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Saturday, December 22, 2007

Why Scientists like Artists

It is often said that Nashvillians possess two lives. One is spent on a day job to make a living. The other unfolds during the off hours, when we pursue our musical aspirations. If the music works out, we will quit our day job. I was once privileged to meet someone who was about to make this lucky transition. She was recording her first CD. Because I had never witnessed a recording session, I asked her whether I could not tag along to experience what it was like. She graciously agreed, and I ended up visiting a recording studio.

It was different from what I had expected. The location was somewhere in the countryside a forty-minute drive from Nashville. The producer worked out of his basement. Below the keyboards and mixers, I saw plenty computer equipment. The music could be heavily computer-generated. Essentially, this man was able to produce the sounds of all instruments in a band by himself, except the steel guitar. I was told that this was one rare instrument whose sound could not be synthesized to satisfaction yet. On my day, the soundtrack for the steel guitar was recorded. After that my friend sang. She was cooped up in a sound-insulated booth that doubled as the closet for the washer and the drier on other days. All afternoon, my friend repeated the same line until her voice almost broke and she needed a lolly pop to continue singing.

The producer was working with a man who possessed the golden finger that came down on a button exactly at the point in time when the line had to be spliced into the song. My friend had to sing the line precisely the way the man with the golden finger demanded. What he asked for was so nuanced, I could hardly hear the difference. He was profoundly insistent and perfectionist about the process. My friend gave her best to deliver. After three hours, I myself imagined hearing what the man with the golden finger was aiming at. The day went by like a breeze. My friend told me afterwards that she had spent many weeks like this and was not quite finished yet. Her hard work eventually paid off with a collection of beautiful songs, opening the way into the Bluebird Cafe. In Nashville, music means business!

I am not musically versed in any respect. I am a research scientist. What struck me most about the production process was its similarity to the work I know. The beginning of any research study is an idea, that is the hypothesis. The scientist shapes the hypothesis and designs the experiments to prove or disprove it. The results provide new insights. Things may turn out different from expectation. The hypothesis will change and experimentation proceeds until a break-through is achieved.

Watching my friend at work that day, I learned that making a song adheres to the same procedure. The singer/songwriters and producers shape the tune and the lyrics of the song until they fit perfectly together and all aspects fall in place. Eventually a new song is born. In this process as much as in scientific research, experience is essential for the design of a flawless product, pure and free of contradiction. As many scientists teach, my friend became a councilor. She published a collection of interviews with successful singer/songwriters, giving advice to those who wish to pursue this career. Today, she coaches young talent to get started. You may visit her here.


Addenda
  • When we listen to Bob Boilen's segment on NPR's All Things Considered entitled "Moby: One Song, Two Days, Three Versions" broadcast today, we grasp immediately that artists and scientists are striving in the same fashion to perfect a product shaped countless times in their imagination. In that sense humans seem unique. No other creature we know is able to accomplish such act of creation (05/04/10).
  • It is fascinating how similar the creative process in the arts and the sciences can be. The eminent pharmacologist Otto Loewi had the idea for the experiment that would prove the existence of neurotransmitters and win him the Nobel Prize in his dreams. Keith Richards had the fundamental idea for "I can't get no satisfaction", one of The Rolling Stones' signature songs, in his dreams as well. Loewy needed to scribble notes down on a pad that he had placed on his bed stand. He had had the dream of the experiment on a prior night, but had nothing to write it down with at that time, and forgotten the details when he awoke. When the dream re-occurred, he was prepared with pad and pencil, finding his notes next morning. Richards habitually took his guitar hooked up to a tape recorder to bed and woke up one morning, finding the basic tune for the fabled Stones song recorded on the tape. Listen to this, at times mildly strained, interview with Terry Gross broadcast on National Public Radio's Fresh Air under the title "The Rolling Stones' Keith Richards Looks Back At 'Life'" today in context with Richard's just-published memoir entitled "Life" (10/25/10).
Jazz



Tuesday, December 18, 2007

About the Value of Exercise after Brain Injury

Brain injury is a life changing event. Your health care provider may help you with a stay in a rehabilitation clinic for a number of weeks, where you learn how to deal with your new life. Then, you are on your own.

Christopher Reeve taught us that it is important to remain upbeat and exercise. Occupational therapy is essential. Nerve cells need stimulation for recovery and repair. Reorganization may occur. Synapses, that is the contacts between the nerve cells, may strengthen with stimulation and use. To advance recovery from hemiparesis after stroke, one novel treatment, Constraint-Induced Movement therapy, entails the temporary restraint of the functional limb while the patient is encouraged to carry out tasks with the paralyzed limb.

We understand little about the repair of broken connections between nerve cells, when, for instance, a sudden snap of the head pushes the brain so forcefully inside the skull that the long processes of the nerve cells are severed. This effect is known as axonal shear. By contrast, extensive knowledge has been gathered on the effects of ischemia, that is when the blood supply to the brain tissue is disrupted, and strategies are being developed to rescue nerve cells under this condition.

We have learned that functional recovery depends on low concentrations of the excitatory neurotransmitter glutamate in the extracellular fluid. Glutamate in high concentrations may cause nerve cells to fire electrical impulses at high rate in intense oscillations causing convulsive seizures. Moreover, too much glutamate may trigger programmed cell death.

Furthermore, free radicals need to be eliminated. Free radicals are highly reactive chemicals that can modify the molecular machinery of the cell to such extent that vital functions cease. They accumulate in high concentrations when the blood-brain barrier is breached, the brain tissue is flooded with fluid, and blood perfusion is disrupted.

Neuroprotective agents are currently tested that may help to minimize the adverse effects of glutamate and the exposure to free radicals.

In addition to medication, however, the right amount of exercise seems instrumental. Remaining passive does not help recovery. On the other hand, one should not overdo it. Too much stimulation may harm already stressed nerve cells. The keys to success are regimen and persistence. One needs to continue exercising at a steady pace, though progress seems elusive.

The tasks to be carried out appear nonsensical at first, because the goals are unattainable. Try anyways. For example, the challenge may consist of playing Tetris, although the clusters of squares disappear from view in the part of the visual field blinded by a cortical stroke cortical blindness). Frustratingly, you may not be able to track the squares, when it counts most. Keep at it! You will do better than you believe. Chances are that you will improve as the days go by, recovering visual function over time.

This is the advice I should have given a former colleague who called me one day out of the blue and asked me what could be done in such a case. Taken by surprise, I could not come up with the idea until after we had hung up. Sadly, she did not leave her number.

You may give it a try here:


Addenda
  • Maggie Fox posted a report with the title "Computer exercise helps stroke victims "see" again" on Reuters today, describing a research study that demonstrates that this idea works (04/01/09).
  • Yesterday, Roni Caryn Rabin posted a report with the title "Study Raises Estimate of Paralyzed Americans" in The New York Times that according to a recent survey commissioned by the Christopher Reeve Paralysis Foundation 5.6 million Americans suffer from paralysis. In roughly 1.3 million people the cause is spinal cord injury. Stroke constitutes the most prevalent cause with 1.6 million cases (04/21/09).
  • Listen to this informative interview with Dr. Olajide Williams by Rebecca Roberts entitled "'Stroke Diaries' Provide Insight For Survivors" on NPR's Talk to the Nation today about recovery from stroke. We can still progress in recovery a very long time after the event (05/06/10).
  • This Wall Street Journal video sums up concisely the progress of research in the recovery of function after brain and spinal cord injury (10/26/10):
  • In the video below with the title "Robot legs help stroke survivor to walk again" Reuters' Stuart McDill reported yesterday on a promising application of a computer-assisted exoskeleton that may help people recover walking after a stroke (11/29/2011):
  • In their article published online by Science magazine last week, Van den Brand and others (2012) provided an appealing proof of a new concept facilitating the rapid recovery of function after spinal cord injury in paraplegic rats. The procedure entails infusion of neurotrophic substances into the cerebral motor cortex and precisely-timed electrical stimulation of the spinal cord, stimulating growth of new nerve cell connections, as well as robotics-supported physical exercise. Watch the demonstration in the video below narrated by Reuters' Jim Drury two days ago (06/02/2012):
Reference
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Sunday, December 16, 2007

Fahrenheit -459.67

Molecules need to be on the move to react with each other. Inspired by his observations on the thermodynamics of gas molecules, the Irish scientist Lord Kelvin conceived it useful to set to zero the temperature, at which molecular motion must come to a standstill. Today, his idea is recognized in the international system for measures, and units of temperature have been named in his honor. Extrapolation from experimental observation has pegged -459.67° Fahrenheit to zero degrees Kelvin. At this temperature, the molecules reach the state of lowest kinetic energy and greatest stability.

However, at higher temperature, molecules are in motion and chemical reactions occur. As a result, energy may be set free. Although this energy can be used to fuel other chemical reactions, some will dissipate unused. The loss is called entropy. Entropy commonly increases with the multitude and the complexity of the reactions, summarily advancing our universe toward Lord Kelvin's endpoint.

Life is an effort to stem this progress. In order to survive, living things need to preserve energy like surfers tirelessly weaving up and down the face of a wave. Every descend fuels the next ascend. Organisms as a whole as much as the cells they are built from have to meet this challenge. This is our lot in life.

In the battle against entropy, nothing lasts forever. The building blocks of living cells are subjected to wear and tear. They need to be continuously repaired or replaced. Even constant upkeep may not suffice. Most cells possess a limited lifespan. Primordial cells must continue proliferation to make up for the losses.

To satisfy these needs, cells rely on two essential tools. One tool is a repository of construction plans for the cellular components. The DNA in the cellular nucleus encodes these plans. The other tool is the machinery that reads the plans, can duplicate them and use the instructions to synthesize the proteins needed to build the cells' components and even entirely new cells. It is existential to protect the plans and keep the machinery functional in order to prevent the manufacture of faulty, useless, and even harmful products.

Free radicals, e.g. highly reactive forms of oxygen, constitute a major group of agents that may modify the construction plans and interfere with proper protein synthesis. Aromatic products of the incomplete combustion contained in barbecue and cigarette smoke, e.g. benzo[a]pyrene, are another group.

Cells possess quality control and repair mechanisms to contain the damage such agents cause, entering into a ceaseless contest between destruction and restoration. If vital functions cannot be repaired, either because of the magnitude of the damage or because the repair comes to a halt, the cells die.

In addition, cells may contain programs that are specifically in place to enact their death (apoptosis) and are used in regular development. For example, skin fuses our fingers together early in embryonic development. Eventually, programmed cell death separates the digits. When the programs for cell death are disabled and programs for cell proliferation are falsely engaged, the tissue may grow out of control, a condition known as cancer.

In the battle for renewal, the brain holds a special place among our organs. Nerve cells proliferate only in a few places in the mature brain, e.g. the olfactory bulbs and the hippocampus. Replacement is a scarce option. Much of the maintenance and repair is left to different cells called glia. The picture shows an early rendering of these cells in the work of Auguste Forel. He called them spider cells.

To date, the precise role of glia remains little understood. Early scientists believed that they constitute the glue that holds the brain together. We know now that one major type, astrocytes, plays an important role in keeping the environment viable for the nerve cells. They remove salts and molecules from the fluid in the extracellular space, preventing levels that would trigger cell death. In contrast to nerve cells, astrocytes multiply after brain injury inflicted by stroke and trauma, producing a gliosis. Astrocytes are also known to enter proliferation erronously. The most deleterious brain cancer, glioblastoma multiforme, is of astrocytic origin.

Microglia are the other major type of glia in the brain.  Their role is more mysterious than that of astrocytes. The difficulty mainly arises from the fact that these cells change considerably in appearance as part of their reaction to brain injury. In the absence of direct observation, it is hard to ascertain whether and how the various cell forms are related that scientists identify as microglia. Hence, it remains difficult to pinpoint their origin. A scientist I worked with had evidence to believe that the microglia accumulating at the site of injury are derived from cell populations resident in the brain. Others believe that they consist mainly of bone marrow-derived white blood cells that infiltrate the brain from the blood stream through a blood-brain-barrier rendered leaky by the injury. Recent findings support both contentions.

Irrespective of their provenance, microglia are supposed to provide the immune response of the brain. They are known to incorporate the debris left behind by dying nerve cells. They attain a plum shape in the process and some remain unchanged on location for many years, even decades, after the insult. We do not yet understand, why they reside there and what purpose they still serve. Regardless, I take it that they are good soldiers in our cosmic fight against entropy and see to it that we do not reach Fahrenheit -459.67 too quickly.

Addendum
I omitted to mention a formidable tool of living cells to stem entropy: enzymes. Enzymes are catalyzing proteins. That is, they facilitate chemical reactions that may happen only at random otherwise by bringing the components of the reaction together, accelerating the biochemical processes important to vital functions of living cells. Compartmentalization of enzymes, that is confining enzymes in distinct parts of the cell, helps organize the reactions into orderly sequences of separate processes, enabling meaningful signal transduction and the regulation of enzymic activity involved in cell anabolism and catabolism as well as in protein synthesis, replication and proliferation. The eminent biochemist Jaques Monod argued in his famed book "Chance and Necessity: An Essay on the Natural Philosophy of Modern Biology" that the first biochemical process of life in its simplest form might have been an enzyme synthesizing nucleic acids containing the information needed to synthesize this enzyme, hence empowering the protein to replicate itself. Alas, enzymic reactions are profoundly temperature dependent and come to a halt far above zero degrees Kelvin.

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