WHAT SNAPS YOUR SOCKS?

                           By Raymond W. Ruddon

 INTRODUCTION

For many years there has been on my desk a foot mannequin covered with a white sock on which is printed a little sign: “What Snaps Your Socks?”  Sometimes, as the seasons change my office administrator brings me a change of socks for the mannequin. I have a Christmas sock, an Easter sock, and a St. Patrick’s Day sock. I’m still hoping for a St. Valentine’s Day sock.

The original white sock covered mannequin was a retirement gift from a colleague of mine, who spent a long and exasperating day going from shoe store to shoe store in Manhattan asking if they had a spare foot mannequin. After putting up with a series of discomfiting sneers and sotto voce comments such as “What a creep,” he finally found an understanding sales person who realized that it was for a joke and not some sexually perverse fetish, and he retrieved one from the store room. The next chore was to find a sock that fit, and my colleague found one in a child’s shoe store. He packed the sock-fitted foot into a Saks Fifth Avenue box, had it gift wrapped, and presented it to me with a flourish at my retirement party (I’ve actually had three retirement parties in my career, but more about that later).

Ever since receiving this “gift,” I have displayed it on my office desk wherever I was working. Everyone who has come into my office, be they deans, upper management personnel, faculty, business associates, students, postdoctoral fellows, lab technicians, secretaries, or anyone else, always asks: “Why do you have a foot on your desk?” or sometimes a less respectful: “What the hell is that supposed to mean?”

Regardless of the question or who the questioner is, I always give the same answer. What follows is a shortened version of it. When I was a young faculty member in the Pharmacology Department at the University of Michigan Medical School, I worked with a more senior faculty member, who became a mentor for me. He was a crusty old gentleman, who didn’t put up with any sloppy thinking, scientific or otherwise. When asked a question, his answers were always curt and to the point. One day, having come to the end of my ideas for what experiments to do next, I asked him timidly: “What should I do next?” Barely controlling his anger, he exclaimed in a voice loud enough so everyone in the lab could hear: “Just do what snaps your socks, damn it.”

Later, reflecting on his words, I realized that they contained some pretty good advice, and I have frequently used the same proclamation over the years with my students, fellows, and junior colleagues. So much so, that it became one of my enduring identifying remarks. Hence, the mannequin.

Most people finally get it, but some never seem to. It’s usually the ones who do get it who have become the most successful scientists. The take-home message is this: A good scientist follows his or her nose – one experiment leading to another based on logic, but most importantly, based on what is the most interesting and exciting thing that they can find out by doing the next experiment.

CHAPTER ONE: WHAT MAKES A SCIENTIST?

This is a question that I have frequently asked myself since I retired from actively running a laboratory. The reason for my curiosity is twofold: I still often struggle with who I am and how I got here and wonder what my legacy will be, if any, and will it be a lasting one? Also, sometimes students who have a latent interest in science ask me what they should do to get ready for a career in science. The answer can be summarized in a few words: you need curiosity, passion, imagination, serendipity, luck, love of poetry as well as of history, music, literature, and at least one great love in your life to share it with. This book is a travel log of how one scientist got there.

A few years ago, there was an article in the New York Times Sunday Magazine about Nobel Laureates and what events in their lives enabled them to win the Nobel Prize. I was somewhat surprised about how much they had in common (although it made sense when I thought more about it) and how much I had in common with them. I must quickly add here that I have never won a Nobel Prize, and, as far as I know, have never been nominated for one.

 1. CURIOSITY

 Parents 

Parents are most often the ones who begin to instill in us a sense of curiosity about the world. I was lucky enough to have a mother and a father who both did this, but in very different ways. My mother was a lover of flowers and often let me help with her gardening, explaining as we went around the flower beds what each flower type was, how they grew, what nutrients they needed, and how much sunshine and water. Try as she might to convince me otherwise, my favorite flowers were the dandelions that grew in the Manion’s front yard that I passed every morning on my walk to and from elementary school. I would pick a bunch of them on my way home and proudly present them to my mother when I got home.   She dutifully praised my taste in beauty and placed them in water in one of her prettiest vases. She was also my best pal and took me on trips with her to Washington D.C., Gettysburg, and Niagara Falls. At each stop, she told me about the history of each site, the natural beauty of the landscape, and how each fit into our Nation’s heritage. Her job as she saw it was to raise me and my two sisters with a sense of wonder and respect for the world around us.

 She took this job very seriously and also was my chief provider of the essentials of my youth. She was the one who bought me my first baseball glove, with a signature I thought was real of Luke Appling, the star Chicago White Sox shortstop. Of course, that was the position I dreamed to play. She encouraged me to use my imagination about games of baseball that I played in our backyard, never making fun of me as I would imagine a full nine inning game by hitting sticks with an old cracked bat. Depending on how far the stick went, it was an out, a single, double, triple, or if over the backyard fence, a homerun. I would also pitch a complete game by bouncing a tennis ball off of the garage door. I was Bob Feller when the Tigers were up and Hal Newhouser when the Indians were up. A panel on the garage door served as the strike zone, and I played the opposing team’s fielders, infield if the ball bounced back on the ground and outfield if the ball popped up.

My father was much less involved in my life than my mother. He had been the president of Federal Motor Truck Company when it was a major manufacturer in Detroit, and worked for the War Department during WW II, which was the time I was growing up and attending Gesu Parochial School. He taught me how to throw a curve ball and explained the reason why it curved. In his youth, he had had a tryout with the Cincinnati Reds. He also taught me how to swim and to catch Northern Pike out at Portage Lake. You had to know about their habitat and where they might be depending on the time of day and the water temperature. Things I still remember, though I’ve never been as successful at it as he was.

Teachers

I was fortunate to have some great teachers during my developing years. I attended the University of Detroit High School, a Jesuit school in Detroit. The Jebbies as they were called by the students were known as the most intellectual of all the Catholic orders and they instilled in us a sense of discipline and the importance of learning, athletics, and manhood. The three teachers whom I remember best are Fr. Nash, and two Jesuit scholastics (in training for the priesthood) Mr. Murphy and Mr. McPartlin.

Fr. Nash taught freshman Latin. He made the Latin quizzes into baseball games by dividing the class into two teams; Army and Navy. Each team was asked questions by going down the line of students lined up on each side of the room, and at the end of the quiz, the team with the fewest “errors” won. By this rather simple ploy, Fr. Nash instilled in us how learning could be fun - a lesson I never forgot and tried to use in teaching my children and students in future years.

Mr. Murphy taught Ancient and Medieval history. This was my introduction to how civilizations developed. He made it come alive. I could visualize and experience through his guidance the ancient kingdoms of Egypt and Babylon, the seven wonders of the ancient world, Alexander the Great’s conquests, the Athenian democracy and civilization, Pericles, the great philosophers Socrates, Aristotle, Plato, the great Greek playwrights and architecture, the beginnings of modern science, mathematics, and medicine. And of course, the history of the Catholic Church and its great philosophers and missionaries: Augustine, Thomas Aquinas, Ignatius Loyola (founder of the Jesuits), and Francis Xavier. He didn’t back away from discussing the Inquisition – how it started, the evil it embodied, and how it eventually faded away. This taught me about the importance of intellectual honesty, no matter how difficult it was to admit what makes you uncomfortable.

Mr.McPartlin taught us Homeric Greek- a staple of the classical Jesuit education. We read the Iliad and the Odyssey in the original Homeric dactylic hexameter. This was a beautiful language. I can still remember the first three lines of the Odyssey in ancient Greek and the wonderful onomatopoeia of the stone bounding down the hill and coming to rest after Sisyphus lost control of it. We had to learn the difficult Greek alphabet in order to read these texts and that caused a lot of angst for many of us, but the lesson was that sometimes you have to do difficult things and learn to be patient to accomplish something important. Mr. McPartlin wasn’t always patient with us when we repeatedly stumbled over the same text. Ignatz was his favorite moniker for slackers, and what became a favorite class joke was his bellowing at me: “Ruddon, genius alone is not enough. Success is 99% perspiration and 1% inspiration” (something I seem to remember that Edison also said).

In College, at the University of Detroit, I also had some remarkable teachers whose lessons of life stuck with me. One of them was my English teacher Mr. Spencer. He exposed us to the great literature of the western world (no political correctness in those days), but most of all he was an incredible stickler for precise language. I can still visualize my incredibly marked up term papers. They were so covered with red ink marks that I could barely see my written lines underneath them. The importance of precise language is one of the most important lessons that I ever learned, much to the chagrin of my graduate students when it took an average of six drafts for me to approve their manuscripts for submission to a scientific journal.

A later reinforcement of this in my experience was when one time I was selected for jury duty in Ann Arbor on a case involving the cutting down of a tree that fell the wrong way into the street and hit a car, injuring the driver who was a physical therapist and who couldn’t go back to work as a result of the accident. The case turned on the point whether if the tree had been properly topped before cutting down, would it have gone into the street. Thus, the charge to the jury was: Was the felling of the tree an inherently dangerous act. The importance of the simple article “the” or “a” would determine the outcome of the case. The judge told the jury that the charge to them was meant as he wrote it, i.e., was the felling of the tree an inherently dangerous act? If so, this would make the property owner as well as the tree cutters liable. The jury found for the plaintiff based on the use of the article ‘‘the” vs. “a” and awarded the plaintiff X thousands of dollars more. This was another memorable lesson that I also later shared with my students.

Other college courses that contributed to me professionally, although at the time I couldn’t have imagined that in my wildest dreams, were music appreciation and art history, both required courses for science majors and pre-meds, thanks to the foresight of the Jesuits at U of D college. The music course was a bit of a joke and none of us took it seriously. It was an automatic A if you made it through, which everyone did because the exams were to list the period type of music played on the phonograph (remember them?) as baroque, classical, or romantic and the name of the composer. If anyone in the class knew the answer, it was blurted out for all to hear, but the instructor never figured that out and we all got perfect scores. Nevertheless, this course made a great subliminal impact on me, and I became a huge fan of classical music, which has given me hours of peace from stress and provided inspiration, scientific and otherwise ever since.

The art history course introduced me to the great painting, sculpture, and architecture of the world, which at the time I thought was a total waste of my time, but again this had a lasting impact on me and instilled a further appreciation of beautiful things. Interestingly, when I got to graduate school in Ann Arbor, I saw a number of the Greek revival houses that had been mentioned in my art history class.

Another unforgettable lesson that I learned at UD College was the importance of keeping detailed records. One of my chemistry lab instructors (himself only a grad student) insisted that our lab notebooks be detailed, accurate, and up-to-date. He was a pain in the butt about it. He said that if someone picked up your notebook 5 years from now, they should be able to repeat your experiment exactly. This was some of the best scientific advice I ever got and it came in handy over the years when a crucial question came up about the accuracy or authenticity of an experiment (sometimes with intellectual property or FDA approval consequences). One of the most important things I learned from this instructor I still carry with me, and I used it often when having lab meetings with my grad students and postdoctoral fellows. It was this: reams of data are unimportant unless they are tied to answering the question. I would frequently stop a student in the middle of his or her presentation and say: “That’s really nice data, but what is the question?” They would often look hurt and puzzled and I knew what they were thinking: “What’s wrong with Dr. Ruddon? I have all these beautiful gels and cellular images and he doesn’t get it.” The more senior members of the lab would smile and take the student aside after the lab meeting to explain the quirks of “the boss.”                        

 2.  SOME OF NATURE’S LITTLE GIFTS   

Some experiences with Mother Nature also hone one’s view of the world and these can contribute to the awe of discovery.

Common Dandelion (Taraxacum officnale)

Not only were dandelions to me one of the most beautiful and plentiful flowers in our neighborhood and frequently picked and brought home as bouquets for my mother, they are I found out later an example of a natural remedy for many ills and a source for food. They are definitely not something to just dismiss out of hand, but rather an example of how we can often overlook the importance of nature in our lives and in our scientific thinking.

The dandelion is a perennial herbaceous plant with long, lance-shaped leaves. They’re deeply toothed and the name comes from the Old French word for lion’s tooth: Dent-de-lion. The dandelion’s well known yellow composite flowers are 1 to 2 inches wide and grow individually on hollow stalks 2 to 18 inches tall. Each flower head consists of hundreds of tiny ray flowers. The flower head can change into the familiar white, globular seed head overnight. Each seed has a tiny parachute, to spread far and wide in the wind. This is why they can populate a lawn or field so abundantly. Dandelions are well adapted to a modern world of fancy lawns as well as sunny untended, open spaces. They are a particular nuisance to the connoisseurs of the perfect lawn. They were introduced into the Midwest from Europe to provide food for the imported honeybees in early spring. They now grow virtually worldwide. Unless you pull up the taproot, they will regenerate. Thus, the determined, but careless weed puller does nothing more than help them to reproduce if they don’t also pull out the taproot. Dandelions are also a source for food. Dandelion greens can be added to salads to provide a hearty, slightly bitter taste. They can also be used to make wine. The leaves are very nutritious and provide a good source of beta carotene, iron, calcium, as well as a number of B vitamins, vitamins C, E, and D, and essential minerals such as magnesium and zinc. They were also at one time a popular herbal remedy for inflammatory conditions, gallstones, hepatitis, and poor kidney function. The lesson from all this is don’t underestimate things that appear worthless without looking deeper into their essential nature.

My Mother’s Flowers

Two of my Mother’s favorite flowers were African Violets, which she grew in pots in our sunny breakfast room, and hydrangeas, which grew in abundance in the yard outside the kitchen window. Although these have primarily aesthetic value, hydrangeas also have some limited use to make tea.

The African violet (Saintpaulia) is a genus of six species of  herbaceous perennial flowering plants in the family Gesneriaceae, native to Tanzania and adjacent southeastern Kenya. The genus is named after Baron Walter von Saint-Illaire (1860 – 1910), who was the district commissioner of Tanga province and discovered the plant in Tanganyika (now Tanzania) in 1892. Specimens were submitted to the Royal botanic Gardens, Kew, in 1884 and 1887. Later six species were characterized. The flowers are 2-3 centimeters in diameter, with five-lobed velvety petals that grow in clusters of 3 to 10 or more on slender peduncles. Flower colors in wild species can be pale violet, deep purple, pale blue, or white. Several species are endangered due to clearance of their native cloud forest habitat for agriculture. This is another example of the consequences of modern population growth and environmental carelessness. In this case, who will care or even notice except those who treasure these small beauties?

Hydrangea is a common name for a genus of 70 to 75 species of flowering plants native to southern and eastern Asia (China, Japan, Korea, the Himalayas, and Indonesia) as well as North and South America. There are two floral conformations. Mophead flowers are large round flower heads resembling pom-poms, or as the name implies, the head of a mop. In contrast, there are also lacecap flowers that are round, flat flower heads with a center core of less showy fertile flowers surrounded by outer rings of showy, sterile flowers. In most species the flowers are white, but in some specious they can be blue, red, pink, or purple, depending on the pH and aluminum content of the soil. Hydrangea blossoms are produced from early spring to late autumn.

In Japan, a sweet tea called ama-cha   is brewed from Hydrangea serrata and is used for a Buddha bathing ceremony on April 8, believed to be Buddha’s birthday. The tea is poured over a statue of Buddha in the ceremony and served to people in attendance. A legend has it that the day Buddha was born, nine dragons poured Amrita over him; ama-cha is used in place of amarita in Japan, Caution must be used in ingesting hydrangeas, however, because they contain cyanogenic glycosides that can release cyanide if heated or smoked. Thus, another caution about nature, not everything that is beautiful is harmless and may even be dangerous.

Cracking the Genetic Code for flower color

My youthful experiences in admiring my mother’s favorite flowers and others that I observed made me wonder how they got their native colors. I didn’t learn about genetics until several years later, but when I did, I realized what the answer must be.  It’s in their genes, which code for different color pigments. Mother Nature has picked a limited array of colors for each flower type, but you can make a much larger array of colors by placing various genes into the flower’s seeds. Color- producing pigments include:

1. flavonoids, which are common in roses and produce various shades of red and blue,
2.  carotenoids, found in sunflowers and marigolds and produce yellow and orange coloring,
3. Chlorophyll, which gives plants their green color.

Imagine what you could do by adding a mixture of some of these genes. You could theoretically produce an endless array of colors. Wouldn’t that make your mother smile?

3. PASSION

Many scientists and physicians whom I know or know about are passionate people, both about their science and about life. Many are also musicians, authors, poets, sculptors, or painters. These include Lewis Thomas, Bert Vogelstein, Walker Percy, William Carlos Williams, Arthur Conan Doyle, Somerset Maugham, Anton Chekhov, and many others.

Laboratory scientists may not ever see patients, though some do, but their passion for discovering things that will improve human life is most often what drives them. This is coupled with the powerful aphrodisiac of discovering new things that nobody else knew before. One of the most rewarding scientific adventures is to take a clinical observation back to the lab to try to determine the cause of the clinical condition that was observed, then coming up with an experimental solution and taking the idea back to the clinic to prove that you had found an answer. These days, this is the kind of research that “snaps the socks” of the National Institutes of Health grant review study sections. It’s called “translational research.”

Love/Companionship

As in all walks of life, love and companionship are important for a successful career. This is particularly true for scientists. Good science requires long hours in the lab, often at unusual times of the day, trips to scientific meetings to present their research (which is really a requirement for getting known in a research area and for getting funded.) This requires patience by spouses, children, friends, relatives, and bill collectors.

In some cases romance can start in the laboratory and lead to life-long collaborations in both science and raising a family. Some famous examples are the Curies, the Cories, and the Millers (at the McCardle Institute in Madison, WI). In my case, the issue can be summed up in the dedication to my book the 4^th edition of Cancer Biology:

“I dedicate this book to my spouse Lynne Ruddon, who has been my best friend and the love of my life for over 50 years. Her continual and unflagging patience and support have made possible whatever success I have experienced in my professional career.”      

Believe it or not, this relationship started with a homerun. Not the one you are thinking of, but the one that Bill Mazeroski hit in the 1960 World Series. This was a grand slam that enabled the Pittsburgh Pirates to beat the New York Yankees in game seven and win the series. In those days you couldn’t get a drink of hard liquor in Ann Arbor, where we were in school, so we went to the Gingham Inn in Ypsilanti so we could have a drink and watch the replay of game seven. I was so impressed with Lynne’s knowledge of baseball that I was stricken with admiration and affection. She had been living in Chicago as a youngster and was a great Cubs fan (that in itself is a recommendation for loyalty and true grit). What other woman in the universe could name the whole Cubs starting lineup for the 1945 World Series against the Tigers. I was a great Tigers fan and could name their starting lineup, so this was a relationship made in heaven. She had moved to Pittsburgh to finish high school and, of course, became a great Pirates fan. The Gingham Inn date was only our second or third date, but I knew then that this was the girl for me (that and the wonderful lemon chiffon pie that she baked for me one time when we were having dinner at her place.) Curiously, I have not seen the likes of another pie like that one in almost 50 years of marriage. I used to say that was grounds for annulment, but after having three wonderful children and a great life together, that doesn’t hold up as an issue.

 4. RIGHT PLACE/ RIGHT TIME, SERENDIPITY, ADVERSITY, JOY OF DISCOVERY

Right Place/Right Time

Like most undergraduate students in college, I didn’t really know what I wanted to be when I grew up. Sometime during my sophomore year, I thought that I wanted to be a dentist, so I became a chemistry major with a minor in biology and made sure that I took all the prerequisite courses for admission to dental school. The terribly rational reason for this choice was that the father of my best friend was a dentist. We called him “Doc Douglas.” He had a great life style and was a wonderful, kind, and knowledgeable person. He also made a good living, I could tell from the big house they had in Detroit, the nice cottage that they had on Portage Lake, and the new cars that he got every couple of years. On top of that, he took every Wednesday off to go fishing and often took my friend and me along. My own father, on the other hand, was a business man, worked long hours every day, and sometimes on Saturday morning. This seemed to make him grumpy a lot of the time, and he didn’t seem to enjoy life nearly as much as Doc Douglas.

As I approached my senior year, I had to start thinking about the dental school entry exams. In addition to being able to demonstrate  knowledge in chemistry, biology, and mathematics, etc., you had to pass a manual dexterity test by carving a piece of chalk to some required shape. Now, to say that I am all thumbs is an understatement. Usually, I was lucky to have any thumbs left after hitting them so often when I was trying to build something. In addition to that problem, I really didn’t have a good feel for what dentists did all day. Luckily, before it was too late to change course, I took a tour of the U of D dental school. The tour went through the anatomy and pathology labs as well as the clinics. After a day of watching dentists in training struggling to get into peoples’ wide open, gaping mouths, often assuming what appeared to me to be unbelievable contortions to do so, and viewing all the gore in the dental path lab, I began to get some doubts about whether this was for me. But what really did it were the graphic photographs of oral pathological conditions hanging as demonstrations on many of the clinic walls.  After a couple of days of reflection, I reached the conclusion that this was not for me.

So, next question: what do I do with the rest of my life? Not an easy question, to which many people can attest. After much rumination and many glasses of beer with friends at the Stadium Bar as well as some helpful conversations with chemistry faculty, I decided to try to pursue a career in chemistry. I completed my B.S. with a chem major and enrolled in an M.S. program in chemistry at U of D.

After I inadvertently started a couple of fires in the organic synthesis laboratory and spent hours trying to synthesize a couple of obscure chemical structures and coming out with about a nanogram of final product, I wasn’t sure that this was the career for me either. Fortunately, I had time to take an advanced course in biochemistry. This snapped my socks as someone once said. The professor, Dr. Jon Kabara, was an inspiring teacher and made the Krebs cycle and the protein synthesis pathways come alive. In addition, he had a very attractive lab tech and I found myself spending a lot of time in his lab observing how to do biochemical experiments. Doc. Kabara also would point out where a biochemical pathway might become abnormal in certain disease states. I thought that this was kind of neat and had the first glimpse of how my chemistry background might be useful. But how and what could I do about it? Here’s where being in the right place at the right time paid off.

It happened that the Chair of the Chemistry Department, Dr. Everett Henderson, had received his Ph.D. in chemistry at Iowa State University in Ames , Iowa. One of his classmates in the doctoral program was Lauren Woods, who was at the time a faculty member in Pharmacology at the University of Michigan. “What’s pharmacology?” I asked.  Dr. Henderson explained that it was the study of drugs: their chemistry, how they work in the body, what clinical and toxic effects that they have, and how studying them can lead to the discovery of new drugs.

This was an “Aha!” moment for me. I could see immediately that this was the sort of thing that I was looking for. While I was in his office, Dr. Henderson called Dr. Woods and set up an appointment for me to meet him in Ann Arbor. This is one of those points where I could say: “And the rest is history.” If I did that, the story would end right here, but I think that I have more to say (and hopefully some useful and interesting things).

I met Dr. Woods in his office in Ann Arbor at the U of M Medical School. His office was next to a beautiful, apparently brand new, bustling lab with people in white lab coats scurrying around doing what looked like interesting things. A lot of the equipment looked similar to what I was used to in chem. Labs, with one important difference. There were various items that were designed to hold animals for injection or surgery and one very intriguing one that I later found out was a miniature stereotaxic apparatus for making precise drug injections into various regions of the brain.

Dr. Henderson had apparently told Dr. Woods that I was a good student and I had sent my academic transcript ahead of time, so he knew a bit about me. Right off the bat, Dr. Woods seemed interested in me, and I told him that I was looking for a course of study that would utilize my chemistry background in a way that would lead to health-related outcomes. He then described to me the program that the Pharmacology Department at Michigan had initiated to obtain both a Ph.D. in Pharmacology and an M.D. degree (this was 1959 – a long time before the National Institutes of Health realized what a good idea this was and funded the Medical Scientist Training Program aimed at supporting M.D.- Ph.D. programs).

Dr. Woods then took me down to see Dr. Maurice Seevers, the department chairman. I was impressed immediately with his gruff, no nonsense, but very friendly demeanor. I later learned that he was a world famous pharmacologist, who knew more about narcotic analgesics than anyone and who still directed a world renowned research program in that field. After a few minutes of conversation, during which I told him a little of my background and interests, he turned to Dr. Woods and said: “So you think that this fellow is a good candidate for the M.D. – Ph.D. Program?” I could see out of the corner of my eye that Dr. Woods nodded.

Moe (as he was affectionately called as I later found out) then turned to me and said “see you in September.” He then charged out of the office and bellowed to the woman sitting outside his office. Her name was Dotty Norton, who was the doyenne of the department and who basically ran its whole administrative apparatus (again learning this later).

“Dotty, ”he said loudly in his gruff but kindly voice. This fellow’s name is Ruddon. Sign him up for the M.D. – Ph. Program for the fall. Get him all the info about admissions, med school interviews, etc.” Then to me extending his hand: “ Dotty will take care of you. Any questions, just call her. Next, he abruptly turned and entered back into his office. “Dotty, when you’re done there, get that SOB Wilson on the phone for me.”

That was it. I was accepted to grad school just like that. No admissions review committee. No beating around the bush. No waiting to get a letter in the mail. No need to request early admission or be put on a wait list. Of course, I did still have to take the MCAT exam and be interviewed for admission to med. school.  All that went OK and I matriculated in the fall of 1959. This is another of those “and the rest is history moments,” but of course it ain’t over till it’s over as someone once said.

I tell this story about my admission to grad school in more detail than may be necessary to make an important point. Another important characteristic of a good scientist is having good insight into people. This is essential for deciding who to hire as lab assistants, and accept as grad students, post doctoral fellows, summer interns etc. Most good scientists seem to have this knack. Of course, sometimes mistakes are made, and the hope always is to find out quickly so as not to waste your time or that of the people who come into the lab. I’m not sure how you learn how to do this. It seems to be an innate skill. Some scientists use little mental gymnastic questions. Others, myself included, want to know what kind of non-scientific interests someone has. For example, by asking things like: What do you read? Do you like history? Do you like opera? Are you a sports fan? What do you like to do in your spare time? Some of this may seem a bit irrelevant, but I’ve found that it often gives insight into someone’s character and collegial spirit so essential for a well functioning lab. I obviously also look at transcripts and letters of reference, but I’ve often found that isn’t always a good way to pick those who will become the best scientists. Often it’s the late bloomers who do the best, so an overall GPA may be borderline, but if you notice that the Cs and even a D or two all disappear in the last year or two of undergrad education once the individual finds what they are interested in, this may indicate a winner.

Serendipity

What I have been discussing above could come under the heading of “serendipity.” This beautiful word has an interesting history. (The description below is derived from an essay entitled “Serendipity, a Graceful Word” by Roald Hoffmann.)

In 1754, Horace Walpole (the son of the Prime minister of England under George II) wrote a letter to his friend Horace Mann in which he describes a lucky discovery of the provenance of a painting of the beautiful wife of Duke Francisco de Medici that he had admired and that Horace Mann had purchased for him. Horace Walpole wrote:

“ This discovery indeed is almost of that kind that I call serendipity, a very expressive word, which as I have nothing better to tell you, I shall endeavor to explain to you: you will understand it better by the derivation than by the definition. I once read a silly fairy tale called The Three Princes of Serendip. As their highnesses traveled, they were always making discoveries, by accidents and sagacity, of things they were not in quest of…”

Serendip was an Arabic name for Ceylon. The book Walpole read, which went through many editions, was a collection of Oriental tales, loosely translated in the 16^th century from Persian into Italian by Christoforo Armeno.  Oriental romances of adventure and cleverness were popular in Walpole’s time. It’s conceivable that Walpole was also influenced by reading Voltaire’s Zadig, published just a few years earlier.

Of course, we are all familiar with Louis Pasteur’s famous remark: “Chance favors the prepared mind,” which is a translation of what he actually said: “Dans les champs de l’observation, le hazard ne favorise que les esprits prepares.” But it takes more than blind luck to recognize a truly new discovery. Can the characteristics that allow one to do that be taught? This is a question that every scientist should be concerned with so that a legacy of discovery can be passed on to future generations of scientists. The attributes for being able to recognize new and exciting things that fall into one’s lap include:

Curiosity, a sense of wonder, and openness to the unexpected even if it goes against the central dogma of the scientific field.

The mind needs to be in awe of nature and open to unforeseen connections between natural phenomenon. Parents can inspire this sense of awe in their children by their example and by pointing out the beauty of natural surroundings. A problem is that we often tend to lose this sense of awe as we age unless we continue to be inspired by discovery and creating a sense of reward for new discovery in our students and colleagues. In a practical sense, this can be achieved by making sure that students, post docs and young faculty get to be first authors on publication of their work. Just remember that sense of reward and accomplishment when that first publication comes out!  

Concentration on a Seemingly Insoluble Problem.

Another word for this might be called “focus” or persistence in the face of apparent insurmountable obstructions, e.g., the experiments that don’t seem to work or be repeatable ( like the calf thymus chromatin problem discussed below.)

1. Staying involved in the nitty-gritty activities of the lab.

Sometimes the seemingly most trivial detail of an experiment can reveal a new discovery. I give an example below from my own lab in which forgetting to add a key reagent in an experiment led to a remarkable discovery. Some of the best scientific results come as a result of good luck. The trick is recognizing when it occurs and knowing what to do with it.  

We were studying human chorionic gonadotropin (hCG) as a diagnostic tumor marker. hCG detection in a young woman’s blood is usually an indication of pregnancy, but in a young man’s blood it usually means that he has testicular cancer. hCG is also a diagnostic marker for a type of cancer that occurs in the uterus called choriocarcinoma and is observed to be present in the serum of patients with some other cancers, e.g., certain gastrointestinal tumors.

hCG is a protein with two parts (subunits) called alpha and beta. In normal pregnancy, these two subunits are tightly linked together. However, in cancer patients’ serum, the two subunits frequently circulate as unassociated “free” alpha and beta. We wanted to find out why this was so. We thought it might give us another clue that could be exploited to develop more sensitive diagnostic tests or if the abnormal lack of association of the subunits was due to some defective biochemical step in the tumor cells, that might provide a new target for anti-cancer drug development.

We had developed in the lab a rather simple way to get at the rates and amounts of alpha and beta synthesis, association, and secretion from placenta or cultured cancer cells. The method was to add radioactive amino acids or sugars to organ or cell cultures of placenta or tumors, wait various periods of time, then break the cells open and add antibodies to “immunoprecipitate” the free or associated subunits. This is what is called a “pulse-chase” experiment. The detection method used at the end of the experiment is to separate the free or combined subunits on a tubular gel in which free subunits and associated alpha-beta hormone migrate differently based on exposure to an electric field. This is called gel electrophoresis. When the gels are exposed to sensitive film, the radioactive bands “light up” as dark bands that can be scanned in a photometer or cut from the gel and counted for amount of radioactivity to quantitate the amount of free subunits or associated dimer. This is called autoradiography.

This was usually the first experiment that any new person who came into the lab was asked to do, sort of sending them to triple A ball before being called up to the big leagues. Over the years, at least 20 new technicians, students, or post-doctoral fellows had run this experiment successfully. The usual gel after exposure to x-ray film showed two sharp bands representing the alpha and beta subunits when the immunoprecipitation was carried out after reducing the cell extract with a chemical called a reducing agent that separated the associated subunits. In other words, the gel from the free alpha antibody immunoprecipitate had one sharp band as did the gel from the free beta immunoprecipitate, whereas the gel from the reduced alpha-beta dimer immunoprecipate showed a sharp alpha and a sharp beta band migrating at different parts of the gel.

One day, we had a new post-doc in the lab who was asked to run the classic “Ruddon” experiment. I was flabbergasted when he brought me the autoradiographs from the experiment. The gel with the free beta subunit didn’t have one nice sharp band, but several fuzzy bands on the film. I said in a rather chagrined voice to the post-doc: “At least 20 people have run this same experiment and I’ve never seen this result before. What did you do wrong?” He sheepishly replied: “I don’t know. I followed the protocol very carefully.”This is where my strict directions on how to write up a lab notebook came in handy. I always demanded that the first time an experiment was run that the protocol be recorded in exquisite detail so that a neophyte could reproduce the experiment exactly. So I said: ‘Let me see your lab book!”

I went over every word with him carefully. I only detected one omission. It didn’t indicate anywhere in the write-up that he had added the reducing agent, so I asked him: “did you add the reducing agent to the gel buffer?” “If it’s not stated there, I guess I forgot,” he replied. What in fact he had discovered was a series of folding intermediates of the beta subunit that are sequentially folded along a pathway leading to the final form of the protein. This new and startling result now opened the door to finding out what the steps were in the production of the beta subunit and how these steps controlled the rate of alpha-beta assembly and how normal placenta differed from cancer cells in this process. Of course, it took us several more years to figure out all the details of this process.  The take-home message is clear: always be extremely meticulous in recording what you did in an experiment and don’t just blow off a result that at first glance looks screwy.

Other ways that serendipity can be fostered is by exposing a research group to scientists from totally different backgrounds, for example by meeting with biomedical or chemical engineers. Engineers tend to think more about practical solutions than many biomedical scientists do and may have access to clever gizmos to solve tough problems. One example of that for my group occurred when we met with a chemical engineer who was an expert in microfluidics. He had a neat instrument that could separate and isolate individual cells of different phenotype that made analysis of these differences much easier. In order to keep this interaction going we formed a “gizmo club ‘ between his lab and mine that met once a month, where we would brainstorm about all sorts of seemingly crazy ideas.

I was fortunate to participate in another series of meetings among scientists of very diverse backgrounds who, on the face of it, seemingly had nothing in common. This too led to some “crazy” new experimental designs. Although the topic was cancer, the “non-cancerologists” had some  probing questions that most of hadn’t thought about, like how far down the evolutionary tree of the animal kingdom is cancer observed, e.g., do clams get cancer? Or fruitflies? Or other lower animal species? The interesting answer made by one of the ecologists in attendance was that cancer begins to appear in animal species that have an immune system. As it turns out, this is a very important point. Other questions posed by the group included: what causes cancer? How many “hits” on a cell are needed to produce a malignant cell? Does a cancer need to progress through some definitive series of genetic alterations before it becomes invasive and metastatic or are some cancers aggressive almost from the beginning? Cancer biologists have been wrestling with these and similar questions for decades. The intention of these meetings was to bring a group of very smart scientists from other fields together to get a fresh look at things. The group included the “usual suspects’ with expertise in basic biochemical and molecular genetics research, clinical oncologists, and cancer epidemiologists, but also mathematicians, engineers, ecologists, botanists, anthropologists, entomologists, and virologists.

These turned out to be exciting and enlightening meetings ( the fact that they were held in Santa Barbara, California didn’t hurt either.) Not to take anything for granted, early in one of the first days of the meeting someone asked the Talmudic question: “What is cancer?” It was startling to hear the disagreements and varied opinions of the “experts” in the group. There was wide disagreement about some of the questions posed above relating to the number of required hits, whether all cancers had to go through a defined number of genetic mutations before they became metastatic (the so-called Vogelgram named after Bert Vogelstein, from Johns Hopkins, whose lab defined the steps that a colon cancer cell goes through to become metastatic).   Although most of the cancer scientists could agree on a few characteristics, each one had their own modifications and caveats to be considered.

Like all good academic groups, we appointed a committee to come up with a consensus definition. As the most gullible person in the group, I agreed to chair the committee. After the exchange of numerous phone calls, e-mails, and faxes, we came up with dictionary type definition as well as a more detailed description (see R.W.Ruddon, Cancer Biology, 4^th edition, Oxford University Press, 2007, pp 4-5).

The agreed upon definition was:

Cancer is an abnormal growth of cells caused by multiple changes in gene expression leading to dysregulated balance of cell proliferation and cell death and ultimately evolving into a population of cells that can invade tissues and metastasize to distant sites in the body, causing significant morbidity and, if untreated, death to the host.

The agreed description was:

Cancer is a group of diseases of higher multicellular organisms. It is characterized by alterations of the expression of multiple genes, leading to dysregulation of the normal cellular program for cell division and cell differentiation. This results in an imbalance of cell replication and cell death that favors growth of the tumor cell population. The characteristics that delineate a malignant cancer from a benign tumor are the abilities to invade locally, to spread to regional lymph nodes, and to metastasize to distant organs in the body. Clinically, cancer appears to be many different diseases with different phenotypic characteristics. As a cancerous growth progresses, genetic drift in the cell population produces cell heterogeneity in such characteristics as cell antigenicity, invasiveness, metastatic potential, rate of cell proliferation, differentiation state, and response to chemotherapeutic agents. At the molecular level, all cancers have several things in common, which suggests that the ultimate biochemical lesions leading to malignant transformation and progression can be produced by a common but not identical pattern of alterations of gene expression. In general, malignant cancers cause significant morbidity and will be lethal to the host if not treated. Exceptions to this appear to be latent, indolent cancers that may remain clinically undetectable (or in situ), allowing the host to have a near normal life expectancy.

1. Interdisciplinary research

Serendipity and innovation can also be fostered by interdisciplinary research (IDR). IDR is thought to be of such  national importance for fostering innovation that the National Academy of Sciences studied this extensively and issued a detailed report in 2004 (“Facilitating Interdisciplinary Research, National Academy of Sciences Press, tracking number #198 108 181 613 48,  Washington, D,C.,2004)

The report defines IDR as “ a mode of research by teams or individuals that integrates information, data, techniques, tools, perspectives, concepts and/or theories from two or more disciplines or bodies of specialized knowledge to advance fundamental understanding or to solve problems whose solutions are beyond the scope of a single discipline or area of research practice”(you can tell this was written by a committee).

IDR is deemed critical for innovation, perhaps more so now than ever because of the inherent complexities of nature that are more and more rapidly being discovered due to modern technology and modern society (we are now a global scientific village). This has become obvious in a number of research areas where we have hit stone walls of knowledge limitations. In the health sciences, for example, it has become increasingly apparent that the common chronic diseases such as cancer, diabetes, autoimmune diseases, and neurodegenerative disorders as well as aging are multidimensional and due to more than one genetic or epigenetic alteration. The global energy crisis and global climate change are other examples where the knowledge and data from multiple fields will be necessary to unravel the answers to these problems.

Since IDR Involves people of disparate backgrounds, one challenge is the extra time it takes to build consensus, to build common language without secret jargon, and to understand the variety of cultures involved. Industrial and national laboratories have longer experience than most academic institutions in the support of and processes for IDR. Universities are frequently stuck in a hide-bound culture of individual-focused activity - a sort of fighter pilot mentality. That is usually what it takes to get promoted after all. The main criteria are: how many senior author publications are there? How many RO1 grants is the faculty member the principle investigator on? What kind of national recognition does he or she have, e.g., service on NIH study sections, invitations to speak at national and international symposia, number of citations in citation index? Being a second or middle author on a paper doesn’t usually count for much even if that contribution was key to the success of the study.

These obstacles have to be overcome for IDR to flourish in an organization. This will also require a different approach to undergraduate and graduate education. Both kinds of students should be encouraged to seek out interdisciplinary courses that are at the interfaces of traditional disciplines and that address important, hard to solve scientific and societal problems. Students should also be strongly advised to gain research experience in laboratories that focus on IDR projects. For example, Ph.D. students in biomedical research degree programs should learn something about human medicine by taking courses in human pathology, public health, human genetics, and other medically related fields. Academic institutions should identify and facilitate policies, research processes, and funding that foster IDR. They also need to change promotion guidelines to recognize the importance of IDR endeavors, for example, by giving some priority and institutional funding to collaborations among basic biomedical scientists, clinical researchers, engineers, mathematicians, bioinformatics experts, and business school faculty (to address how products can be developed and brought to market, and how to initiate start-up companies.   

Adversity

People in every walk of life have to face adversity during their careers. Scientists are by no means alone in this. However, many (most?) scientists seem to be particularly sensitive and emotional sorts, perhaps because they often feel as much like artists as they do scientists and have an artist’s sensitivity to failure and criticism. (Although I have yet to meet a scientist who has cut off his ear as a result.)

I remember how hurt I was about my first two manuscripts being turned down by a top scientific journal, perhaps something like a frustrated poet trying to get his first poem published in the New Yorker magazine. And then, the worst crisis of all – getting your grant rejected by an NIH study section. Getting your grant is crucial not only for your scientific viability but even your livelihood – putting food on the table, getting your kids through college, and every other thing that costs money. You read with glum demeanor all the usual criticisms in study section reviews of grants until you’re ready to scream: the research is unfocused, too ambitious, not enough preliminary data to support the hypothesis, not sufficiently hypothesis driven, no clear indication that the experiments planned will lead to a definitive conclusion, not clear that the principle investigator has the expertise to carry out some of the proposed complex experiments, etc., etc., etc.

Another very frustrating experience is when experiments don’t work, especially if you’ve tried every possible variation of the protocol and even more especially if it’s an experiment that always worked before, albeit perhaps at a different institution. What is different in the new place? You wonder. The water? The building air circulation? The phase of the moon? What? The experience of a colleague of mine is instructive in this regard.

My colleague had moved from the Rockefeller Institute in New York to the University of Michigan in Ann Arbor. He was working on the structure and function of chromatin, the combination of DNA and proteins that controls the expression of genes in a cell. He tried for a couple of months to repeat the experiments that he had done in New York, but without success. The chromatin was being isolated from calf thymus glands that he received from slaughterhouses. One day he thought that he should actually ask to be in the slaughterhouse in Michigan to see how the thymus was being obtained. He was allowed to do so by the slaughterhouse boss. He watched the process. Then it hit him. In New York, the calves were killed by the kosher method of exsanguination after cutting the carotid arteries, leading to rapid death of the animals. In Michigan, they were being killed by bludgeoning, causing a much slower death and as a result more time for the cells in the thymus to lyse and their chromatin to be degraded. Thereafter, he started going to a kosher slaughterhouse, and he could then successfully complete his former experiments. This shows how well rounded scientists have to be.

Joy and Fun

One of the great things about being a scientist is the joy of discovery, and being able to be your own boss in designing what to do next. (The latter is perhaps more true in an academic setting, but it is also true in the more enlightened private companies.) Also, science is not only hard work, it is fun. Finding out about new stuff is fun. The kinds of people that you usually come in contact with are fun. The more successful labs exude this sense of fun. They often do things together such as fishing, deep sea diving, forming jazz groups, going on picnics, forming softball teams, etc.  It always helps if one or two people in the lab are a bit zany.

I was fortunate enough to have some zany people in my lab from time to time. One of these was a grad student named John. John was one of those people who after you were around him for a few weeks knew that he was going to be a successful scientist and science administrator, which turned out to be very true. He was clearly a leader from the start. As a student, John lived with a group of students who liked to grow their own vegetables in a garden behind their rented house. They also had a small vineyard in their yard and made their own wine and other salubrious beverages.

One evening I came into the lab to see what was going on. Most of my students frequently worked evenings and weekends in the lab without being told that was expected of them. They were all well rounded individuals but knew the importance of completing good experiments, most of which don’t start at 9 AM and end at 5 PM or at some convenient, predictable time (unfortunately, this trait seems to be less evident in this totally connected, text messaging world we live in now – not to mention that no one wants to read a scientific book any more, if it’s not online it must be old news - forget it baby, but this subject is for another time).

As I came into the lab, I could hear the media pump running in the back lab (in those days we made all our own cell culture media). I started to walk to the back lab when another student named Alan came up to me and started to describe the experiment that he had done that day. It was a long complicated experiment so it took several minutes to describe. When he was finished, I again started for the back lab. “Wait,” he said. “I need to plan the experiment that I want to do next, and I need your advice.” My advice was, you guessed it, “Do what snaps your socks.” I did listen to the key elements he had in mind and gave him my encouragement. Then once again I moved toward the back lab. Again he stopped me. “Wait, I think that Lora also wants to tell you about her data.” About this time I was getting suspicious and headed directly toward the sound of the pump. John was sitting outside the laminar flow hood intently watching a yellowish fluid pass through our several thousand dollar stainless steel Millipore filter apparatus into bottles that looked suspiciously like beer bottles.

“John,” I exclaimed, “what the hell are you doing.” Caught en flagrante so to speak, he looked up at me sheepishly and admitted that he was filtering his homemade beer. I castigated him in an angry voice, exclaiming “Don’t you know how much that filtering apparatus cost and how dependent everyone in the lab is on that for getting pure culture medium?” He admitted that he did and promised to clean it thoroughly before the following morning, which he did. I never saw the stainless steel sparkle so much! But even better, he gave me a couple of bottles of his beer, which I have to admit, was pretty good.

But the most “fun” of all (though a better word is feeling of pride) is watching the students grow in scientific maturity and achievement to the point where they are smarter than you are. They are in a true sense your scientific “children.” One of my older doctoral students has since introduced me to my scientific grandchildren and great grandchildren. That was a real “socks snapper.”

Philosophy

All scientists develop over the years a philosophy not only of science but also of life. Because I moved around a lot in my career and had a number of different jobs with different responsibilities, I developed a philosophy of what one should do in taking a new job:

1. Praise youth and they will prosper (old Irish proverb)
2. Find small fires, pour kerosene on them, and get out of the way.
3. I never met anyone I didn’t learn something from whether they be auto mechanics, custodians, animal care takers, faculty, students, or administrative staff. So listen up. You need them all to be part of the team and their success depends on you. If they are successful, so will you be.
4.  Talk to the “‘people in the trenches” who are doing the real work, ask them what needs to be done, and do it.
5. Develop a “to do” action list before you start the job, modify it as you go, and develop an annual strategic plan with bench marks, responsibilities for implementation, and deliverables to be assessed each year (this is one area that industry people understand better how to do than academics, who tend to be more laissez-faire).

Below is another philosophical list that I developed one time when I was an Associate Dean for Research at U of Michigan Medical School (later in my career but more about that later), and found myself the only “deany” person in the office and was proclaimed King for the Day by the staff.

1. Everyone must pat themselves on the back three times today.
2. You must say at least one kind word to a colleague outside your immediate area.
3. Learn one new thing today and pass it on.
4. Dancing is only allowed in the offices, not in the hallways, so as to avoid a public disturbance.
5. Write if you get work and hang by your thumbs (old Bob and Ray saying. I don’t know what it means either.)
6. Be passionate about one job to be done today (think of the beach scene in From Here to Eternity. If you’re too young to remember this, you’re too young).
7. If you disagree with someone today, arm-wrestle them to see who wins the argument.

                       Proclaimed by Raymond III

                                 King for the Day

FIVE:  LOVE OF HISTORY

I’m a firm believer in knowing the history of the field in which you work. In my case, that’s the history of where drugs come from. Since I am a cancer biologist/pharmacologist, I am fascinated by the history of the development of anti-cancer drugs.

The idea for the first clinically effective anti-cancer drug came from the effects of a poisonous gas used in World War I. It started on the Western front in 1917 at the battle of Ypres in Belgium. The Germans started using chlorine gas to immobilize allied troops on the battle field. Later, they started using the even more toxic mustard gas, and the allies retaliated with their own use of this agent. Mustard gas is a vesicant that causes severe burning of the skin, eyes, and lungs if inhaled. A peculiar toxic effect was noted at autopsy of the soldiers who died from exposure – their lymphatic tissue appeared to be totally destroyed and their white blood cell count was extremely low.

Fortunately, mustard gas was not used in WW II, but the Allies were prepared to retaliate if Hitler decided to use it. As the Allies were advancing up the Italian peninsula in 1943, they had a liberty ship, the S.S. John Harvey, loaded with mustard gas anchored in Bari harbor in southern Italy. This was top secret information and very few people knew about it outside of FDR, Churchill, General Eisenhower, and a few others. Neither the army commanders nor the Italian Bari port authorities had any idea what was on the ship.

In December, 1943, a German air strike destroyed the ship, releasing mustard gas and creating a mustard gas containing oil slick in the harbor. Survivors in the sea and those on land who were exposed to the fumes developed severe burns in the skin, eyes, and respiratory tract. The nature of these burns went undiagnosed for several days because the allied port authority, who had learned the nature of the cargo of the John Harvey, refused to reveal that, presumably out of fear of enemy reprisals and the negative effect of any publicity. It took a careful and painstaking investigation by Lieutenant Colonel Stewart F. Alexander, a U.S. Army physician with training in chemical warfare, to determine the nature of the poison. But by then, it was too late to help many of the victims, and the mortality rate reached 13 percent of those exposed, with many of the fatalities due to infection (precipitated by low white cell production in the bone marrow) and internal bleeding.

The known lympholytic effects of mustard gas (also known as sulfur mustard) led two pharmacologists (the reason for the emphasis will be noted below) Louis Goodman and Alfred Gilman, working under a War Department grant on the mechanism of action of mustard compounds, to wonder whether this effect could be utilized to treat lymphatic tumors. They explored this idea by treating mice bearing an experimental lymphosarcoma with another compound of the mustard chemical class called nitrogen mustard. The treated mice had a remarkable increase in life expectancy and some appeared to be cured of their disease. The investigators, working with their clinical colleagues, then got permission to try the drug in a patient with a severe case of lymphosarcoma. The effect was truly dramatic. The patient was in the terminal stages and had severely compromised ability to breathe and swallow because of the large tumor masses in the mediastinum and other sites. After a daily intravenous dose of nitrogen mustard (also called mechlorethamine or HN2) for 10 days, the tumor virtually melted away before their eyes and the patient could again breathe and swallow easily. Unfortunately, after about a month, the tumor started to return and a second course of treatment produced only a transient response, and a third course had virtually no effect. A troublesome side effect of bone marrow toxicity was also noted. Thus, in this very first demonstration of a clinically effective anti-cancer drug, the same problems still with us today of drug resistance and severe toxic side effects were noted. Since that time a number of other effective anti-cancer drugs have been discovered and developed, but many of the problems seen with the first one still occur.

Another curious thing happened in the case of nitrogen mustard. Since it was war time and this was top secret research, it was not allowed to be published until 1946! Imagine having discovered the first effective drug treatment for human cancer and not being able to tell the world about it, and even worse not being able to have access to the first drug that could actually help patients with this terrible disease. Oh, the wonders of government secrecy.

Another important (for me and fellow pharmacologists) anecdote about the discovery of HN2 relates to giving credit where credit is due. This came up when I read the wonderful and elegant historical account of the Italian campaign by Rick Atkinson called The Day of Battle  (I also highly recommend his account of the North African campaign called An Army at Dawn). Rick mistakenly identified Goodman and Gilman as two pharmacists. Now, I have nothing against pharmacists. Indeed, they are key members of the medical care and health care delivery team and often know more about drug effects and interactions than physicians. However, pharmacologists are more focused on determining mechanisms of drug action, new targets for drug discovery, and the basic biology of tissue effects of drugs.

I wrote a letter to Rick through the publisher Henry Holt and Company and within a few weeks received his kind acknowledgement of the mistake, which he corrected in the second printing.

SIX: THE ROLE OF POETRY IN SCIENCE

Since I am an amateur poet, this topic has a special place in my heart. Similes and metaphors are the stuff of poetry, and similarly are used extensively in science. The vocabulary of science is replete with jargon that is meant to convey scientific ideas clearly. Unfortunately, such jargon is often gobble de gook to non scientists. Poets have a similar problem. Poetry at its essence is subliminal. Poets who are asked where their words and ideas come from, usually say that they don’t know until the words actually flow from their pen. Poems are full of myth, dreams, and fantasies, some of which seem obscure and are very subjective  (in spite of what Paul de Man and the deconstructionists may say). I expect that people who read my poetry will take away their own meaning that may be quite different from my subliminal thoughts that led to the written words. Thus, a challenge of poetry is to cast words in a structure (poetry has sights, smells, structure, and music at its essence). Thus, it might be a good idea to encourage scientists to incorporate poetry into the way they think about and communicate important ideas uncovered by their research. This may help scientists find ways to facilitate getting the ideas and language of science out into the public domain, which would benefit science. Let’s try a little of this to see if it works.

               MY LIFE AS A CELL

Choices choices choices

I have too many choices

I am a stem cell you see

Don’t yet know what I want to become

The choices are almost infinite

And lead to very different lives

I could be a big toe

A kneecap

A pancreas

A neuron

A penis even

I’m getting all sorts of signals now

Beginning to bombard my nascent receptors

Here in the womb

Some from my fellow cells

Others from adult cells in my mother

More subtle because I only feel them faintly

Trying to get through the blood-placenta barrier

I think that I’d like to be a neuron

That way I can migrate all around my new body

Until I find where I’d like to be

Where the environment suits me

And I can pick my friends

Depending on things they make

Like dopamine, serotonin, norepinephrine

Or some other neurotransmitter

Depending on the mood I’m in

I can fire off or stay resting until I’m ready

Or some neuronal connection tickles my fancy

It might be enjoyable to be a pancreas

How sweet that could be

Surrounded by sugar all the time

But if it gets too sweet

I could just secrete a little insulin

To get back to normal

I would also be responsible for digesting lots of foods

I could handle a lot of different cuisines

Italian French Chinese Thai Mexican

For whatever mood I’m in

On the other hand it might be fun to be a big toe

I could spring like Baryshnikov

Provide the starting push off the blocks for an Olympic sprinter

Stay fixed on first base to stretch for that low throw

For the last out in the ninth inning of the World Series

Or even better reach out to touch a lover’s big toe

             ARCHITECTRONICS

The structure of things to come

And that have been

The bony spicules of the head of the femur

Line up in stress lines

Like the arches of a bridge

Or a cathedral

The inside of our cells

Can be mathematically reduced

To a geometric design by Escher

We are all one gaia principle

The structures that the mind can conceive

Nature has already thought of

Microfilaments attached to microtubules

Neurons contacting neurons

Dendritic attachments that cling and respond

All designed to move the body and the mind

To touch the inner matrices move and touch again

Integrins binding to ligands providing the cellular stress

To move feel move

Providing the tensile integrity

Inborn

In our cells

In our souls

In our meaning

In our responsibilities

In our suffering

In our love

We are defined

Designed to touch feel react touch again

The tactile rebound of ourselves

Loved unloved loved again

SEVEN:   STRONG INFERENCE: HOW SCIENTISTS THINK                      

Certain systematic methods of scientific thinking may produce much more rapid progress than others. One of these methods has been termed “Strong Inference” (J.R. Platt, Science, 134: 347, 1964)

Strong Inference is just the straight forward, “old fashioned” method of inductive reasoning that goes back to Francis Bacon. Although the steps of inductive reasoning are familiar to most scientists, the continual systematic application of this inductive process is frequently forgotten in the rush to get more data, without stopping to ask: “What’s the question?” The key steps in the process include:

1. Devising alternative hypotheses to the “central dogma” of the lab and devising experiments to exclude them. This is sometimes called “entertaining the Null Hypothesis.”
2. Drawing a “logic tree” of the work flow needed to rule in or rule out various hypotheses. It might look something like this:

Experiment one

                             (to test A vs. B)

      B is ruled out ------------------  A is positive

Experiment two

                ( to test whether C or D helps explain A)

      C is positive-----------------------------D is negative

Experiment three

            (to test whether E or F explains C)

      E is negative---------------------------F is positive

Experiment four

              (to test whether G or H explains F)

G is positive--------------------------------H is negative

G is the best answer to the experimental question

1. Keep in mind the proper controls for each experiment. As one of my professors said to me: ‘The three most important things about any experiment are: controls, controls, controls.”
2. Keeping detailed lab notebooks is crucial. As noted above under Serendipity in regard to the hCG folding experiments, this can be the difference between making a great discovery and ignoring a failed experiment as an artifact. How many scientists (and grad students and post docs for that matter) take the time to write down crucial next experiments at the end of every experiment? This was a crucial step in discovering the folding intermediates of hCG.

At times we all become method oriented rather than problem oriented. This is particularly enticing with all the fancy new equipment that becomes available every year. This can become very seductive in trying to keep ahead of competitors.

Bottom line, one of the most important things to remember is that it is just as important to rule a theory out as to rule it in. “ A theory is not a theory unless it can be disproved” (J.R. Platt, ibid).

One trap that scientists all too often fall into is confusing correlations with cause-effect relationships. One of my favorite examples of this is a data plot correlating the incidence of colon or breast cancer on the ordinate with the number of Mercedes automobiles per capita in a given country on the abscissa. There was a straight-line correlation between the two, i.e., driving a Mercedes causes cancer! (note; this data was more true before economic globalization and traffic jams of Mercedes and BMW automobiles in Beijing, New Delhi and cities in other burgeoning economic powerhouses.) These data though obviously not proving cause-effect, do indicate something important, namely there is something about life style in economically rich countries that relates to certain cancers. This is most likely  related to high fat , high protein diets, obesity,  and other “western“ life style characteristics such as early menarche and late menopause (i.e., lifetime length of exposure to high estrogen levels) as real risk factors for breast cancer (not the car that people drive).

Another trap that scientists can fall into is believing that something can be proved mathematically without experimental data. As John Platt  (ibid) notes: “Many - perhaps most – of the great issues of science are qualitative, not quantitative, even in physics and chemistry…. proof or disproof… is in fact strongest when it is absolutely convincing without any quantitative measurement.” Take for example the astounding ability of penicillin to cure infections when it was first introduced. It didn’t take a randomized double blind clinical trial to verify this effect. Also, it took many years before the mechanism of penicillin’s action was understood. I don’t believe that this should be taken to mean that statistical significance in a biological experiment is not important because biological variability-- a problem that physicists don’t usually have to deal with – rears its troubling head when one is comparing the effects of compound or manipulation X vs. compound or manipulation Y in a biological system. As some skeptics are fond of saying: “You can prove anything with the right statistics.” Though not universally true, common sense is often as good or better than statistics, for example, a claim made a number of years ago in a leading medical journal that a woman who drank three small glasses of an alcoholic beverage a week was several fold more likely to get breast cancer than those who did not drink at all, or at least claimed that they didn’t.

To put it another way, relating to the points made above, a scientist can measure, compute, and analyze data mathematically but fail to design experiments to exclude alternative hypotheses. This doesn’t advance science significantly.

One of my favorite examples of how a mathematical proof can be misleading was published in a paper entitled “ The Outlook for the Flying Machine” by Professor Simon Newcomb of Harvard University (Ha!) in which he mathematically “proved” that a heavier than air machine could never fly (S. Newcomb, The Independent: A Weekly Magazine, October 22, 1903). Professor Newcomb concluded that  “[May not our] mathematicians of today… be ultimately forced to admit that aerial flight is one of that great class of problems with which man can never cope,  and give up all attempts to grapple with it?” On December 17, 1903, Orville Wright made the first flight in a power-driven heavier than air machine at Kitty Hawk, North Carolina.

EIGHT: WHEN IT IS CONVENIENT TO SAY “I AM A SCIENTIST”

Most scientists have the dilemma of explaining to friends and family what it is that they actually do. In my experience, I usually get that eye rolling, glance away, “huh?” response when I say, “I’m working on biological markers for cancer.” They may get an idea of what that means, but when I follow up by saying  “ I’m studying the synthesis, protein folding, and secretion of the hormone human chorionic gonadotropin (hCG), I get that quizzical look. More women than men know what hCG is because it’s the pregnancy hormone that turns little urinary dipsticks blue and leads to joy or horror depending on the circumstances. However, almost no non-physician knows what hCG has to do with cancer, unless they have a friend or family member with testicular cancer. The hormone hCG is a definitive diagnostic marker for testicular cancer and for a type of uterine cancer called choriocarcinoma. It is also a marker, though a less definitive one, for a few other cancers such as certain gastrointestinal tumors.

Our research was aimed at trying to find out why the hormone produced by cancer cells is somewhat different from that produced by the placenta in a normal pregnancy. On the face of it, this might seem like a real who cares question (this sort of question about the seeming irrelevance of basic research to real world issues is often posed by the general public and congress members who don’t know that some very important original findings about key cancer pathways in humans came from yeast, fruit flies, and frogs). In our lab’s case, determining the differences between placental hCG and tumor hCG (as described above) could lead to a more specific test for cancer and potentially a new target for anti-cancer drugs.

But back to the question of why sometimes it’s important to be able to say “I’m a scientist” in order to avoid unwanted tasks. This statement may sometimes be followed by an expletive so that the full statement is: “I’m a scientist. Damn it.” I’ll provide an example of this.

One time shortly after the birth of the first of three daughters, my wife Lynne asked me to help her wall paper the new nursery. We started pasting on the striped pink wall paper when she had to go to the grocery for more baby formula. She asked me to continue hanging the wall paper and to be sure to get the stripes straight up and down. She showed me how to snap a chalked plumb line against the wall to ensure the straightness of the stripes. Well, to say that “I flubbed up” is an understatement. Even though I carefully tried to snap the plumb line in the correct position, the wall paper turned out to look slightly crooked even to my eye. But my wife has an artist’s eye, and slightly crooked might as well be sideways. When Lynne returned, she was furious when she saw the botched job I had done. She berated me in a loud voice telling me how incompetent I was even for simple tasks that any well prepared husband should know how to carry out. I lost my temper big time, tore the wall paper off of the wall, wadded it up, and threw it on the floor in disgust, loudly proclaiming “I’m a scientist. Damn it. Not a wall paper hanger!” Believe it or not, 50 years later, we are still happily married, but I never hung a shred of wall paper again.

NINE: SOME EXCITING NEW AREAS IN BIOMEDICALSCIENCE

Personalized Medicine and Systems Biology

Much has been made of the potential breakthroughs in medicine that completion of the human genome project will provide. So far, only a glimmer of the advantage for human health has been seen. The potential impact is huge. Once fully realized, this knowledge will enable prediction early in life of who is likely to get a certain disease and allow institution of chemoprevention and lifestyle changes to delay or circumvent the worst sequelae of such diseases. It will be used to develop pharmacogenetic profiles predicting who will and who will not respond to a certain drug and who will and who won’t be likely to suffer severe side effects from the drug. Knowledge of the human genome sequence and its epigenetic regulation will provide a complete profile of the genetic alterations involved in the pathophysiology of various diseases such as cardiovascular disease, diabetes, autoimmune diseases, and cancer in individual patients. Moreover, it will provide for a complete genetic and biochemical profile of the diseased cells themselves. This latter project is already being done to profile individual cancers in people. Most likely, the biggest impact of characterization of the diseased cell will be realized first in oncology. In sum, the ability to do all these things is leading to a new age of enlightenment called “personalized medicine.”

Personalized medicine has as its principle that for every human disease, the molecular changes that occur in patients’ tissues, the rate and nature of disease progression, and the way each person responds to drugs is unique. This is not taken to mean that each of the 7 billion plus people who populate the earth will require separate diagnostic approaches and separate therapies, but rather that individuals can be stratified into subgroups based on their genetic profiles and that of their disease. It is not easy for pharmaceutical companies to come to grips with this prospect, because the age of the blockbuster drug is evolving into the age of orphan or sub-orphan drugs.

To realize all these advantages, current technology will have to evolve to provide rapid, cost-effective, and readily available procedures. Some of this technology is already at hand or close to being realized. It requires further refinement and scale-up to make it practical.

Here are some of the challenges:

1. There are 3 billion base pairs of DNA in the human genome. When each of 10 to the 14th power cells in the average adult human divides, every base has to be copied perfectly or a potential disease-causing mutation could occur. Of course, in most people this is a rare event because each of us has robust DNA editing and repair systems to keep this from happening, but all it may take in some instances is for one of these base changes in a key gene to sneak through and trigger a malignant event. We also have mechanisms that recognize mutated cells and kill them off by detecting DNA damage, leading to apoptotic cell death. In addition, our bodies have mechanisms that recognize altered cell surface molecules and kill off aberrant cells by immune defense systems.
2.  More than 2 million single nucleotide polymorphisms (SNPS) have been detected in the human genome. Many of these are involved in determining and individual’s susceptibility to disease, response to environmental toxins and drugs, and other parameters of general health and longevity.
3. Many of the technologies for rapid, high throughput, cost effective analyses of genomic, proteomic, and metabolomic profiles are still evolving.
4. The science of systems biology is revealing that the interactions among DNA, RNA, proteins, carbohydrates, lipids, and indeed all the components of cells and tissues are extremely more complex than had been realized previously.

“Systems biology” is a conceptual framework to study, think about, and quantify the types of biological information contained in cells, tissues, organisms, and populations of individuals. It is these interacting networks that modulate and regulate life. Systems biology begins at the level of a cell’s component molecules and extends hierarchically from that. Systems biology attempts to do the following (J.R. Heath et al. Mol. Imag. Biol., 5, 312, 2003):

1. Analyze biological systems by measuring steady-state and dynamic relationships of a system in response to genetic or environmental perturbations across their developmental or physiological time dimensions.
2. Define protein biomodules (e.g., groups of proteins that execute a particular phenotypic function such as glucose and galactose metabolism or protein synthesis) and the protein networks of life (e.g., the skeletal framework of cells and their signal transduction pathways).
3. Delineate gene regulatory networks that govern the expression patterns of proteins across developmental or physiological time spans.
4. Delineate the cells’ effective integration of the protein and gene regulatory networks.

A clue as to how complex all this will be is seen from the incredibly complex genetic and protein-protein interaction networks in lower organisms. For example, global mapping of a yeast genetic interaction network containing 1,000 genes revealed over 4,000 interactions.  In the roundworm C. elegans, more than 5,500 interactions were identified in one subset of proteins. In the fruit fly Drosophila, a total of 10,623 predicted gene transcripts produced a map of 7,048 proteins and 20,405 interactions.

These data provide some insights into how complex a problem it will be to define the systems biology of human beings. Interactions among biologists, chemists, physicists, engineers, computer scientists, and mathematicians will be required to figure all this out. The technologies of gene expression arrays, proteomics, molecular imaging, electrical engineering, nanotechnology, and microfluidics will all be involved in developing the “lab-on-a-chip” and the “nanolab” of the future.

Gene Expression Microarrays

Gene expression microarrays are carried out by different methods to find out the profile of genes transcribed into messenger RNA in given cell types. For example, to determine gene expression in tumor tissue, mRNA from a tumor sample is reverse transcribed into a cDNA, labeled with a fluorescent dye and allowed to bind (hybridize) to oligonucleotide sequences representing the sequence of  a number of genes on a microchip. The intensity of the fluorescence (relative to a reference RNA) is used to determine the amount of expression of the genes represented on the chip. The powerful technique of DNA microarrays has enabled investigators to look inside cancer cells and ask which genes are turned on or off and how cancer cells differ from the normal cells in their tissue of origin. This type of information has enabled subtyping of cancers of a given cell type, staging of cancers, estimations of prognosis, propensity of cells to metastasize, and response to chemotherapy. In addition, DNA microarrays are providing information on potential new targets for chemotherapy and for discovery of biomarkers for diagnosis and screening. For example, microarray technology, with its ability to interrogate up to 40,000 genes in a single sample, has been used for the molecular classification of human breast cancers. These data can be used to correlate estrogen receptor status with gene expression profiles and to project clinical outcomes, likelihood of response to various drugs, and metastatic potential.

Nanotechnology

The term nanotechnology is derived from the Greek word nanos  (dwarf). In its technology usage, nano- is a prefix for something that is one billionth part (10 to the – ninth power) of a specified unit, e.g., nanometer, nanosecond, etc. In the fields of chemistry and physics, the term is usually used to define particles of 1 to a 100 nanometers in diameter. This is equivalent to about the size of 200 gold atoms assembled together or 1/10,000 the width of a human hair. Using nanomaterials to store information, all 25,000 pages of the 1959 edition of the Encyclopedia Britannica could be stored on an area the size of a pinhead.

One of the first practical uses of nanotechnology has been in the design and manufacture of transistors for microprocessors in computers. In the future, nanoscale transistors only a few atoms wide will be used to store up to 10,000 times more information than is currently possible on microprocessors. The field of nanotechnology now encompasses several fields, including engineering (e.g.,nanomaterials, nanoelectronics, microfluidics), computer science, biology, and medicine.

One can envision using nanodevices to implant in the body to detect specific biological markers of cancer and other diseases. For example, implantable sensors could be designed to emit a signal that could be detected outside the body. One nifty futuristic concept is the coupling of nanosensing devices with a drug delivery system that could be implanted on the same microchip into a tumor vascular bed to detect a tumor marker and then release a drug. “Nanovectors” can be designed to deliver drugs to targeted tissues by using, for example, drugs coupled to nanoparticles of gold, silica,  or dendritic polymers.

Molecular Imaging

Molecular imaging is a science designed to detect individual biochemical markers in or on cells by using techniques such as magnetic resonance imaging (MRI), radioisotope imaging by gamma camera or positron emission tomography (PET), optical imaging using bioluminescence, fluorescence, or ultrasound (J.Gelovani et al. Cancer cell, 3,327, 2003). One of the exciting things about molecular imaging is the ability to “see” individual molecular entities in living cells and even in vivo in a non-invasive manner. This is a powerful way to ask questions about protein-protein interactions, drug-receptor binding in target tissues (pharmacodynamics), and a number of other biological events in cells. One intriguing application of intracellular molecular imaging is the ability to determine gene expression in vivo by using PET imaging of a gene’s protein product (M.  Duobrovin et al. Proc. Natl. Acad. Sci. USA, 98, 9300, 2001).

Stem Cells

There has been tremendous excitement, not without some controversy of an ethical, political, and scientific nature, about stem cells. Until recently, it had always been thought that stem cells, those self renewing, pluripotent cells that exist in an embryo, were only present in highly proliferative tissues such as bone marrow, skin, and gastrointestinal tract epithelium. In some tissues such as the brain and heart, self-renewing stem cells were thought to be nonexistent. It has been a true revolution in cell biology to find out that self-renewing, multi-potent stem cells exist in every organ of the body of mammals and most likely of humans. These cells presumably are called on to proliferate in response to tissue injury and are involved in tissue repair.

Of course, if such cells could be generated from various adult tissues such as skin fibroblasts and bone marrow, especially if these cells were taken from the individual in whom these cells might be used as a transplant, one could visualize a whole new way to repair injured  or diseased organs. This has led to a great deal of excitement, and indeed, such experiments are under way in some cases such as spinal cord injury.

The more controversial part of this research involves embryonic stem cells because the harvesting of pluripotent ES cells from an embryo  causes destruction of the embryo. Even though adult stem cells taken from skin or bone marrow can under certain culture conditions be induced to differentiate into multipotent stem cells resembling those of multiple tissues such cells do not have the complete plasticity of ES cells. ES cells grown in cell culture are capable of producing multiple cell types including vascular, neuronal, pancreatic, and cardiac cells as well as cells of other organs; thus, the huge excitement about the potential of these cells for treatment of human disease (reviewed in N. Rosenthal, N. Engl. J. Med., 349, 267, 2003).

TEN: ALL SCIENTISTS NEED A THINKING PLACE

Scientists need a place that lends itself to thinking great thoughts. Sometimes it’s an everyday place like Archimedes bath tub where he discovered the principle of displacement while stepping into a full bath. He realized that the water that ran over equaled in volume the submerged part of his body, and later he developed the concept that a body immersed in a fluid is subject to an upward force (buoyancy) equal in magnitude to the weight of fluid it displaces. This is called the Archimedes Principle. After the first flash of enlightenment in the bath tub, legend has it that he hopped out of the bath and rushed naked into the street yelling triumphantly: “Eureka!” “Eureka!” (Greek for I have found it!).

Another example is Kekule’s discovery of the structure of the benzene ring. He deduced the ring shape while gazing into a fire in his fireplace. In his reverie he visualized a snake seizing its own tail (this is a common symbol in many ancient cultures known as the Ouroboros). He used this concept, and together with his knowledge of carbon-carbon bonds, drew the 6 membered carbon ring structure that is the basis of the benzene ring structure.

The concept for the bubble chamber is another example. The inventor Donald Glazer first thought of this while he was drinking a cold beer in the Pretzel Bell in Ann Arbor in 1952 when he was a young faculty member at the University of Michigan. He noticed the stream of bubbles rising through the beer, and this was the Eureka moment for him that led to the development of an instrument to measure the path of charged atomic particles accelerated by an atom smasher. As particles push through the liquid they create a trail of tiny bubbles that can be photographed through the window of the chamber. This provides physicists with insight about the particles and their relative forces. In 1960, Donald Glazer was awarded the Nobel Prize in Physics for his invention of the bubble chamber.

While I have yet to discover something that might lead to a Nobel Prize, I do have a thinking place that has led to some good ideas about experiments in protein folding. This place can be best described by the following poems.

                         MUD BAY

Tall reeds bent in the fog by Mud Bay

The kind as kids we used to break off

Put between our teeth and swim under water

Pretending we were Tarzan sneaking up on the enemy

They were turning brown now in the fall

The cattails were exploding in disgust at summer’s loss

Even the red-winged blackbirds seemed more circumspect

The ducks floating in the dense fog didn’t move

The muffled cough from the blind revealed their woodenness

The brown moribund leaves fluttered to their final rest

Giving the water a fertile earthy smell

Leaving their now bare branches clutching black fingers skyward

There was a rusty galvanized minnow bucket on the bottom

Sunk halfway in the mud and covered in green moss

Left at the end of some fisherman’s dream

A small-mouth bass going for his lure

Before hope was gone and green had turned

To red-gold or brown and given up

Pirouetting their last dance to earth

The sky blackened to the west

Suggesting an ominous ending

To this already glum day

           SEARCHING FOR A NEW THINKING PLACE

There is a time and a place

Where things come to an end

And new beginnings must be found

Beyond the old horizons of the mind

A search for where the secret places

Of thought can be revealed once again

The old thinking places

Have become crowded uninhabitable

It’s time to turn the bow of the canoe

To leave the beloved wild rose white water lily

Purple lustrife turtle hunting place

That no longer holds the magic of a quiet dawn

Heard now is the sound of bulldozers

Moving the earth filling in the wetlands

For people of another generation

That I do not know or understand

I turn the bow to a new heading

Across the lake toward a channel

All but hidden by tall green reeds

In the shadow of the green hills

Where we once sat on a log

Chewing Granny Smith apples

And wondering if that was the day

That we would find the big boulder

That marked the final resting place

Of the Indian Princess

Maybe in this new little creek

I could remember

What I had almost forgotten

Where I can think again

Without the intruding sounds

Of a populace gone mad with progress

I hope this can be the place

The new thinking place

Where I can still reach

Beyond the pale of my mind

CHAPTER II.  LEARNING FROM NATURE  

1. FIELD OBSERVATIONS  

I learned many important things about nature and life by my observations during my years at Portage Lake in Michigan. The things I sawpiqued my interest in learning more about natural science.

Red-winged Blackbirds

I used to see these beauties during my morning canoes. They were always there in the summer months perched atop cattails or on the bare branches of dead maple trees surrounding a small bay called Dollar Bay because of its perfectly round shape. These birds are one of the most abundant bird species across North America. The males are glossy black with scarlet and yellow shoulder patches. When they’re feeling cocky and full of themselves they puff out their breasts. Females, on the other hand, are a subdued streaky brown, probably so they are less noticeable to potential predators who might endanger their nest.

The red-winged blackbirds have a tumbling happy “conk-la-lee” song that indicates the return of spring when they arrive back up north. An interesting nature vs. nurture question is why do chicks moved from one nesting population to another resemble more their foster parents than their birth parents? This suggests that the difference between populations results from environmental rather than genetic factors. A similar question can be asked about identical human twins raised by different adoptive parents. How much of the difference between such siblings can be attributed to the environment as opposed to a difference in subtle gene expression differences inherited by the twins, e.g., genetic imprinting differences, mutations, or epigenetic differences? This is still an interesting question in human molecular genetics.

The red-winged blackbird species is highly polygamous. Males may have up to 15 mates and they are fiercely territorial. They have been known to attack much larger animals, even humans, who get too close to their nests.

The females are great nest builders. They weave a platform of stringy plant material, using wet leaves and stems over which they add more wet leaves and decayed wood. Then they “plaster’ the walls with mud to make a cup 3 to 7 inches deep and 4 to 7 inches wide. Finally, they feather the nest with fine dry grass to make it cozy- a palace fit for a kingly bird indeed. The blackbirds have a healthy, low calorie, mostly vegetarian diet of insects in summer and corn and wheat grains in winter. No high cholesterol problems here. They may live up to 15 years.

Painted Turtles

Another one of my favorite inspirations from nature involves painted turtles, those denizens of fresh water lakes, marshes, and creeks. They have been part of my life since my youth. Catching them and training them to race was part of my summers as a boy and a tradition carried on by my children and grandchildren. Our favorite thing to do is to put them in a big galvanized tub, which we make as homey as we can for them by putting in rocks that they can climb on to sun themselves. We also decorate the tub with lily pads and a little sea weed. For dinner we provide dried insects or sometimes for a special treat, a minnow or two.

The big events are the turtle races. By placing two 4 to 5 foot two by fours parallel to each other about 3 feet apart, we form a racetrack. We put another two by four at the back of the track to prevent them from going the wrong way and leave the other end open, thinking that they will be motivated to run toward the water as a possible escape route. The turtles, of course, each have a name like “‘mossy,” “pokey,” “scratchy,” or much to my chagrin, “Nana” and “Hat,” nicknames for grandma and grandpa. Up to 6 entries are allowed, one for each grandchild. After all bets (at least one tootsie roll or cookie required) are placed in a bowl, the turtles are placed on the track, headed in the right direction, and given a slight nudge. “They’re off,’’ shouts the starter. Each backer cheers loudly for their entry, but they can’t push their hero along. They can only touch them to turn them around if they start heading the wrong way, but can’t advance them. The winning turtle gets an extra minnow. The winning stable gets the bowl of tootsie rolls and cookies.

It’s a sad day when the turtles have to be returned to Mud Bay or Dollar Bay, where they are usually caught. This occurs the day that everyone has to head home. Each turtle is gently placed over the side of the pontoon boat on to a lily pad, and a few tears are shed as the turtles, finally realizing where they are, scurry off under water toward the reedy shore line. Sometimes the turtles are given an identifying mark with some nail polish on the bottom of their shells to see if we catch the same ones again. That’s never happened as far as I can remember.

The grandchildren always have lots of questions about the turtles. I knew some of the answers, but I had to look up a number of the answers on the internet.  Here they are:

1. How can you tell a boy turtle from a girl turtle?

Male painted turtles are generally smaller than the females and they have longer front claws and longer, thicker tails. Males also have concave bottom shells to make mounting females during copulation more feasible. Strangely, there are no genetic males or females like the XX and XY chromosomal differences in humans. Their sex is determined by external temperatures during embryogenesis. Colder temperatures produce males and warmer ones make females. There must be just enough temperature variation during mating season to get an adequate supply of both sexes. Mother Nature at her best again!

1.  What do painted turtles do in the winter?

They spend the coldest months burrowed in the soft mud at the bottom of their fresh water habitat.

1. How long do they live?

They can live up to 40 years in the wild, but less in captivity.

1. Where do they sleep?

They sleep under water buried in the sand or mud at the bottom of their habitat. Painted turtles need to breathe air so that’s why they need to resurface periodically when they are in motion during the summer months when they like to sun themselves on a lily pad or piece of floating wood. They are poikilothermal animals so they need to be in the sun to warm their bodies. In winter when they are hibernating, their body metabolism is so low that they don’t need much sun or oxygen. A frustration is when you see one sunning himself on a lily pad and try to sneak up on him quietly in the canoe, they see you or sense the motion of the boat and dive under water, but you know they have to resurface in a few moments. The trick is to guess where they will come up and keep the net poised ready to pounce.

1. What do they eat?

They eat minnows, insects, and various water plants.

1. What is the shell made of?

The shell is made of bone and connected to the spine and ribs. Even though they produce boney tissue as they develop, they don’t have teeth. But they have a hard beak that allows them to chew what they can’t swallow whole. Painted turtles have 13 separate bone plates called scutes in their shell. As the turtle grows, it sheds the outermost layer of scutes and grows new larger ones. The new scutes have rings around the outer edges and you can tell their age by counting the rings on the scutes.

1. Can turtles communicate by making sounds?

They don’t have vocal cords, but you can hear them hiss if they get angry.

Thus, even the lowly turtle can teach us a lot about how nature works. They are creatures that always snapped my socks.

Dragonflies

Another of the wonderful gifts of nature that I observed on my jaunts around Portage Lake were dragonflies. They would sometimes perch on the top of my canoe paddle or on the gunnels of the canoe, batting their diaphanous wings and showing off their marvelous hues of blue, yellow, orange, red, or emerald green. They taught me how delicate and yet powerful a creature can be. Like a helicopter, they can hover in space or fly in six directions: up, down, forward, back, and side to side. But how much prettier they are than a helicopter!

Dragonflies belong to the suborder Anisoptera of the order Odanata. Anisoptera comes from the Greek: an (meaning not), iso (equal), ptera (wings) (Corbett, P.S., Dragonflies: Behavior and Ecology of Odonata, Cornell University Press, pp. 559-561. ISBN 0-8014-2592-1). Their hind wings are broader than their fore wings. They have large multifaceted eyes that appear to look right at you as they hover in the air in front of you, totally without fear unless you swat at them. They have two pairs of strong, transparent wings and six legs, but they don’t really walk well and appear to stagger as they try to.

Dragonflies are valuable predators that eat mosquitoes and other small insects like flies and ants. They are usually found around lakes, streams, and wetlands because their larvae (‘nymphs”) are aquatic. The females lay eggs in or near water. The eggs hatch into nymphs, which stage may last months (or even years for larger species). When the nymphs are ready to metamorphose into adults, they climb up on a reed or other water plant. When exposed to air, they start to breathe. The adult form then climbs out of its old larval skin and flies off. The adult can live as long as five or six months.

Dragonflies have different symbolic meanings in different cultures (Mitchell. F.L.,  et al. A Dazzle of Dragonflies, Texas A &M University Press. ISBN 1-585-44459-6; Hand, W.D., From Idea to Word: Folk Beliefs and Customs Underlying Folk speech, American Speech 48 (1/2), 67-76, 2007).  This is one of the reasons that they are so interesting. In Europe, dragonflies were often seen as sinister and had such names as “devil’s darning needle” and “ear cutter (ref), linking them with injury or evil. A Romanian folk tale has it that the dragonfly was once a horse that became possessed by the devil and turned into a dragonfly. Swedish folklore maintains that the devil uses dragonflies to weigh people’s souls (ref). In Norway, a name for dragonflies is “eye poker,” and in Portugal it is “eye snatcher,” perhaps referring to their bulging eyes. In Wales, dragonflies were associated with snakes, and they were called “adder’s servant”. It was believed in the southern US that dragonflies followed snakes around and could help them by stitching up their wounds if they were injured.

In Native American cultures, dragonflies were thought to symbolize swiftness or pure water, and they are a common motif in Zuni pottery, Hopi rock art, and Pueblo necklaces. In Japan and China, dragonflies have been utilized in traditional medicine, and in some countries they are a food source; for example, in Indonesia where they are fried in oil and considered a delicacy. In more modern times dragonfly designs are frequently used motifs in jewelry or for upholstery fabrics.

Dragonfly shape has also been used in geography. For example, an ancient name for Japan was “Dragonfly Islands” because the shape of the Japanese archipelago on a map looks like one. Also, in Japan, dragonflies symbolize courage, strength, and happiness, and some boys are named “Tombo,” which means dragonfly.

Nature is indeed a wonderful teacher of biology and one that many scientists have used as an inspiration for their work. In fact, as we will see, many important scientific discoveries were originally made in Mother Nature’s little creatures.     

CHAPTER III. WHAT NATURE HAS TAUGHT US ABOUT HUMAN BIOLOGY

CELL CYCLE REGULATION

The development of our knowledge about cell cycle regulation is a fascinating story and takes us through a tale of fundamental discoveries in yeast, sea urchins, clams, fruit flies, frogs, mice, and humans. This story serves as a wonderful example of why fundamental basic research should be supported for its own sake, even though its primary aim at the time may simply be the pursuit of knowledge.

The story of the factors involved in cell cycle regulation goes back many years. Definition of distinct phases of a cell division cycle, i.e., G1, S, G2 and M became established in the mid to late 1950s when tritium labeling and cell synchronization techniques became available to score mitoses and to measure the time between one mitotic wave and another in cycling cells. This method consists of labeling cells with a pulse of radioactive, tritiated thymidine, taking a sample of cells at various times after the labeling, fixing the cells, and counting the percentage of mitoses that are labeled in autoradiograms at each time point. The percentage of labeled mitoses will rise from zero to a peak as the cells that were in S phase (making DNA and incorporating thymidine) at the time of the pulse go through mitosis. Following the peak, there will be a trough in labeled mitoses, as the cells that were in G1 at the time of labeling go through M phase. A second cycle will then show a similar peak of labeled M phase cells as the first wave of cells come back through the cell cycle, but the peak will be lower because of dilution of the 3H-thymidine as another round of DNA synthesis occurs (figure). In this way, the classic cell cycle of G1 – S – G2 – M was established.

It became clear from early studies of yeast cells by Lee Hartwell and colleagues that certain genetically controlled factors played a key role in regulating the cell cycle. Various mutants had defects at specific phases of the cell cycle progression. This led to the concept of cell cycle “checkpoints,” the specific genes for which were subsequently discovered by Hartwell and others (reviewed in Ruddon, R.W. Cancer Biology, Oxford University Press, 4^th edition, pp. 143-151, 2007 ), and these genes are similar in every species from yeast to humans.

CELLULAR DIFFERENTIATION

In multicellular organisms, including higher animals and humans, specialized tissues and organs start developing in the embryo and go through a series of differentiation steps culminating in the highly differentiated organs (e,g., heart, lung, liver, kidneys, etc.) of the adult. This involves a carefully regulated sequence of expression of a large number of genes. Again, scientists first learned about how this works by studying some fairly primitive organisms, including  yeast, slime molds, round worms, sea urchins, fruit flies, zebrafish, and chickens. As more has become known about the genomes of these organisms and of humans, it has become clear that there are “orthologous” genes, i.e., genes shared by many organisms. The proteins coded for by these genes have similar gene sequences and function that can be traced all through evolution. A number of these orthologs are involved in cell differentiation processes in all species.  For example, 50% of the genes of fruit flies have human equivalents and almost every human gene has a counterpart in the mouse.

The yeast S. cerevisiae was the first eukaryotic organism that had its genome completely sequenced. The round worm C. elegans was the second. These genomic sequencing data and that of higher organisms and humans that followed has allowed a direct comparison of orthologous genes from widely divergent organisms and provides background information on how similar genes in humans function. These shared genes carry out fundamental biological processes such as intermediary metabolism; DNA and RNA synthesis and processing: protein folding, trafficking, and degradation; and a number of cellular cell differentiation steps. There has, of course, been some sequence and functional divergence during evolution, yet a surprising number of similar functions have been passed on to humans.

APOPTOSIS

Apoptosis is a term derived from a Greek word that means “falling off” as of petals from a flower or leaves from a tree. In cell biology it refers to a mechanism of cell death. Apoptosis plays a vital role in the embryonic development of multi-cellular organisms, including humans. It is required for tissue remodeling during organ development, causing no longer needed cells to die and allow for development of more mature cells in a tissue. It is also an important mechanism in cancer development because a balance between cell proliferation and cell death that takes place in normal tissues is lost, leading to a dysregulated accumulation of abnormal cells in a tumor. Understanding the mechanisms of apoptosis and what regulates it has become important in learning how cancer progresses and how anticancer drugs work. Mutations in genes that regulate apoptosis are frequently seen in cancer cells.

Indeed, the study of cell death is a lively field. Apoptosis is only one of the ways that cells die and exhibits cellular characteristics different from cell necrosis, the other common mechanism of cell death. Necrosis is seen in tissues after exposure to toxic agents, starvation, or traumatic injury and is characterized by clumping of chromatin, swelling of cellular organelles, cell membrane disintegration and infiltration of inflammatory cells.  Apoptosis, on the other hand, is characterized by compaction of chromatin into sharply delineated masses, condensation of the cytoplasm, and outcropping of cytoplasmic blebs, called apoptotic bodies, that become pinched off from the dying cells. The enzymatic machinery involved in apoptosis was first discovered in the round worm C. elegans , and later the orthologs of these genes and their protein gene products were identified in mammalian, including human, cells. Overexpression of a gene called bcl-2 that protects cells against apoptosis was first observed in human lymphoma cells and later in other cancers (reviewed in Ruddon, R.W., Cancer Biology, Oxford University Press, 4^th edition, pp. 151-156, 2007).

CONCLUSION

I have had quite a varied career; some might say a crazy career. I spent over 30 years of it as a professor in academic institutions, mostly at the University of Michigan, but also I was at the National Institutes of Health for 5 years, the University of Nebraska for 7 years, and the Johnson & Johnson corporation for 7 years. I was at U of M for three stints: 1959 – 1976, first as an M.D., PH.D. student and then as a faculty member in the Department of Pharmacology in the medical school; then in 1981- 1990 as chair of the Dept of Pharmacology and Associate Director for Basic Science Research in the UM Comprehensive Cancer Center; in 2004- 2006 as Senior Associate Dean for Research and Graduate Studies in the med school, and finally in 2006-present as Professor Emeritus of Pharmacology.

At NIH, I was Director of the Biological Markers Program at the National Cancer Institute (1976-81). I served as Director of the UNMC- Eppley Cancer Center at the University of Nebraska Medical Center (1990-97 and as Corporate Director and then Corporate Vice President for Science and Technology at Johnson & Johnson corporation (1997-2004. I moved every 7 years on average. I guess because I am part boy scout and like new challenges.

Each of these positions have been rewarding and intellectually challenging. I would like to think that my growing up as a student of nature as well as my education at the Universities of Detroit and of Michigan and professional experiences thereafter all contributed to my ability to do each of these jobs with some success. Graduate students and medical students interested in biomedical research often come to me, as they are finishing their programs, to ask me about career opportunities in the various venues where I worked. They often ask me what my favorite job was. This is very difficult to answer because I thoroughly enjoyed each one of them as well as living in different cities, including Ann Arbor; Frederick, Maryland; Williamstown, Mass. (where I carried out a sabbatical at Williams college); Omaha, Nebraska; and Princeton, New Jersey. Each position provided an opportunity to do something very different from what I had been doing. In addition, I think, immodestly perhaps, that I was able to change a paradigm or two in the way things were being done at each place.

Finally, I still think that the best advice to give students and aspiring young scientists is to do “what snaps your socks.”