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How does Science work?

My education has been sorely lacking in the philosophy and history of science. I’m pretty sure that’s the case for most molecular biologists, and probably scientists in other fields as well. Most of us absorb the scientific method over years of exposure, rather than concrete study of the philosophy or history of the scientific method. I’m starting to feel like that’s a major hole in my education that I might gain some benefit from plugging. Everybody’s heard of Kuhn’s ‘paradigm shifts’ (even if we don’t exactly know what they mean), and we all had some “training” in the “scientific method” (visualize air-quotes), but I’m thinking I should take a deeper look at how things really work. Could a better enumerated understanding of the scientific method make generating research questions easier?

I’m increasingly sure that one of, if not the, most important skill for a scientists is learning how to ask questions. Formulating good, easily testable, likely to be successful, interesting questions is something I’ve been struggling with quite a bit. (I’m intentionally avoiding using the word hypotheses because I want to include exploratory, non-hypothesis driven research also.)

Some people seem to have a natural knack for formulating questions, and I’m pretty sure I’m not one of them. I came across this post at Bitesize Bio about the philosophy of science, leading me to some great lecture notes for an intro to biology class explaining something about the scientific method. I wish my professors had been that coherent and had introduced some of those ideas.

The continuum of scientific methods described below (copied from Brandon, RN, Does biology have laws? The experimental evidence. PSA 1996, vol. 2, 444–457.) is an interesting framework for scientific questions. If nothing else it’s kind of fun to try to place the work you’re doing somewhere on the graph.

continuum of scientific methods
Description from A blog around the clock:

Collecting the information about all the species of birds and salamanders in the mountains of North Carolina is not a test of hypothesis and is not manipulative (and is not experimental) - yet it is certainly science (place a dot in the bottom right corner of the graph) - it provides important information about the natural world. If patterns emerge from such a survey and prompt new ideas about species distribution, this can then be tested in a more experimental fashion.

Human Genome Project is highly manipulative (and expensive!), yet it is not hypothesis-testing (place a dot in the bottom left corner). Nobody predicted that we would find anything but the four nucleotides known to make up DNA. We had no predictions as what the sequence will be and what would it all mean. Once the work was done, we could use the HGP as a tool for testing new hypotheses, e.g., how many genes do we have, how they are related to the genes of chimps, how diverse are particular gene sequences in human population as a whole, etc.

Paleontology is somewhere in the middle. It is somewhat manipulative (it takes hard work and a lot of people to do it) and it is somewhat hypothesis-testing (place a dot smack in the middle of the graph). Paleontologists do not dig randomly - they dig in particular places on the planet in particular layers of the sediment, looking for fossils of particular kinds of organisms. For instance, a group recently did an excavation in a particular bed of Late Silurian layer, looking specifically for a fossil of an early tetrapod, i.e., a transitional organism between fully aquatic and fully terrestrial mode of life. They discovered exactly that - a fossil named Tiktaalik whose fins were better suited for walking on land than that of fishes (like mudskippers, catfish and lungsfish), yet not completely evolved for land use as in amphibians.

Sometimes nature provides an experiment that tests a hypothesis (a dot in the top right corner). For instance, a biogeographical model of island succession was tested when the volcano Krakatoa erupted and eliminated all life from the island. The scientists went there and observed which organisms flew in from the mainland, in which order, and how the ecosystem passed through several stages until it reached its mature stage, thus confirming (and somewhat modifying) their hypotheses.

I’m still not sure I understand the idea completely. For my own work, at least, I spend a lot of time manipulating data other people in the group have generated and mostly just describing it, while trying to find some patterns that I can generate hypotheses about. I guess it’s the molecular version of collecting information about all the birds and salamanders, but hoping to coming up with a few testable hypotheses along the way.

Does having a better understanding of how the methods you use fit into the larger framework of the scientific process help you to be a better scientist? I’m not all that sure it does for everyone, since several people I know to be good scientists couldn’t care less about the philosophy of science. Yet I have a feeling it could help me. I guess won’t know until I put the effort in to educate myself and find out.

Toward a Genetic Suicide Note

The Oct 15 edition of Biological Psychiatry published two articles on the epigenetics of suicide. Typically, suicide in the young and old is blamed on childhood abuse, maltreatment and related “environmental” stressors. It’s believed that suicidal tendencies stem from the frontal cortex and hippocampus. Obviously, everything leads back to a gene or two at some point, making, as my PI would say, “this hypothesis somewhat lacking in explanatory power.”

Two recent studies show evidence in the depressed suicidal brain of what authors like to call “epigenetic” mechanisms, defined here as “a chemical modification of the DNA and/or the histone proteins associated with it.” In this case, the authors believe a small but vital stretch of DNA which regulates codons, or DNA sequences that code for proteins, is being both under and over expressed in the brains of depressed suicide victims. This region regulates the production of a neurotransmitter protein, GABA-A a1, known for its calming affect–think Prozac. The confusion lies not at the level of the gene, or even the protein, but at higher levels: divisions and subdivision of the prefrontal cortex where these expression levels are collated and the possible conflation of depression with suicide.

Another confounding factor is the timing of expression levels of this regulatory region. If the autopsied frontal lobe of adult suicide victims is chemically different than what it was preceding the suicidal state, then the expression levels could be a result of the suicidal state and not the cause. However, if expression levels were already present, for example brought on by an early childhood psychological trauma that led to a mood disorder, then the scientists would be on to something. In other words, are these expression levels acting as a genetic suicide note? There is some evidence that this the case, since a similar region regulating similar genes in the frontal cortex is under constant epigenetic alteration throughout the brain’s development. A commentary in Biological Psychiatry on the two papers:

Therefore, one might speculate that alterations in DNA methylation and other types of chromatin modifications eventually could emerge as key events in a pathophysiological cascade originally triggered by adverse events and various stressors in childhood and adolescence, then impairing GABAergic and other neurotransmission and significantly increasing the risk for suicidal behaviors in the context of mood disorders or schizophrenia and other psychiatric disease.

Of course, the larger issue at hand is the brain itself, a three-dimensional, highly intricate and interconnected wet-works of microscopic data processors encased in a hard shell, and how to get at it. Unlike most behavioral research, this one is unique in that it takes a direct approach to brain research–as opposed to those dime-a-dozen MRI studies–by studying the nasty bits of the newly dead parts.

All in all, the argument for epigenetics seems kind of lazy since the authors haven’t shown heritability in chromatin modification in the gene they’re studying.

Moonlight Sonata

No brushwork, but a pallet knife pushing yellow, green, dark gray, titanium white, and persian blue.

Some Chicken Soup for the Science Writer’s Soul

Blake Stacey has a good deal of insight at the end of an essay that needs wider dissemination. The part I’m concerned with is about the vulgarization of science in the mainstream media.

When the connective tissue of the science is cut away, we lose our ability to understand how progress is being made. Even when the popularizers of science are not actively spreading nonsense because it sells, they are fated to miss the meat for the gristle. What matters is no longer the facts of the science, but the story it is easiest to tell.

The tendency in science writing when one approaches difficult to explain terrain is to launch into a great diversion effort of the material by changing the focus to something more palatable. In other words, if you can’t explain the science, gloss over as quickly as possible and move on.

. . . the temptation will always be to plump for the “social” angle and emphasize the personalities of the physicists involved. This leads you to classic failure modes like the “Oppressed Underdog,” David readying his slingshot at the Goliath of the scientific establishment. My “typical statement” is a paraphrase of Jacques Distler, who pointed out this problem almost six years ago; it’s still alive today, and kicking more than ever. We see it frequently enough in physics, but even biology is not immune, when the science turns on relationships among propositions. You don’t need intimidating jargon, though it helps: all you need is for the actual relationship between David’s idea and Goliath’s orthodoxy to be mathematical in nature.

In defending this thesis, I recognize that I’m leaving myself open to the accusation that I am an “elitist” - indeed, even an Elitist Bastard. How dare I suggest that science is not readily transparent, that the training one receives in climbing the steps of the ivory tower is necessary to enjoy the view from the top? I cannot refute this calumny: all the water in the Tennessee River cannot wash out an MIT degree or a year spent in France. Yet, if education is to mean anything, we must confront its problems as they stand. If we do not identify the obstacles in our path and work honestly to overcome them, then the process of education will be a useless charade, and the hope of a scientifically literate populace will be more distant than ever.

The Oprah-fication, tripe-based Chicken Soup for the Soul approach to science writing today, coupled with generally poor science knowledge among the citizenry, paves the way for the Deepak Chopra’s of the world. And the rot runs deep, at times clear up to the New York Times, New Yorker and The Best American Science Writing series.

Unfortunately, backseating science to front-load an article with the personal narrative or human aspect is what’s taught at Johns Hopkins where I earned a degree in science writing. (sources say that this is also the case in MIT’s new science writing program). Atul Gawande’s Complications: Surgeon’s Notes on an Imperfect Science was what we were told to aspire to as an example of award-winning science/medical writing. The book contains well-written science-free accounts of medical curiosities and the patient/doctor relationship, and that is all.

None of my writing instructors were ever scientists, so I witheld my criticisms; a decision I now regret. This may sound damning, but they were not interested in conveying science or educating the public, only in putting a human face on everything we wrote. More’s the better if we slipped a little “vulgarized” science in undetected lest our reader dash his foot upon a hard concept.

Stupid is as Stupid Does

A piece in the recent issue of Science runs with a captivating title: It’s the Sequence Stupid!. Also a bad joke considering the research model discussed is Down Syndrome. Anyway, according to work done on transgenic mice with Down Syndrome, the authors say,

[Wilson et al.,] findings also call into question one of the basic tenets of comparative genomics: that evolutionary conservation can serve as the primary tool for finding functional sequences [and] although many conserved noncoding sequences are functional, and interspecies comparisons can help us to identify these motifs, narrowing our attention only to these sequences must result in an incomplete understanding of the regulatory code. Indeed, this approach guarantees missing the species-specific regulatory instructions that make us different from mice.

So, what did they find? The researchers gifted a cohort of mice a few genes, the entire human 21 chromosome, relying on the mouses regulatory regions to govern them. They sat back and observed. Their tests showed that the regulatory mouse regions not only understood the foreign chromosome, but, in a way, honored its human integrity by incorporating it into mouse cells. Maybe all this tells us is that mouse and man are not that dissimilar. What about fish and human?

The Fugu hematopoietic transcription factor gene, Lck (Lymphoctye tyrosine kinase), is 4.2 kb, (twenty times shorter than its human ortholog), but apparently all the important stuff for this gene is functionally the same between teleosts and mammals. Fugu, like e. coli, keep a tidier sequence than most mammals, which is why theirs is often the preferred promoter element for regulating T cell activity in mouse models, despite some amino acid differences. The two promoters for Fugu Lck are only 2.3kb away from the coding region, whereas in humans, the proximal promoter is 40kb from the start of transcription. That’s not very proximal if you ask me, and makes me wonder how the hell they alighted on the sequence in the first place. Good work whomever!

Still, only a quarter of the entire Fugu gene (830 bp) is required to regulate human T cell maturation (in Jurkat cell lines). The obvious answer, then, is that the proximal and distal Lck promoters in Fugu are similar enough to human to regulate production of human LCK proteins, implying that this teeny stretch of non-coding DNA has been conserved in teleosts and mammals for 400 million years. Well, it must be useful.

The authors of the Science piece argue that they stumbled upon a highly conserved yet-to-be-deciphered genetic grammar somewhere in the transcriptional region that enables a mouse cell to read direct human genetic sequences. What about other closeley related species, or distant relatives, such as gator and girzzly? Their recommendation is ENCODE and more bioinformaticists.

Armed with this paper, Larry Moran shakes it like a stick at the evo-devo crowd and the cis-elements they rode in on.

A.M. Turing: Can Machines Think?

First, a primer on the topic. According to Turning, Artificial Intelligence has three criteria.
1. Humans born of natural means are excluded
2. Any engineering method may be deployed in the “machine’s,” construction.
3. Although the “machine” is constructed, the manner of operation cannot be satisfactorily described by the constituting components (parts do not equal whole).

To help understand how to approach such a question, Turing devised a game, called the Imitation Game. The game consists of three players; a male, a female and an interrogator. The interrogator can not see the other two players, but can ask them questions. The answers are typed so voice is not a factor.

The object of the game for the interrogator is to distinguish the male from the female. The object for the male is to trick the interrogator, and the object for the female is to help the interrogator choose correctly.

Thus, we have Turing’s revised question.

Will the interrogator decide wrongly as often when the game is played like this [with a computer rather than a man] as he does when the game is played between a man and a woman?

He concludes.

In about fifty years’ time it will be possible to program computers…to make them play the imitation game so well that an average interrogator will not have more than 70 percent chance of making the right identification after five minutes of questioning.

Common Objections to Turing’s Conclusion:
1. The Theological Objection
Religious Leader in Funny Hat: Only creatures with souls can think and souls can only come from God

Turing: If man can create babies (with souls) then why can’t they create other things with souls? Additionally, the Bible is not a reliable source.

2. The “Heads in the Sand” Objection
Conservative Republican: The consequences of machines thinking is too scary to even think about.
Turing: This objection is not really an argument, just an avoidance of the issue.

3. The Mathematical Objection
Philosopher
: There is a finite limit to a computer’s knowledge whereas human’s have no limit, therefore computers are inferior.
Turing: It is not proven that man’s knowledge is limitless. Since that is the basis of this argument, it falls apart.

4. The Argument from Consciousness
Liberal Arts Major: Machines do not feel emotions nor are they able to create art. (music, poetry, etc.)
Turing: It is impossible to test this. One can never really know if a man is feeling emotion unless we were inside that man’s head. Therefore we can never know if a machine thinks without being inside that machine’s head.

A Few Discussion Questions I Came Up With:

1. Do you think that Turing’s revised question is a valid replacement for the question, “Do machines think?” How might this change the question at hand?

2. Do you think that machines have reached the point where they are able to “trick” humans? What would be the repercussions for our society?

3. According to the definition of “machine” as given by Turing, would Robocop fit the criteria?

4. What would Aristotle (think teleology) have to say about Objection 1?

6. In Objection 2, it states that the fear of machines thinking comes from the idea that humans would loose our “commanding position” if machines think. So, would we?

7. If a machine can out wit a person, would that mean that it could think?

8. Do you think that a machine must be able to feel emotions or create art in order to “think”? Do you think that machines must be able to feel emotions or create art in order to be considered AI?

9. If it were proven that machines had advanced to the point where it was impossible to tell them apart from a human when playing the imitation game, would that make the machine a humanoid or quasi-human? What other criteria would they need to have?

Midwest Cynicism

I think successful articles are accessible, revealing, and challenge our notions of what is. The theme of this article is uncertainty and change, embodied in a black candidate, in a predominantly white working-class state imploding under unemployment.

Party’s Over

This just in.  A team of scientists recently observed a small hunting party of Pan troglodytes in Senegal using sharpened spears. We’ve known for a long time that chimps fashion tools within a “foraging context,” be it cracking nuts with rocks or prodding termites with sticks. This is different, unprecedented. According to the paper published in Current Biology, these advanced Senegalese chimps of the Fongoli community are into weapons manufacturing. They start with a suitable branch, remove sundry leaves and ancillary twigs, strip bark, then gnaw one end to a hurty point for vicious thrusting and forceful impaling of prey. The victim, a nocturnal prosimian, the cute bushbaby.

Tool use has been previously defined as “the external employment of an unattached environmental object to alter more efficiently the form, position, or condition of another object, another organism, or the user itself when the user … is responsible for the proper and effective orientation of the tool.” †

To add another strange fold to the story, the researchers report that youngsters and females were wielding the spears. Typically, male chimps do the hunting. This may cause us to rethink our own tool-making evolution, possibly giving females a greater role in that department. If, that is, we’re around long enough to ponder such questions.

Today it’s bushbaby kabobs, tomorrow it’s human babys. The days of our dominance as a species have cycled to End Times. “Ho hum.” you say. “The day I see a troglodyte win Project Runway then I’ll start to worry.”

† B. Beck, Animal Tool Behavior: The Use and Manufacture of Tools by Animals, Garland Press, New York (1980).

Infamous Art

I submit a poem inspired by the art of Stephen Gammell, illuminating one of my favorite childhood book series.

Ghouls and ghosts and creeps unite!
Look at the way the moon alights
Shadowing our length among the trees,
We’re festooned about the canopied eaves,
Leering down from dead-leaf heights
–Sneering at the grownups affright
To worldly economic unease
As their children group like Ovis aries
Chewing toward their dental blight.
Adults, let not your fears decease
Your offspring be ours Halloween night.

Francis Collins’ Politcal Coming-out

The former head of the National Human Genome Research Institute wrote an op-ed in the Virginia-Pilot endorsing Barack Obama for president. The Pilot has a modest readership of 186,500, is losing its local ownership to a national news conglomerate, and competes with The Daily Press in a tri-county region of 1.7 million, many of whom are military.

Collins, a Virginia native, is a moderately well-known scientist–lodged somewhere between Steven Pinker and E.O. Wilson in the national concsious. Using his hometown paper as his moment of political coming-out makes some sense instead of the obvious New York Times. However, his keeping-it-real gesture and his timing are not without political merit. The majority of American’s polled who actually watched the last debate said Obama swept the floor with McCain’s hairplugs. On the day Collins’ article was published Obama had a 12 point lead over McCain in this Tracking Poll. Not only is McCain unpopular, but Obama’s numbers haven’t fallen below 50 this month.

The Virginia-Pilot doesn’t make op-eds available online, so I placed a scanned copy below. The piece begins with a few statistics for a feel of legitimacy, but this is an op-ed piece, and Collins opines gingerly, outlining Obama’s outline of initiatives for science and technology in a Democrat controlled White House and Congress.

After suffering under the yolk of an Administration whose politicization of science sunk to never-before-seen fathoms, whose cronyism filled environmental regulatory agencies with corporate foxes–and whose political litmus tests banned others from hundreds of federal advisory committees–whose cynicism cravenly kowtowed to a small yet annoying coterie of fundamentalist retards, thus allowing the actual, unthinkable possibility of creationism entering the classroom–and the no less shameful banning of human stem cell research and ignorant cautioning against creating ungodly chimeric abominations in the laboratory, whose systematic misrepresentation of the data muzzled its own–and in some cases had them fired–when their results didn’t jive with republican talking points, and whose initial failing to fill key scientific posts, such as naming a presidential science adviser and NIH director, was a damaging sanction placed upon every American scienctist from day one. Taken together this is a vile epidemic and Collins the M.D. rises to the occasion:

As a citizen, a scientist, a physician and a son of Virginia, I am deeply concerned about these trends and continued lack of National leadership.

Whoa! Now that Collins has resigned, free of the Hatch Act that checks the mouth of all federal employees (ahem), he wastes no time charging in, guns blazing, with strong words for the current Administration’s bad ideas and McCain’s identical ones. Behold more righteous indignation:

I regret to say that I have found little comfort in Sen. John McCain’s plan.

Hot dog. Them’s fighting words. Or, this is a political maneuver to curry favor with the next president. And as with all politcal maneuvers, there’s a rush to the middle-ground: that wasteland of words, that Clintonian triangulation of opaque rhetoric. For the last eight years Collins collected a paycheck from the federal government, was witness in real-time to the damage done, and no-doubt felt the financial strangulation of basic research in his own institute for close to a decade. And now, his first public response is barely a vertebrae above spineless, a wag of the finger. I say, if you want to play politics, go in whole hog or don’t go in at all.