Discovering neurosurgery: new frontiers

The 2011 AANS Presidential Address

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Over the centuries, discoveries of lands unknown, treasures lost and buried, and formulas to delineate physicochemical processes have led to advancements in our understanding of how the world is structured and governed. In science and medicine, discoveries are frequently made following deliberate periods of observation and experimentation to test hypotheses. However, in some instances, discoveries may arise either following a “eureka moment” that transcends rigorous scientific experimentation or following a serendipitous observation. In many instances, scientific discoveries will lead to new inventions that are aimed at improving the manner in which tasks or operations are performed. In this address, some of the key discoveries in science and medicine that have impacted significantly on the field of neurosurgery are described. Some of these include discoveries in neuroanatomy, anesthesiology, infectious diseases, antisepsis, and radiology. Discoveries in the field of molecular science, from the discovery of DNA to next-generation DNA sequencing, which have helped improve the diagnosis and prognosis of neurosurgical patients with conditions such as brain tumors, are also described. In the end, these discoveries have led us to new frontiers in the subspecialty practice of neurosurgery. Navigating our way through these new frontiers will undoubtedly lead to additional discoveries that are unimaginable at present but bound to improve the future care of neurosurgical patients.

Abbreviations used in this paper: AANS = American Association of Neurological Surgeons; GBM = glioblastoma multiforme; NREF = Neurosurgery Research and Education Foundation.

Abstract

Over the centuries, discoveries of lands unknown, treasures lost and buried, and formulas to delineate physicochemical processes have led to advancements in our understanding of how the world is structured and governed. In science and medicine, discoveries are frequently made following deliberate periods of observation and experimentation to test hypotheses. However, in some instances, discoveries may arise either following a “eureka moment” that transcends rigorous scientific experimentation or following a serendipitous observation. In many instances, scientific discoveries will lead to new inventions that are aimed at improving the manner in which tasks or operations are performed. In this address, some of the key discoveries in science and medicine that have impacted significantly on the field of neurosurgery are described. Some of these include discoveries in neuroanatomy, anesthesiology, infectious diseases, antisepsis, and radiology. Discoveries in the field of molecular science, from the discovery of DNA to next-generation DNA sequencing, which have helped improve the diagnosis and prognosis of neurosurgical patients with conditions such as brain tumors, are also described. In the end, these discoveries have led us to new frontiers in the subspecialty practice of neurosurgery. Navigating our way through these new frontiers will undoubtedly lead to additional discoveries that are unimaginable at present but bound to improve the future care of neurosurgical patients.

Man cannot discover new oceans unless he has the courage to lose sight of the shore.

Andre Gide

It has been a great honor for me to serve as the president of the American Association of Neurological Surgeons for 2010–2011. Upon completion of the 79th annual meeting of the AANS in Denver, I will return to the University of Toronto to become the RS McLaughlin Chair of Surgery. The departmental office is located in the Banting Institute (Fig. 1), named after Sir Frederick Banting, the discoverer of insulin. Prior to the discovery of insulin in 1922, juvenile diabetes was a death sentence. Survival was measured in months not years. Based on his conviction that a cure for diabetes would be found within soluble extracts of the endocrine pancreas, Banting, along with Charles Best, performed experiments that led to the purification of insulin and its successful use in the first human clinical trials.13 The third patient in the world to receive insulin therapy was Elizabeth Hughes, the daughter of famed U.S. presidential candidate and Secretary of State, Charles Evans Hughes. In 1923 Elizabeth Hughes came to Toronto to be treated by Banting. With the discovery of insulin, Elizabeth Hughes lived a long and productive life, and died at age 74, having received more than 42,000 injections of this life-saving hormone.13

Fig. 1.
Fig. 1.

Left: Photograph of the Banting Institute of the Faculty of Medicine, the University of Toronto. Named after Sir Frederick Banting, the discoverer of insulin. Right: Historic plaque commemorating the discovery of insulin and mentioning the roles played by Frederick Banting, Charles Best, J.J.R. Macleod, and James Collip in the discovery process.

While the discovery of insulin must be ranked with some of the most important discoveries in modern medicine, in neurosurgery we too have much to be proud of in terms of the discoveries that have helped to shape our field. Today, I am delighted to share my thoughts on neurosurgical discoveries with you as we explore the theme of this year's meeting, Discovering Neurosurgery: New Frontiers.

Discovering Denver as a Frontier City

First, a few words about our assemblage here in Denver, a true “frontier” city. I begin with the famous word “eureka,” from the Greek, meaning “I have found it,” that is, the joy of discovery. The term is most famously attributed to the ancient Greek scholar Archimedes, who reportedly proclaimed “eureka” when he stepped into a bath and noticed the change in the water level. At that instant in time, he understood that the volume of water displaced must be equal to the volume of the part of his body that he had submerged. He is said to have been so eager to share his discovery that he leaped out of the bathtub and ran through the streets of Syracuse naked.

“Eureka” is also the motto of the state of California. In this context, it refers to the momentous discovery of gold near Sutter's Mill in 1848. Few can argue with the significance of the gold strike from the standpoint of the subsequent migration to the western part of the country. The California Gold Rush of 1849 had a profound impact on the establishment of Denver as a city a decade later. In November 1858, General William Larimer, a land speculator from eastern Kansas staked a claim across from the growing town of Auraria in Colorado, and called it “Denver” after James W. Denver, the governor of the Kansas Territory.4 In the spring of 1859, George A. Jackson and John H. Gregory discovered gold in the mountains west of Denver. Just as with the 49ers who flocked to the California goldfields a decade earlier, hordes of “59ers” headed to Denver to strike it rich. More than 100,000 59ers pioneered across the parched and sprawling wilds of the desert to seek out their fortunes near Denver.27

In 1893 J.J. Brown was appointed superintendent of the Ibex Mining Company near Denver, and what followed was a fortuitous combination of ingenuity, timing, and good luck. Ibex miners hit a layer of slippery dolomite sand that made it impossible to drive a shaft toward the gold. Brown discovered that the use of bales of hay supported by stout wooden timbers held the sand back and enabled a mine shaft to be dropped and the rich gold deposits to be found.34 This discovery led to huge profits for the Ibex Mining Company and instantly made J.J. Brown a wealthy man. Brown was married to perhaps the most famous Denverite of all time, Margaret Brown (Fig. 2).

Fig. 2.
Fig. 2.

Photograph of Margaret Tobin Brown (1867–1932), perhaps better known as the “Unsinkable Molly Brown” as she survived the sinking of the Titanic on April 14, 1912. Throughout her life she promoted the cause of women, especially during the Suffragist Movement, and with her husband, J.J. Brown (1854–1922), became one of Denver's most famous citizens. Reproduction Number: LC-USZ62-94037. Photoprint by Bain News Service. George Grantham Bain Collection (Library of Congress).

Margaret Brown, better known as the “Unsinkable Molly Brown” was born in Hannibal, Missouri, in 1867 and moved to Leadville, Colorado, and married J.J. Brown in 1886. She survived the sinking of the Titanic on April 14, 1912. Throughout her life, she promoted the cause of women during the Suffragist Movement, and she traveled the world extensively, becoming fluent in Russian, German, and French.34 At the Barbizon Hotel, she died quietly in her sleep at the age of 65. An autopsy revealed that she had died of a primary brain tumor. We are indeed fortunate that the life and times of Molly Brown is the subject of this year's Louise Eisenhardt Lecture, given by Kristen Iversen (Fig. 3), who has written the definitive work on this famed Denverite.34

Fig. 3.
Fig. 3.

Photograph of Dr. Kristen Iversen delivering the 2011 AANS Louise Eisenhardt Lecture.

Discovery of the Scientific Method

What I wish to discuss in this address today is alluded to on the program cover (Fig. 4). Depicted on it are 1) a series of scientific equations that predict the responses of the brain to external forces, with which all neurosurgeons have familiarity; 2) a compass, slightly turned to signify the historical importance of the role of navigation in traversing uncharted territories, be they on land, at sea, or in the depths of the human brain; and 3) a lateral view of the brain itself to signify our collective interest as neurosurgeons in the structure and function of this unique organ system.

Fig. 4.
Fig. 4.

Program guide and theme of the 79th AANS Annual Scientific Meeting—Discovering Neurosurgery: New Frontiers.

First, some words on the origins of scientific equations. The generation of equations that can predict physical and chemical reactions must be considered as one of the ultimate demonstrations of humankind's intelligence and creativity. The development of the scientific method, which helped to crystallize the modern approach to science, is considered one of the major achievements in the history of science and investigation. The first clear record of the use of the scientific method can be traced to Alhazen, who developed rigorous experimental methods to test theoretical hypotheses.2 Alhazen's Book of Optics exerted great influence on Western science. In 1620 Francis Bacon outlined a new system of logic to improve upon the old philosophical process of syllogism in his book Novum Organum (The new tool).51 In 1637 René Descartes established the framework for the scientific method in his treatise Discourse on Method (Fig. 5).21

Fig. 5.
Fig. 5.

Famous historical personages who discovered and promulgated the modern-day scientific method. A: Alhazen Ibn al-Haytham (965–1040 AD), who wrote the influential Book of Optics in Arabic. Gregory Primo Photography, photographers-direct. com. B: Sir Francis Bacon (1562–1626), whose book entitled Novum Organum (The new tool), provided a novel approach to scientific inquiry. ©iStockphoto.com/GeorgiosArt. C: René Descartes (1596–1650), whose work entitled Discourse on Method influenced generations of scientists. ©iStockphoto.com/GeorgiosArt.

Adherence to the scientific method has paved the way to countless discoveries throughout the past several centuries. Observations are followed by the genesis of a testable hypothesis. The hypothesis is then used to make predictions. These predictions are then tested by experimentation. When consistency is obtained, the hypothesis becomes a theory. A theory is then a framework within which observations are explained and predictions are made (Fig. 6).

Fig. 6.
Fig. 6.

Algorithm depicting the protocol used for the scientific method, including the creation of a theory or hypothesis, followed by prediction, experimentation, and observation steps.

Just as the scientific method was promulgated in the 1600s, 12 men gathered on a damp night in November 1660 at Gresham College in London to hear the young and not-yet-famous Christopher Wren give a lecture on astronomy. When he had finished, the 12 men decided to form an association called “the Society,” which met weekly to witness experiments and to discuss scientific matters. By 1662, it had secured a Royal Charter from King Charles II and became known as the “Royal Society.” Together, members of the Royal Society invented the process of scientific publishing and peer review, and in so doing, created modern science.10 Since then, fellows of the Royal Society have created whole new branches of science, split the atom, and discovered hydrogen, the double helix, and the electron. They have invented the Internet; developed profound theories on evolution, gravity, and motion; and furthered our understanding of everything from astrophysics to biodiversity.10

Today, as in the past, the Royal Society's interests remain an inspiration to recite. It is, and always has been, an inclusive society where only the quality of science matters and where country of origin and personal wealth do not. Today, the Royal Society provides an impressive 350 research fellowships annually and supports the work of over 3000 scientists throughout the world (Fig. 7). In the words of Bill Bryson, author of Seeing Further, “If we have an Earth worth living on a hundred years from now, the Royal Society will be one of the organizations our grandchildren will wish to thank.”10

Fig. 7.
Fig. 7.

Current edifice of the Royal Society, whose mandate is to support the best in science and the best scientists worldwide. ©royalsociety.org.

Discovery of Target Destinations Through Navigation

The second topic on which I will speak is discovery through navigation. The discovery of places unknown, whether by sea or land, required the invention of the compass, which is generally attributed to the Chinese more than 2000 years ago. The compass arrived in Europe in the 1300s following exchanges along the Silk Road to China. The inventor most often recognized for the modern design of the compass is Flavio Gioia from Amalfi.3 With the design of the new compass, the great age of exploration and discovery followed. The legendary and monumental journeys of Henry the Navigator, Christopher Columbus, Vasco da Gama, and Ferdinand Magellan were made possible with this and other navigational tools.

In January 1803, President Thomas Jefferson sent Congress a secret plan for the exploration and discovery of the “Western Ocean.” The ensuing adventures of Lewis and Clark and their multicultural corps of discovery is a defining saga second to none in American history. Their mission was to discover the fabled Northwest Passage. Lewis and Clark were outstanding journalists, leaving behind journals and texts of over 1 million words. Their journey of discovery, like most great ones before and since, was predicated on equal parts of hope and ignorance, sustained by fortune and determination, and consummated by discoveries that were unimaginable at the outset.57

Interestingly, the forerunner of America's Lewis and Clark was Canada's David Thompson. Thompson has been called the greatest practical land geographer that the world has produced. Before the journeys of Lewis and Clark, Thompson mapped almost 3 million square miles of North America. He was probably the first to see the whole geography of western North America and understood how it affected organic life, economy, and human society. The land had been inhabited for millennia by diverse groups of Native peoples, and he was able to speak to them in their languages and to learn from them.43

In his riveting and highly acclaimed book Sea of Glory, Nathaniel Philbrick, this year's Cushing Orator (Fig. 8), describes the incredible story of the U.S. Exploring Expedition (or “Ex Ex”) of 1838–1842.50 Contrary to popular thought, America's first frontier was not the West; it was the sea. After 4 years at sea, the Ex Ex logged 87,000 miles, surveyed 280 Pacific islands, mapped 1500 miles of the icebound Antarctic coast, and acquired thousands of specimens and artifacts that would become the foundation of the collections of the Smithsonian Institute.50 It was one of the largest voyages of discovery in the history of Western exploration.

Fig. 8.
Fig. 8.

James Rutka (left), president of the AANS, presenting the 2011 Cushing Oration Award to Nathaniel Philbrick (right), famed US historian and author of several land discovery and new frontiers books, including In the Heart of the Sea, Sea of Glory, Mayflower, and The Last Stand.

The principles of navigation used to discover new lands and places have been paramount in creating the modern-day map of the human brain and in our approaches to a myriad of human neurosurgical diseases. Horsley and Clark invented the first stereotactic head frame in 1908, which was used for primate surgery.31 Horsley's system, and all that follow, use a set of Cartesian coordinates in an orthogonal frame. In 1947 Spiegel et al.59 described the first frame-based stereotactic system for operations on the human brain. In 1951 Lars Leksell38 developed the Gamma Knife, in which a series of collimated electromagnetic beams delivered radiation through multiple cobalt sources.

Modern neuroimaging has enabled the real-time spatial fusion of images of the brain using fiducial markers. Neuronavigation systems have evolved with the ever-increasing capabilities of manipulating data through complex mathematical algorithms using robust computer technologies. In the past 20 years alone, virtually every neurosurgery center in North America has at least one system for neuronavigation. Just as for the early land and sea explorers, the principles of neuronavigation are nearly identical—to guide the neurosurgeon toward a destination accurately, reliably, and consistently.

Discovering Neuroanatomy

The third topic on discovery on which I will now speak is the human brain itself. There can be little argument that the sine qua non of the neurosurgeon is the study of neuroanatomy. Our knowledge of human neuroanatomy was revolutionized by the great works of Andreas Vesalius of Brussels who, in his work entitled De Humani Corporis Fabrica, established the beginning of modern observational science and research.56 With this publication, Vesalius is ranked as one of the greatest discoverers in all of science. Vesalius was among the first to popularize the use of the observational method in cadaveric dissections. His tome is an exquisite piece of creative art and science with a perfect blend of format, typography, and illustration.56

Refinements in human anatomy and human neuroanatomy, in particular, have followed since this time. All of us, since medical school to the present time, have studied laboriously from the great neuroanatomy textbooks to hone our skills and to prepare ourselves for the neurosurgical approaches we use to treat our patients. As subspecialists, neurosurgeons have focused on the development of practical neurosurgical anatomy. In this field, the works of three influential individuals come to mind.

The first is Kenichiro Sugita, who was arguably the most influential and innovative neurosurgeon in Japan. During the formative years of his career in Nagoya, he was continuously innovating in neurosurgery with the design of microvascular instruments, a head frame and retractor system, and his internationally acclaimed aneurysm clips.

As chairman of neurosurgery at Shinshu University, Dr. Sugita amassed a large clinical experience, treating patients with the most difficult intracranial tumors and vascular lesions. There, he published his famous Microneurosurgical Atlas in which he illustrated the neuroanatomy of many of the complex operative procedures he performed over his career.61 As a clinical fellow in Nagoya in 1990, under his direction, I had the great privilege of watching a canvas spring to life with Dr. Sugita's recollections of the most important steps in the dissection and clipping of a complex middle cerebral artery aneurysm. Dr. Sugita was a true renaissance man who influenced the careers of innumerable neurosurgeons worldwide (Fig. 9). In his name and honor, the AANS is truly pleased to create the AANS-Sugita International Symposium, which recognizes the major neurosurgical contributions of this giant in the field. And we are especially honored to have bestowed upon Professor Shigeaki Kobayashi, Dr. Sugita's disciple at Shinshu University, this year's International Lifetime Recognition Award (Fig. 10).

Fig. 9.
Fig. 9.

Innovative and highly skillful, Japanese neurosurgeon Kenichiro Sugita was a true renaissance man with demonstrated expertise as a cellist, author, artist, downhill skier, tennis player, and world historian.

Fig. 10.
Fig. 10.

Dr. Shigeaki Kobayashi received the 2011 AANS International Lifetime Recognition Award in Denver. He helped Dr. Sugita establish the Department of Neurosurgery at Shinshu University. After Dr. Sugita, Dr. Kobayashi held the position as chair of the department from 1988 to 2003. He became president of both the Japanese Congress of Neurological Surgeons and the Japan Neurosurgical Society. He was also named as the chief medical officer of the 1998 Nagano Winter Olympics.

Second is Dr. Al Rhoton, known to all of us for his tremendous devotion to and mastery of human neuroanatomy. Over the years, Dr. Rhoton has described and popularized numerous neurosurgical approaches to the brain, including the choroidal fissure approach to the third ventricle and the lateral approach to the cavernous sinus, among many others.25,46,48,64 As with Vesalius, Dr. Rhoton's neuroanatomical dissections and specimens are masterpieces to behold, each taking dozens of hours from inception to completion. The AANS is indeed pleased that Dr. Rhoton's monumental slide collection will be captured in all its glory in a 3D digital project to be announced at this meeting (Fig. 11).

Fig. 11.
Fig. 11.

Dr. William Couldwell (left), secretary of the AANS, together with Dr. Al Rhoton (right) during the AANS Annual Meeting in Denver where Dr. Rhoton was recognized and thanked for the creation of the novel Rhoton 3D CD/DVD project.

And finally, I should like to draw attention to the incredible neuroanatomical illustrations of Ian Suk, arguably the most famous neurosurgical illustrator in the world today (Fig. 12). Ian is a graduate of the University of Toronto Department of Biocommunications and is currently on the full-time faculty of the Department of Neurosurgery at Johns Hopkins University. He recently discovered hidden brainstem and spinal cord images within Michelangelo's paintings in the Sistine Chapel, a topic on which he will speak to us as this year's Kurze lecturer.62,63 There can be no question that the legacy of these individuals has contributed to the tremendous neurosurgical experience, as demonstrated today by Robert Spetzler in his Rhoton Family Lecture (Fig. 13), and you will hear tomorrow from Jon Robertson during his Richard C. Schneider Lecture (Fig. 14).

Fig. 12.
Fig. 12.

Dr. Ian Suk, neurosurgical illustrator from Johns Hopkins University, was recognized this year as the Theodore Kurze lecturer. In his presentation, he spoke of the incredible concealed neuroanatomical discoveries within the painted figures in the Sistine Chapel.

Fig. 13.
Fig. 13.

Dr. Robert Harbaugh (left), treasurer of the AANS, presents the 2011 Rhoton Family Lecture award to Dr. Robert Spetzler (right). Dr. Spetzler delivered the talk, “The Quiet Revolution: Retractorless Surgery.”

Fig. 14.
Fig. 14.

Dr. Troy Tippett (left), past president of the AANS, presents the 2011 Richard C. Schneider Lecture award to Dr. Jon Robertson. Dr. Robertson delivered the talk, “Visual Dimensions of Future Neurosurgical Education.”

Discovery of Painless Surgery

The revolution in modern-day neuroanatomy as promulgated by Vesalius was the first in a series of events that made it possible to perform neurosurgery on patients. On October 16, 1846, William Thomas Green Morton, a Boston dentist, unveiled before an audience of physicians in Boston a small glass vaporizer containing a quart of ether and fitted with an inhaler.20 He opened the nozzle and asked the patient Edward Abbott, a printer, to take a few whiffs of the vapor. John Collins Warren, the first dean at Harvard, then stepped forward and painlessly removed a tumor from Abbott's neck (Fig. 15). After Warren had finished and Abbott regained consciousness, Warren asked the patient how he felt. Reportedly, Abbott said, “Feels as if my neck's been scratched.” Warren then turned to his medical audience and uttered, “Gentlemen, this is no Humbug.”

Fig. 15.
Fig. 15.

The discovery of painless surgery through the use of ether anesthesia in 1846. In this historic painting, which hangs in the Ether Dome at the Massachusetts General Hospital, William Thomas Green Morton, a dentist, is holding a small glass vaporizer to deliver ether anesthesia to the patient, Edward Abbott. John Collins Warren, the first dean at Harvard, is shown removing a tumor from Abbott's neck. Portion of the painting “Ether Day 1846” by Robert C. Hinckley, Boston Medical Library.

The discovery of anesthesia and the conduction of painless surgery was indeed opportune for the times. The Civil War had just begun. The administration of anesthesia allowed for humane amputations of war-torn and ravaged limbs, of which there were thousands. The use of anesthesia during the Civil War empowered surgeons to be bold with their surgical techniques and master the handling of delicate tissues, great vessels, and internal organs better than ever before.55 A militia of skilled operative surgeons was of necessity created. William Alexander Hammond is credited as the first to recognize the importance of subspecialty surgery in treating Civil War–wounded soldiers. He was particularly interested in a specialized hospital for nervous system diseases, and so the Turner's Lane Hospital was created in Philadelphia. His friend was Silas Weir Mitchell, novelist, poet, and physician. Weir believed that scientific investigation was the bedrock of a successful calling in medicine. William Williams Keen, America's first neurosurgeon, was another member of Turner's Lane. Together, they published their findings on conditions such as causalgia (a term they famously coined), ascending neuritis, referred sensation, and traumatic neuroses.70

In his book entitled Bleeding Blue and Gray, surgeon-author Ira Rutkow writes, “That the Civil War occurred in the waning years of medicine's prescientific era heightens its tragedy.”55 Physicians were helpless when confronted with communicable illnesses and devastating wound infections. Within one decade of the war's end, an understanding of the role of microorganisms in producing disease and the principles of antiseptic surgery would become accepted everyday knowledge.

Discovery of the Origins of Infectious Diseases

The Broad Street Pump in London had long enjoyed a reputation as a reliable source of clean well water (Fig. 16). But in the summer of 1854, this pump became nefarious for its role in the outbreak of the cholera epidemic that gripped London. In 1849, famed British physician and anesthetist John Snow had hypothesized that cholera was caused by some as-yet-identified agent that victims ingested through waste matter. In the book The Ghost Map, author Steven Johnson states that “intellectual discoveries are rarely the isolated genius having a ‘eureka moment’ alone in the lab. Great breakthroughs are closer to what happens in a flood plain: a dozen separate tributaries converge, and the rising waters lift the genius high enough that he or she can see around the conceptual obstructions of the age.”35 John Snow had determined through careful and meticulous epidemiological observation that the Broad Street Pump water source was the cause of the cholera epidemic in London. Accordingly, the removal of the Broad Street Pump handle in 1854 was a historical turning point, because for the first time, a public institution had made an informed intervention to stop an epidemic based on a scientifically sound theory of disease.

Fig. 16.
Fig. 16.

Modern-day replica of the Broad Street Pump in London, which became nefarious for its role in the spread of the cholera epidemic of 1854. Dr. John Snow is credited with halting the epidemic by removing the Broad Street Pump handle, which limited access to a highly contaminated water supply. ©Robert David Siegel, M.D., Ph.D., Stanford University.

The transmission of disease by the ingestion of contaminated water or food sources foreshadowed the discovery of antisepsis by Joseph Lister. Lister's great contribution was the application of Pasteur's germ theory to the prevention and control of infection. Based on Pasteur's studies, Lister considered the use of an “antiseptic” with carbolic acid in 1865. Why carbolic acid? It turns out that it had been used on a sewage farm near Carlisle in Northern England.20 There, sewage treated with carbolic acid diminished outbreaks of typhoid and cattle sickness. Lister's classic works on antiseptic treatments were published in the Lancet in 186739 and have influenced the practice and conduct of surgery since their day.

On the Role of Serendipity in Scientific Discovery

Until now, I have been describing discoveries that have often been the direct result of adherence to the traditional scientific method, which I outlined at the beginning of this address. However, it is extremely interesting that some of the greatest inventions and discoveries in the world were accidental, unplanned, and unintentional. The term “serendipity” was coined by Horace Walpole in a letter to Horace Mann, in which he describes his reading of a fantasy tale called The Three Princes of Serendip (the ancient name for Sri Lanka). The three heroes of this tale were always making accidental discoveries of things they were not in quest of.

Perhaps the most famous of all serendipitous discoveries was the discovery of penicillin by Alexander Fleming (Fig. 17). In 1928 Fleming took a 2-week vacation but did not bother to clean up the lab before he left. Upon his return, he saw one especially filthy specimen on a glass plate on which he had left a Staphylococcus culture. A greenish-yellow mold had sprouted on the culture. What Fleming noted was a bacterial free zone around the culture. The mold had been created by Penicillium notatum. The Penicillium stopped the growth of bacteria on part of the glass plate. Fleming named the substance “penicillin” and published his finding in the Journal of Experimental Pathology in 1929.23 As everyone knows, penicillin was used to treat pneumonia, diphtheria, and scarlet fever and saved the lives of thousands of soldiers during World War II.

Fig. 17.
Fig. 17.

Photograph of Alexander Fleming, shown here in his microbiology laboratory, who serendipitously discovered penicillin following the fungal contamination of bacterial culture plates in the lab. ©ImageState RM/www.fotosearch.com.

Another serendipitous discovery was that of x-rays by Wilhelm Röntgen. In late October 1895, Röntgen, a lecturer at Würzburg Institute in Germany, noted a strange radiant leakage from the electron tube with which he was working. The radiant energy was powerful and invisible and capable of penetrating layers of blackened cardboard, producing a white phosphorescent glow on a barium screen, which was accidentally left on a bench in the room. His wife, Anna, was then asked to place her hand between the source of these rays and the photographic plate, leaving a silhouette of the bones of her hand and metallic wedding ring on the photographic plate. Röntgen was astonished with his finding and called this form of light “X-rays.”53 He received the Nobel Prize in 1901.

The serendipitous discovery of x-rays was followed step-wise by other major advances in diagnostic imaging, including the development of ventriculography by Dandy in 1919,17 cerebral angiography by Egas Moniz in 1927,42 CT by Hounsfield in 1973,32 and the MR imaging body scanner by Raymond Damadian in 1977.16 Few of us would argue with the power of the currently available panoply of diagnostic imaging tools that have enabled us to see the brain in all its anatomical, functional, metabolic, and magnetic glory.

But why do serendipitous discoveries happen? Shouldn't the process of the scientific method alone be sufficient to make all discoveries? In the book Scientific Discovery: Logic and Tinkering, Aharon Kantorovich argues that “serendipity in science is not a casual phenomenon.”36 Serendipity supplies science with its blind edge. It enables the human mind to transcend established frameworks of knowledge and established world pictures. Serendipity is essential for the advancement of science because we conduct our scientific investigations from within a given framework.

Great Discoveries in Science and Neurosurgery

A return to the scientific program theme reveals sparks of electricity on the compass points indicating energy transfer. In his book Benjamin Franklin: An American Life, famed author Walter Isaacson stated that it was Franklin who turned the study of electricity from a parlor trick into a science.33 He was the first to establish the nomenclature for electricity by using the terms “positive charges” and “negative charges.” He also described the notion of the “conservation of charge,” which proved to be as fundamental as Newton's law of the conservation of momentum.

In 1750 in letters to the Royal Society in London, Franklin described the use of a tall metal rod to draw some of the electrical charge from a cloud. In 1752 Franklin performed his famous experiment with the kite and key, enlisting the help of his son William. He collected the charge from the heavens in a Leyden jar and convincingly demonstrated the sameness of lightning and electricity. And so the lightning rod became one of Franklin's most celebrated inventions.33

Now fast-forward approximately 100 years to the life and times of Thomas Alva Edison, who was arguably the world's greatest inventor and discoverer. By the time of his death in 1931, at the age of 84, Edison had 1093 patents in his name for devices such as a mechanical vote recorder, a battery for an electric car, and a stock ticker machine.68 Of course, he is best remembered for his invention of the first incandescent light bulb and the first recording machine, which ultimately spawned the development of the music record industry, stereo systems, iPods, and streaming music.60

However, according to Randall Stross, author of The Wizard of Menlo Park, his greatest contribution may well be his discovery of the contemporary system of research and development, as his labs were the forerunners of the interactive think tanks of the modern-day National Institutes of Health/National Institute of Neurological Disorders and Sroke, Microsoft, Disney, Apple, and Google.60 In the 1870s, while in his twenties, Edison created the inventor community in Menlo Park, New Jersey, that became the famous invention factory. There, a critical mass of assistants with backgrounds in multiple areas of science, engineering, and skilled labor was assembled to become America's first research and development community. He used mass brain power to drive the process of invention and marketed the devices that were discovered by using the deep pools of capital that were forming in the late 19th century.68 At Menlo Park, Edison claimed that a modest invention was developed every 10 days, and a major invention was discovered every 6 months. The so-called E List was Edison's method of keeping the latest and most promising ideas at the forefront of discovery (Fig. 18).

Fig. 18.
Fig. 18.

One of Thomas Edison's “E lists” in which he itemizes a wide array of projects to be pursued in the lab at Menlo Park. On it, one can read bold research projects such as a deaf apparatus, an electrical piano, a hand-turning phonograph, and a cotton picker.

The discovery of electricity and illumination had farreaching implications for neurosurgery. Harvey Cushing harnessed the power of electricity to illuminate the field while operating and to control bleeding during neurosurgical procedures thanks to collaboration with William T. Bovie. Bovie was an assistant professor of biophysics at Harvard who had developed an electrosurgical unit as part of his fellowship work for the Cancer Commission. Cushing saw Bovie's apparatus in use in 1926, and over the ensuing months he used the device in two patients with extracranial tumors. He published his experience with electrosurgery in 1928 in Surgery, Gynecology and Obstetrics,14 and electrosurgery became a crucial part of his legacy.67

Discoveries in Cancer and Neurooncology

In the moments that remain in this address, I should like to turn your attention toward discoveries that have occurred in an area of deep interest to me and I know to many of you—namely, cancer and neurooncology. As you all know, cancer remains one of the most common and feared diseases known to man. The heightened awareness of cancer in the public domain suggests that cancer is an old and unconquerable disease. But is cancer truly an ancient disease? The rarity with which cancer was reported in antiquity poses the interesting question of whether cancer is a manmade disease, especially given its increased incidence since the Industrial Revolution.19

What can we learn about cancer from studying other species or historic epochs? Take plants, for example. Plants do not develop cancer. Why? Plant cells are fixed in a cell wall matrix. They are not motile. They cannot metastasize. Plants share many orthologous genes with humans, including numerous tumor suppressor genes and oncogenes. Plants develop tumors, but not cancers, and these are usually caused by pathogens such as fungal infections and geminiviruses. These data suggest that the tumor suppressor genes in plants are more robust, stable, and less likely to be mutated than in mammalian cells. Understanding plant physiology may help all of us to combat cancer.22

Or take, for example, the dinosaurs who roamed the earth for 185 million years during the Mesozoic era. Computed tomography scanning of over 10,000 specimens of dinosaur vertebrae shows a paucity of tumors, and those that were found were probably hemangiomas, osteoblastomas, or desmoplastic fibromas.52 It is quite likely that dinosaurs ate foliage rich in carcinogens, including tannins, phenols, and resins. Why is it then that dinosaurs rarely developed cancers?

After a study of thousands of Neanderthal specimens in Europe, only one example of a tumor was found and was likely an intracranial meningioma with cranial hyperostoses. In Egyptian times, cancer was rarely documented. The first mention of cancer is from the Edwin Smith papyrus containing the writings of the great Egyptian physician Imhotep, who lived around 2625 BC. Of the 48 clinical cases described on the papyrus, Case 45 illustrates the case of a woman with breast cancer. Following this ancient report of breast cancer in the Edwin Smith papyrus, sadly and curiously, the world literature on the topic of cancer is conspicuously silent.44 In the book The Emperor of All Maladies: A Biography of Cancer, Siddhartha Mukherjee states that if cancer existed in the interstices of these massive epidemics, it existed in silence, leaving no easily identifiable trace in the medical literature.44 Cancer reports are surprisingly rare in the literature of the ancients.

As for cancers of the nervous system, one of the first detailed descriptions can be found in Robert Hooper's text The Morbid Anatomy of the Human Brain, published in 1828.30 Hooper distinguished between tumors intrinsic to the brain and those of the dura, and thereby separating meningiomas from gliomas. He describes the case of a superficial GBM and a “black tumour,” which was undoubtedly a metastatic melanoma.

The famed case of a 25-year-old Scottish farmer named Henderson, who presented to London physician Alexander Hughes Bennett with a 3-year history of focal motor seizures, sparked interest in the feasibility of intracranial surgery following accurate clinical localization. Rickman John Godlee was asked to undertake the operative procedure using Listerian antisepsis, chloroform anesthesia, and preoperative localization. Godlee opened the cortex over where the tumor was presumed to be, and he removed the tumor.5 The door was now opened for the refinement of neurosurgical technique and innovation regarding tumors of the brain, such as was performed by Cushing,15 Dandy,18 Penfield,49 Yaşargil,1 and many others. But the real challenge was in the understanding of the biology of primary brain cancers.

Discoveries in the Age of Molecular Medicine

As described thus far, the history of science is an epic story that has been marked by several great trends in intellectual thought, including the Copernican, Einsteinian, Darwinian, and quantum mechanics “revolutions.”54 To these can now be added the revolution in molecular biology. In 1953 James Watson and Frederick Crick published their seminal report on the molecular structure of DNA (Fig. 19). This single-page report, containing a mere 128 lines, provided the basis of the molecular biology revolution and had the power to influence subsequent generations of scientists.69 In their article, Watson and Crick stated, “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.”69

Fig. 19.
Fig. 19.

The molecular biology revolution was heralded by the discovery of the structure of DNA by Francis Crick (right) and James Watson (left). ©A. Barrington Brown/Photo Researchers, Inc.

One of the most significant intellectual achievements of all time, with the potential to influence humankind as never before, is the completion and publication of the Human Genome Project in February 2001.37,66 With these data in the public domain, we are equipped not only to advance our knowledge of the normal regulatory mechanisms of the human organism, but also to facilitate the diagnosis and treatment of human disease, including cancer. With the Human Genome Project, virtually anything is now possible. What is truly revolutionary about molecular biology in the post–Watson-Crick era is that the code of life exists on a digital platform, one that can be accessed and manipulated using tools that are available on virtually every personal computer and with connection to the Internet.65

With the completion of the human genome project, the amount of molecular biological sequence data available in the public databases has reached staggering proportions. To keep pace with this extant database, the science of bioinformatics (or computational biology) has evolved. Bioinformatics has accelerated the pace of research as well as allowing experiments that would have otherwise been impossible, in no small part because of the capability of information exchange on the Internet databases.65

Timothy Berners-Lee invented the World Wide Web as a high-tech library where researchers could share information. It went live on Berners-Lee's computer in December 1990 and consisted of one website and one browser. Following the creation of the Web, any person could share information with anyone else, anywhere. Now, the information necessary to understand the complex interactions between diseases, biological processes in the human body, and the vast array of chemical agents is spread across the world in a myriad of databases, spreadsheets, and documents.6

Numerous new techniques in molecular biology these past 30 years have advanced the pace of scientific discovery: Gene therapy, microarray techniques, and cancer genomics including SNP array analysis, epigenetics, microRNAs, nanotechnology, and advanced or deep gene sequencing have spawned new approaches to cancer therapy. The Cancer Genome Atlas, led by the National Cancer Institute, is a multiinstitutional consortium aimed at improving our understanding of cancer through genomic characterization and high-throughput, next-generation sequencing technologies. Luckily for neurosurgeons and our patients, one of the first tumors to be sequenced by The Cancer Genome Atlas was GBM.12,47

Has there been tangible progress that has benefited our patients in neurooncology? I would argue that there have been several discoveries that have paved the way toward improved patient diagnosis and treatment. Some of these include 1) the use of 1p and 19q loss to predict for chemosensitivity to alkylating agents in anaplastic oligodendroglioma;11 2) the observation that MGMT methylation in GBM identifies a subgroup of patients with extended survivals;29 3) the use of chromosome 22q11 loss to diagnose a posterior fossa tumor in a child as atypical teratoid rhabdoid tumor;7 4) the prediction that medulloblastoma tumors with nuclear beta catenin expression signify the activation of the Wnt developmental signaling pathway and increase the probability of long-term survival for patients;26 and 5) the discovery that medulloblastoma is actually four separate diseases based on molecular genetic profiling.45 Perhaps the most tangible evidence of progress in human brain tumors was delivered today in the Hunt-Wilson Lecture by Richard Gilbertson as he told us of his discoveries in identifying the cell of origin in medulloblastoma pathogenesis (Fig. 20).

Fig. 20.
Fig. 20.

The 2011 AANS Hunt-Wilson Lecture was delivered by Dr. Richard Gilbertson, research scientist from St. Jude's Children's Research Hospital. Dr. Gilbertson spoke on the role of aberrant developmental signaling pathways as causes of childhood brain cancers such as medulloblastoma.

We are indeed fortunate that in our midst today there are numerous neurosurgeon-scientists who have taken us to new frontiers. From the discovery of steroids in controlling cerebral edema,24 to gene therapy for malignant gliomas,40 to polymer therapy for GBM,9 to convectionenhanced delivery for brain tumors and neurodegenerative diseases,8 to deep brain stimulation for depression,41 to stem cells for human brain tumors,58 to the genetic origins of familial cavernomas and arteriovenous malformations,28 to the classification of medulloblastoma as four different diseases,45 and to many more examples, neurosurgery is an exemplary subspecialty in which discoveries continue to drive progress and better outcomes for our patients.

Supporting Neurosurgical Science—How You Can Help

In efforts to help spawn new discoveries and to support science in neurosurgery, the AANS is very proud of its own “Royal Society,” the Neurosurgery Research and Education Foundation, or NREF. Since its inception in 1981 when two research fellowships were awarded, the NREF has grown in size and stature so that each year approximately eight research fellowships and three Young Clinician Investigator Awards are given. Over the past 30 years, the AANS has invested over $6.5 million in the human capital that will most likely succeed and make new discoveries in the future. I encourage all of you to consider giving to the NREF. Give often and give generously. Our future and the future of our patients depend on the funding we can provide for neurosurgery research (Fig. 21).

Fig. 21.
Fig. 21.

Advertisement for the 7th Annual Charity Softball Tournament in Central Park, New York City, held on June 4, 2011, to benefit the Neurosurgery Research and Education Foundation.

Conclusions

In closing, over the course of your careers looking after countless hundreds of neurosurgical patients, all of you will have undoubtedly made several discoveries that improve the way in which you care for them. However grand or small these discoveries are, let the world know. Publish your findings and your results. Reach for new frontiers and latch onto new technologies as they arise in your clinical practice. Strive for excellence in all that you do. What have I discovered as a neurosurgeon? I have discovered that there is no substitute for knowing one's neuroanatomy, and in this regard we should be committed to life-long learning. I have discovered that our craft has developed as a consequence of innovations and pioneering research over centuries, and so this pattern should continue. I have discovered that keeping an open mind is the most assured way of reaching new frontiers and of being prepared to find answers where they are sometimes least expected. I have discovered after 20 years that there are more unanswered questions in brain tumor research than when I started, and so I will continue to devote myself to neurosurgical research. And finally, I have discovered that serving as your president of the AANS has been the greatest honor of my professional career, and I thank all of you for bestowing your trust and confidence in me.

Acknowledgment

The author thanks Christian Smith, Ph.D., for assistance with the Presidential Address presentation.

Disclosure

The author reports no conflict of interest.

References

Article Information

Address correspondence to: James T. Rutka, M.D., Ph.D., Division of Neurosurgery, Suite 1503, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. email: james.rutka@sickkids.ca.

Please include this information when citing this paper: DOI: 10.3171/2011.9.JNS111038.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Left: Photograph of the Banting Institute of the Faculty of Medicine, the University of Toronto. Named after Sir Frederick Banting, the discoverer of insulin. Right: Historic plaque commemorating the discovery of insulin and mentioning the roles played by Frederick Banting, Charles Best, J.J.R. Macleod, and James Collip in the discovery process.

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    Photograph of Margaret Tobin Brown (1867–1932), perhaps better known as the “Unsinkable Molly Brown” as she survived the sinking of the Titanic on April 14, 1912. Throughout her life she promoted the cause of women, especially during the Suffragist Movement, and with her husband, J.J. Brown (1854–1922), became one of Denver's most famous citizens. Reproduction Number: LC-USZ62-94037. Photoprint by Bain News Service. George Grantham Bain Collection (Library of Congress).

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    Photograph of Dr. Kristen Iversen delivering the 2011 AANS Louise Eisenhardt Lecture.

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    Program guide and theme of the 79th AANS Annual Scientific Meeting—Discovering Neurosurgery: New Frontiers.

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    Famous historical personages who discovered and promulgated the modern-day scientific method. A: Alhazen Ibn al-Haytham (965–1040 AD), who wrote the influential Book of Optics in Arabic. Gregory Primo Photography, photographers-direct. com. B: Sir Francis Bacon (1562–1626), whose book entitled Novum Organum (The new tool), provided a novel approach to scientific inquiry. ©iStockphoto.com/GeorgiosArt. C: René Descartes (1596–1650), whose work entitled Discourse on Method influenced generations of scientists. ©iStockphoto.com/GeorgiosArt.

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    Algorithm depicting the protocol used for the scientific method, including the creation of a theory or hypothesis, followed by prediction, experimentation, and observation steps.

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    Current edifice of the Royal Society, whose mandate is to support the best in science and the best scientists worldwide. ©royalsociety.org.

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    James Rutka (left), president of the AANS, presenting the 2011 Cushing Oration Award to Nathaniel Philbrick (right), famed US historian and author of several land discovery and new frontiers books, including In the Heart of the Sea, Sea of Glory, Mayflower, and The Last Stand.

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    Innovative and highly skillful, Japanese neurosurgeon Kenichiro Sugita was a true renaissance man with demonstrated expertise as a cellist, author, artist, downhill skier, tennis player, and world historian.

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    Dr. Shigeaki Kobayashi received the 2011 AANS International Lifetime Recognition Award in Denver. He helped Dr. Sugita establish the Department of Neurosurgery at Shinshu University. After Dr. Sugita, Dr. Kobayashi held the position as chair of the department from 1988 to 2003. He became president of both the Japanese Congress of Neurological Surgeons and the Japan Neurosurgical Society. He was also named as the chief medical officer of the 1998 Nagano Winter Olympics.

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    Dr. William Couldwell (left), secretary of the AANS, together with Dr. Al Rhoton (right) during the AANS Annual Meeting in Denver where Dr. Rhoton was recognized and thanked for the creation of the novel Rhoton 3D CD/DVD project.

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    Dr. Ian Suk, neurosurgical illustrator from Johns Hopkins University, was recognized this year as the Theodore Kurze lecturer. In his presentation, he spoke of the incredible concealed neuroanatomical discoveries within the painted figures in the Sistine Chapel.

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    Dr. Robert Harbaugh (left), treasurer of the AANS, presents the 2011 Rhoton Family Lecture award to Dr. Robert Spetzler (right). Dr. Spetzler delivered the talk, “The Quiet Revolution: Retractorless Surgery.”

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    Dr. Troy Tippett (left), past president of the AANS, presents the 2011 Richard C. Schneider Lecture award to Dr. Jon Robertson. Dr. Robertson delivered the talk, “Visual Dimensions of Future Neurosurgical Education.”

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    The discovery of painless surgery through the use of ether anesthesia in 1846. In this historic painting, which hangs in the Ether Dome at the Massachusetts General Hospital, William Thomas Green Morton, a dentist, is holding a small glass vaporizer to deliver ether anesthesia to the patient, Edward Abbott. John Collins Warren, the first dean at Harvard, is shown removing a tumor from Abbott's neck. Portion of the painting “Ether Day 1846” by Robert C. Hinckley, Boston Medical Library.

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    Modern-day replica of the Broad Street Pump in London, which became nefarious for its role in the spread of the cholera epidemic of 1854. Dr. John Snow is credited with halting the epidemic by removing the Broad Street Pump handle, which limited access to a highly contaminated water supply. ©Robert David Siegel, M.D., Ph.D., Stanford University.

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    Photograph of Alexander Fleming, shown here in his microbiology laboratory, who serendipitously discovered penicillin following the fungal contamination of bacterial culture plates in the lab. ©ImageState RM/www.fotosearch.com.

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    One of Thomas Edison's “E lists” in which he itemizes a wide array of projects to be pursued in the lab at Menlo Park. On it, one can read bold research projects such as a deaf apparatus, an electrical piano, a hand-turning phonograph, and a cotton picker.

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    The molecular biology revolution was heralded by the discovery of the structure of DNA by Francis Crick (right) and James Watson (left). ©A. Barrington Brown/Photo Researchers, Inc.

  • View in gallery

    The 2011 AANS Hunt-Wilson Lecture was delivered by Dr. Richard Gilbertson, research scientist from St. Jude's Children's Research Hospital. Dr. Gilbertson spoke on the role of aberrant developmental signaling pathways as causes of childhood brain cancers such as medulloblastoma.

  • View in gallery

    Advertisement for the 7th Annual Charity Softball Tournament in Central Park, New York City, held on June 4, 2011, to benefit the Neurosurgery Research and Education Foundation.

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