposed more than 60 years ago, but direct proof for its existence has trickled in over the last 30 years. There is also a possible role for the HOOO radical, not shown in the equation, which in turn may be a masked OH. All are reactive molecules, as shown by their short half-lives in water: around 1 minute for ozone, 20 milliseconds for HOOOH and 1 microsecond for 1O2.

Don't get wrapped up in the details of which electrons go where, unless you're more of a chemistry nut that I am.  The reason I am writing about this is that it shows, in just one specific instance, how little we know about human physiology.  You might have thought that if there is one chemical in the body we understand, it would be oxygen.  It turns out that we are just scratching the surface.  There is one form, 1O2 , that is present for mere microseconds.  that makes it extremely difficult to study.  This illustrates nicely how difficult it is to gain a full understanding of The Way Things Work. 

One of my pet peeves, in my line of work, is when I hear a therapist say that he/she is going to "solve the problem once and for all," by "getting to the root cause of the problem."  Now, this is not a diatribe against therapists.  Persons whom I respect highly have claimed that hey know the "root cause" of some neurosis or other.  I would submit the thesis that we are not even close to knowing what the problem really is, much less what the root cause is.  Psychopharmacologists are susceptible to the same kind of thinking.  You may have heard people say that depression is caused by a chemical imbalance: not enough serotonin.  Right.  We all know that serotonin is a chemical messenger that nerve cells use to communicate with each other.  One cell releases serotonin, the serotonin binds to the receptor, and that creates the message.  Ha!  if only it were that simple.  It turns out that there are many different types of serotonin receptor, as illustrated in this excerpt from a different article:

 Although discussed in greater detail below, for purpose of introduction suffice it to say that radioligand binding (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1S, and 5-HT2A), autoradiography and binding (5-HT2C), molecular biology (5-HT1Da, 5-HT1Db, 5-HT1Eb, 5-HT1F, 5-HT2B, 5-HT5A, 5-HT5B, 5-HT6, 5-HT7), and various functional assays (5-HT1P, 5-HT3, 5-HT4) accounted for the discovery of the different populations of sites.

Now it is starting to get a little more complicated, isn't it.  When you consider that each receptor is comprised of several protein subunits, and each subunit exists in different forms -- encoded by different genes -- and that each of these genes can be regulated independently, you see that for each receptor subtype, your brain has hundreds of thousands of different ways to make each one.  All function slightly differently.  We have only the vaguest notions of how those genes are regulated.  So yes, depression is a chemical imbalance, but exactly which chemical is it?  And what kind of balance is supposed to exist?  And how exactly did it get out of balance?

For various reasons, we would like very much to believe that we understand the brain, and how the brain produces various kinds of anguish.  but the fact is, we do not understand.  Not even close.  We don't even know what oxygen does in the body, and oxygen is one of the simplest chemicals there is.  This llustrates how important it is to stick as much as possible to empirically derived data when planning mental health treatment.  It also underscores the importance of having the skills necessary to know what valid conclusions can be drawn from the available studies, and what conclusions are nonsense, no matter how seductive they may be.