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Jack Wells and the key to sleep

By Christine Graham / Intern
July 22, 2002

"Beep, beep, beep"

The grating beep of my Sony alarm clock pulls me out of a deep sleep. "Damn adenosine," I groan, thinking groggily about the upcoming day's research agenda. Soon, the aroma of brewing coffee teases my nose, and the first hot sips soothe my tongue. I thank my lucky stars that we have caffeine to negate the vile effects of adenosine, the chemical that causes drowsiness and reduced brain activity in the morning.

I learned what to curse on mornings like this while spending a semester as a science communications intern in the laboratory of Jack Wells, a professor of pharmacology at the Vanderbilt Medical Center. He studies adenosine, one of the many chemicals that constantly rush through the blood stream as we move unsuspectingly through the day.

On the way to my first meeting with Wells, I got lost in the medical center's maze of white hallways. When I finally arrived at his laboratory, I was flustered, five minutes late and expecting to be met with disapproval and annoyance. Instead, Wells made a joke about both the medical center's construction and my directional skills. Dressed in jeans, a button down flannel shirt and glasses, Wells' appearance coincided with his relaxed demeanor. Through my internship, I learned that Wells applies this easygoing approach towards his research as well: He just tries to ask good questions and then find the right answers.

Wells has spent his thirty-nine-year career studying just two molecules: cyclic AMP and adenosine. Of course, both of these molecules play a vital role in all living things.

Adenosine is a special kind of molecule

Adenosine is a special kind of molecule, called a signal molecule. The body uses signal molecules to trigger specific responses. When it releases signal molecules into the bloodstream, they bind to certain receptors on target cells, causing something inside the cell to change in a very specific fashion. [dfs1]Adenosine is used throughout the body where it can have sundry effects. For example, it affects alertness, heartbeat, blood vessels' diameter and the wound healing process.

Adenosine is only one of many signal molecules in the bloodstream. Each signal molecule has a distinctive shape, like a key has its distinctive groove pattern. These patterns fit together with the shapes of different kinds of receptors that extend outside the membranes of all the cells in the body, ranging from brain cells to heart cells to blood cells. The receptors act as a lock and the signal molecules act like a key.

When an adenosine molecule finds its matching receptor on the surface of a cell, it binds snugly. This contact causes the part of the receptor inside the cell to change and activate another signal molecule inside the cell, called cyclic AMP. Cyclic AMP then triggers a complex cascade of chemical changes within the cell. When adenosine molecules bind to their receptors in heart cells, for example, the receptors are part of a complex protein called a potassium channel that regulates the concentration of potassium ions inside the cell. Because potassium concentration in cardiac cells affects the heart rate, changes in potassium concentration can alter the heartbeat.

The body's signaling system is similar to the game of mousetrap

The body's signaling system is very similar to a childhood game called mousetrap. In this game, the players construct an elaborate contraption of ramps and levers. When a player releases a marble at the top, the ball rolls down a ramp and triggers a lever to release another ball. The series of reactions continues until it eventually lowers mousetrap upon the unlucky "mouse".

Physical feelings, from sleepiness to happiness to anger, are all regulated by systems like this. When a chemical is released into the body, it binds to a receptor and causes a series of reactions that eventually cause us to feel the way we feel. Rube Goldberg would be proud.

As I sip my coffee, I feel my head clearing and my eyes opening wider. Coffee's perking effects are directly related to adenosine's chemical cascade. As we drink our morning coffee, caffeine is released into our blood stream. Caffeine's chemical structure is very similar to that of adenosine, so it can bind to adenosine receptors as well. It does not have adenosine's groove pattern, however, and cannot trigger the release of the next chemical, cyclic AMP, in the cascade within the cell. So caffeine has an effect something like putting a piece of tape over a door lock: It keeps adenosine from binding to a number of receptors and therefore decreases physical feelings of drowsiness.

The complexities of adenosine's effects

Of course, it is much more complicated than that. Adenosine actually has four different types of receptors, meaning the adenosine key can open four different locks, and each receptor triggers different functions in different parts of the body. For example, Wells studies the adenosine A1 receptor, which decreases the heart rate in the heart, decreases wakefulness and brain activity in the nervous system, works as an anti-diuretic in the kidney and helps with wound healing and hair growth throughout the body. Activating one of the other receptors causes an entirely different set of effects.

Currently, doctors prescribe adenosine as a heart medication. The fact that it unlocks all four types of receptors throughout the body, however, means that it has a number of undesirable side effects. To reduce such side effects, drug companies are attempting to create new compounds that act like adenosine, but that are more specific and will unlock only one type of adenosine receptor at a time. Before they can synthesize such compounds, however, scientists must work out the structure of the four adenosine receptors. That is where Wells' research comes in. He is trying to determine the exact part of the A1 receptor that binds with adenosine.

The A1 receptor sticks through the cell's membrane, much like a thread looped through a pants leg to form a hem. The receptor passes through the membrane seven times. The part of the thread looped on the outside of the pant represents the part of the receptor that is in contact with the world outside of the cell and the part of the thread looped on the inside of the pant represents the part of the molecule that is in contact with the cell's interior. The portion of the receptor that passes from one side of the membrane to the other is called the trans-membrane span. The seven trans-membrane spans form a cup-like structure that opens outward on the cell surface. If adenosine molecules are present outside the cell, they can fit into the cup and activate the receptor.

The receptor is a protein constructed from a string of amino acids, which are the building blocks of proteins. There are twenty different types of amino acids, and the chain's order and repetition of amino acids makes the adenosine receptor different from any other type of protein. Somewhere in the chain of two hundred amino acids, there is an amino-acid sequence of about 12 units that constructs the key that fits the adenosine lock. Wells is trying to identify this exact sequence.

Wells' childhood in rural Kansas

This kind of research requires the meticulous laboratory work that Wells loves. It is the kind of work Wells did not even know existed when he was growing up in rural Kansas. However, this lab work also requires a love of discovery and an imagination, both that took root when Wells was a small boy.

Wells grew up on a farm in Jefferson County, Kansas. He cannot even lay claim to a hometown; the nearest town was 5 miles away. Jefferson County was hilly and wooded, full of small farms but isolated from industrial America. The government did not put up electric power lines in Jefferson County until the 1940's and even then, each household received only two power plugs and a bare bulb light fixture in each room.

Growing up in Jefferson County took imagination. Neighboring farms with children were more than a mile away, so Wells had to make up his own games. Every summer when locusts hatched, they became unknowing participants in Wells' games. Wells would attach wheels to a Velveeta cheese box, harness the bugs to the box, and watch the June bug chariots race across the kitchen floor.

Sometimes Wells would walk the mile and a half to the neighboring farm, which had boys his age. They would play games like cops and robbers. The boys were the escaped prisoners, the dog played the prison guard and the corncrib was the jail. The object of the game was to evade the dog as long as possible and stay inside the string of barbed wire that surrounded the property. One particular afternoon, however, Wells careened into the barbed wire, slicing his face open from mouth to ear. His friend's mother almost fainted when she saw the blood and rushed him to the doctor in the neighboring town.

The local doctor was a role model

The doctor was a figurehead in the area and had always been a role model to Wells. Partly because of the doctor's influence and much to his parents' approval, Wells decided to study medicine. He entered Park College in Missouri with plans to go to medical school. When he got there, he realized that he was far less prepared than the other students. It took him a year and a half to catch up. However, he stuck with the sciences, knowing that medical schools favored students who had studied biology and chemistry.

In the process, Wells found that he loved chemistry. Mixing chemicals together to form new compounds intrigued him. So, after making it to his senior year and receiving acceptances to several medical schools, Wells decided to pursue a science career rather than becoming a doctor.

According to Wells, the decision broke his mother's heart. His parents had skimped and saved for years so that he could go to medical school. She, like most people in their area, venerated doctors and never understood why Wells made the decision that he did.

To this day, however, Wells believes that he chose the right profession. "I had no patience for the patients," he remarked. "I was not cut out for medicine and realized that I would much rather do research."

After Park College, Wells continued his science studies at the University of Michigan and received his doctorate in medicinal chemistry in less than three years: two years less than the average. "Everything just fell into place," he said.

From Michigan, Wells went on to Ohio State University as a Research Fellow in the laboratory of chemistry professor Melvin Newman and then in 1963 moved to Purdue as an assistant professor of medicinal chemistry. He was promoted to associate professor with tenure in 1967.

Reasons for moving to Vanderbilt

His stint at Purdue was the only time Wells ever became jaded with science. He was teaching organic chemistry for students and found that he was spending far more time tutoring students than he was spending in the lab. He was neglecting his research, which was his real love. So, when he was offered the opportunity to come to Vanderbilt, he seized it gladly. Wells refers to it as the best move of his life.

When he arrived on campus, Wells began a one-year sabbatical working with 1971 Nobel Laureate Earl Sutherland, a professor of physiology. Working with Sutherland meant working with his entourage of researchers, not interacting with Sutherland himself. Instead, Wells worked with Joel Hardman, an associate professor in physiology.

At the time, Hardman was researching cyclic AMP. He was swamped with work and handed over part of his research to Wells. That got him started and he spent the next fifteen years researching cyclic AMP. Then the drug companies became aware of its medical potential and launched a major private research effort. Wells could not compete with the private labs, so he turned to a different signal molecule: adenosine.

Wells has developed his own views about science

After spending nearly four decades doing research, Wells has developed his own view of the subject. He claims that science is not complicated: You begin by asking a question, then you formulate an hypothesis and finally find ways to prove or disprove it. You just have to make sure you don't fall in love with your hypothesis and stay objective in your analyses, he says.

Wells says that he never expected to be a star and make great big waves in the scientific world. He simply wanted to do good, solid science - he wanted to be someone who asked good questions. When pressed, he will admit that ego is involved in scientific research. Funding for scientists is extremely competitive and a scientist without a high ego and self-confidence will not stay in the field. Science may be simply asking questions; but it is the important questions that receive funding.

At the Vanderbilt Medical School researchers must fund their studies from the grants that they receive. Because researchers must be leaders in their fields to get grants, this system ensures that the level of faculty is maintained, he argues.

Wells smiles as he recounts a rare story about his own fame. His mother and family still live in his old hometown in Kansas where adenosine receptors are far from everyone's mind. Nonetheless, when his mother was at a luncheon one day she overheard men talking about adenosine research. They mentioned Wells' name. When she told the men that he was her son, they informed her that Wells was one of the top researchers in his field. Well recounts this story nonchalantly, as if his mother's pride in the compliment is more important than his own.

Prefers reading detective novels to popular books about science

Although his research has been a driving force in his life, it is not Wells' only focus. When asked which popular science books are his favorite, he answers that he doesn't like science books; He would rather read detective novels by James Lee Burke. After all, he gets enough science through his job.

Wells says that he doesn't usually discuss science with his family. The only exception is when he brags about his youngest son, who works in the business side of science. One reason why Wells doesn't mix science with his family is because many members of his family don't understand the concepts; they just like saying the scientific words, he quips. However, both his wife and his son are educated in science; but Wells says they have more interesting things to talk about. He spends many weekends fishing and camping with his wife and his two sons.

Wells is two years away from retiring. But, just when things should be winding down, they seem to be speeding up. The adenosine A2b receptor that Wells has also researching has been linked unexpectedly with angiogenesis, the development of blood vessels. Wells and his research associates think that they are close to mapping the "keyhole" of this receptor. If they are right, they may be the first lab to do so.

According to Wells, it would be fitting rather than ironic to make such a monumental discovery so late in his career because he believes his thirty-nine years in the field have given him the ability to recognize desirable discoveries in accidental, unsought results." If Wells' lab succeeds, it will certainly provide a serendipitous ending to Wells' career.

Jack Wells' online bio


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