THE GENOMIC INVENTORY IS A GIANT STEP FORWARD THE SPIRIT OF EXPLORATION sequence information and spot the specific signals that CONTINUES identify the beginning and ending of sequences likely to encode proteins. Furthermore, the computer systems Less than a decade into the twenty-first century, th could then sort those proteins by similarity of sequences Hubble space telescope continues to transmit informa- (motifs)within their amino acid building blocks. After tion about the uncharted regions of the universe and sorting, the computers could next assign the genes and clues to the origin of the cosmos. This same spirit of gene products to families of similar proteins whose adventure also is being directed to the most complex functions had already been established. In this way, structure that exists in the universe-the human brain. scientists were rapidly able to predict approximately plexity of the human brain is enormous how many proteins could be encoded by the genome describable only in astronomical terms. For example, (all of the genes an individual has). Whole genome the number of neurons in the human brain (about 1012 data are now available for humans, for some non- or 1000 billion) is approximately equal to the number human primates for rats, and for mice of stars in our Milky Way galaxy. Whereas the possi Scientifically, this state of information has been termed a"draft" because it is based on a very dense, bility of understanding such a complex device is cer- but not quite complete, sample of the whole genome tainly daunting, it isnevertheless true that an enormous What has been determined still contains a very large amount has already been learned. The promise and excitement of research on the nervous system have number of interruptions and gaps. Some of the smaller captured the attention of thousands of students and genes, whose beginning and ending are most certain working scientists. What is at stake is not only the po could be thought of as parts in a reassembled Greek sibility of discovering how the brain works. It is esti- n, held in place by bits of blank clay until further nated that diseases of the brain, including both excavation is done. However, having even this draft neurological and psychiatric illnesses, affect as many has provided some important realities Similar routines allowed these genomic scholars to as 50 million individuals annually in the United States determine how many of those mammalian genes were alone, at an estimated societal cost of hundreds of bil lions of dollars in clinical care and lost productivity like genes we have already recognized in the smaller The prevention, treatment, and cure of these diseases genomes of other organisms mapped out previously willultimately be found throughneuroscienceresearch. (yeast, worm( Caenorhabditis elegans), and fruitfly(Dro- Moreover, many of the issues currently challenging sophila melanogaster)and how many other gene forms societies globally-instability within the family, ilit. current estimates, it would appear that despite the individualized programs of education--could be illu- very large number of nucleotides in the human and minated by a better understanding of the brain other mammalian genomes, about 30 times the lengt of the worms and more like 15 times the fruitfly, mammals may have only twice as many gene perhaps some 30,000 to 40,000 altogether. Compared THE GENOMIC INVENTORY IS A to other completed genomes, the human genome has GIANT STEP FORWARD greatly increased its representation of genes related to nervous system function, tissue-specific developmen tal mechanisms, and immune function and blood coag Possibly the single largest event in the history of ulation. Importantly for diseases of the nervous system biomedical research was publicly proclaimed in June that are characterized by the premature death of 2000 and was presented in published form in February neurons, there appears to have been a major expansion 2001: the initial inventory of the human genome. By in the numbers of genes related to initiating the process ng advanced versions of the powerful methods of of intentional cell death, or apoptosis. Although still molecular biology, several large scientific teams have controversial, genes regulating primate brain size have been able to take apart all of an individuals human been reported, but links to intellectual capacity remain DNA in very refined ways, amplify the amounts of the unproven pieces, determine the order of the nucleic acid bases in Two major future vistas can be imagined. To create each of the fragments, and then put those fragments organisms as complex as humans from relatively back together again across the 23 pairs of human few genes probably means that the richness of the chromosomes required proteins is based on their modifications, Having determined the sequences of the nucleic either during transcription of the gene or after transla- cids, it was possible to train computers to read the tion of the intermediate messenger RNA into the L NEUROSCIENCE
I. NEUROSCIENCE THE SPIRIT OF EXPLORATION CONTINUES Less than a decade into the twenty-fi rst century, the Hubble space telescope continues to transmit information about the uncharted regions of the universe and clues to the origin of the cosmos. This same spirit of adventure also is being directed to the most complex structure that exists in the universe—the human brain. The complexity of the human brain is enormous, describable only in astronomical terms. For example, the number of neurons in the human brain (about 1012 or 1000 billion) is approximately equal to the number of stars in our Milky Way galaxy. Whereas the possibility of understanding such a complex device is certainly daunting, it is nevertheless true that an enormous amount has already been learned. The promise and excitement of research on the nervous system have captured the attention of thousands of students and working scientists. What is at stake is not only the possibility of discovering how the brain works. It is estimated that diseases of the brain, including both neurological and psychiatric illnesses, affect as many as 50 million individuals annually in the United States alone, at an estimated societal cost of hundreds of billions of dollars in clinical care and lost productivity. The prevention, treatment, and cure of these diseases will ultimately be found through neuroscience research. Moreover, many of the issues currently challenging societies globally—instability within the family, illiteracy, poverty, and violence, as well as improved individualized programs of education—could be illuminated by a better understanding of the brain. THE GENOMIC INVENTORY IS A GIANT STEP FORWARD Possibly the single largest event in the history of biomedical research was publicly proclaimed in June 2000 and was presented in published form in February 2001: the initial inventory of the human genome. By using advanced versions of the powerful methods of molecular biology, several large scientifi c teams have been able to take apart all of an individual’s human DNA in very refi ned ways, amplify the amounts of the pieces, determine the order of the nucleic acid bases in each of the fragments, and then put those fragments back together again across the 23 pairs of human chromosomes. Having determined the sequences of the nucleic acids, it was possible to train computers to read the sequence information and spot the specifi c signals that identify the beginning and ending of sequences likely to encode proteins. Furthermore, the computer systems could then sort those proteins by similarity of sequences (motifs) within their amino acid building blocks. After sorting, the computers could next assign the genes and gene products to families of similar proteins whose functions had already been established. In this way, scientists were rapidly able to predict approximately how many proteins could be encoded by the genome (all of the genes an individual has). Whole genome data are now available for humans, for some nonhuman primates, for rats, and for mice. Scientifi cally, this state of information has been termed a “draft” because it is based on a very dense, but not quite complete, sample of the whole genome. What has been determined still contains a very large number of interruptions and gaps. Some of the smaller genes, whose beginning and ending are most certain, could be thought of as parts in a reassembled Greek urn, held in place by bits of blank clay until further excavation is done. However, having even this draft has provided some important realities. Similar routines allowed these genomic scholars to determine how many of those mammalian genes were like genes we have already recognized in the smaller genomes of other organisms mapped out previously (yeast, worm (Caenorhabditis elegans), and fruitfl y (Drosophila melanogaster)) and how many other gene forms may not have been encountered previously. Based on current estimates, it would appear that despite the very large number of nucleotides in the human and other mammalian genomes, about 30 times the length of the worms and more like 15 times the fruitfl y, mammals may have only twice as many genes— perhaps some 30,000 to 40,000 altogether. Compared to other completed genomes, the human genome has greatly increased its representation of genes related to nervous system function, tissue-specifi c developmental mechanisms, and immune function and blood coagulation. Importantly for diseases of the nervous system that are characterized by the premature death of neurons, there appears to have been a major expansion in the numbers of genes related to initiating the process of intentional cell death, or apoptosis. Although still controversial, genes regulating primate brain size have been reported, but links to intellectual capacity remain unproven. Two major future vistas can be imagined. To create organisms as complex as humans from relatively so few genes probably means that the richness of the required proteins is based on their modifi cations, either during transcription of the gene or after translation of the intermediate messenger RNA into the THE GENOMIC INVENTORY IS A GIANT STEP FORWARD 9
1. FUNDAMENTALS OF NEUROSCIENCE protein. These essential aspects of certain proteins sented in this book is the culmination of hundreds of account for a small number of brain diseases that can years of research. To help acquaint you with some of be linked to mutations in a single gene, such as Hunt this work, we have described many of the key experi ington's Disease(see Chapter 31). Second, though ments of neuroscience throughout the book. We also compiling this draft inventory represents a stunning have listed some of the classic papers of neuroscience technical achievement, there remains the enormously and related fields at the end of each chapter, and invite daunting task of determining, for example, where in you to read some of them for yourselves the brains circuits specific genes normally are The pursuit of science has not always been a com- expressed, and how that expression pattern may be munal endeavor. Initially, research was conducted in altered by the demands of illness or an unfriendly relative isolation. The scientific "community"that environment. That task, at present, is one for which existed at the time consisted of intellectuals who shared there are as yet no tools equivalently as powerful as the same general interests, terminology, and para those used to acquire the flood of sequence data with gms. For the most part, scientists were reluctant to which we are now faced. This stage has been referred collaborate or share their ideas broadly, because an to as the end of "naive reductionism adequate system for establishing priority for discover In the fall of 2005, a six-nation consortium of molec- ies did not exist. However, with the emergence of sci ular biologists announced the next phase of genomic entific journals in 1665, scientists began disseminating research. The new focus will be toward refining the their results and ideas more broadly because the pub initial inventories to compare whole genomes of lication record could be used as proof of priority healthy and affected individuals for a variety of Science then began to progress much more rapidly,as complex genetic illnesses (the HapMap project). each layer of new information provided a higher foun Complex genetic diseases, such as diabetes mellitus, dation on which new studies could be built hypertension, asthma, depression, schizophrenia, and Gradually, an interactive community of scientists alcoholism, arise through the interactions of multiple evolved, providing many of the benefits that contem short gene mutations that can increase or decrease porary scientists enjoy: Working as part of a commu- nes vulnerability to a specific disease depending on nity allows for greater specialization and efficiency of individual life experiences. Ultimately, as the speeds effort. This not only allows scientists to study a topic of genome sequencing improve still further and the in greater depth but also enables teams of researchers cost is reduced, it may be possible to predict what to attack problems from multidisciplinary perspec diseases will be more likely to affect a given person, tives. The rapid feedback and support provided by and predict the lifestyle changes that person could the community help scientists refine their ideas and undertake to improve his or her opportunities to maintain their motivation. It is this interdependence remain healthy across space and time that gives science much of its In order to benefit from the enormously rich poten- power tial mother lode of genetic information, next we must With interdependence, however, comes vulnerabil- functions they can control, and w expressed, what ity. In science, as in most communities, codes of accept- other gene products can exert over them. In the nervous rights of individuals while maximizing the benefits system, where cell-cell interaction is the main operat- they receive. Some of these guidelines are concerned ing system in relating molecular events to functional with the manner in which research is conducted, and behavioral events, discovering the still-murky proper- other guidelines refer to the conduct of scientists ties of activity-dependent gene expression will require and their interactions within the scientific community Let us begin by examining how new knowledge is created ac EUROSCIENCE TODAY OMMUNAL ENDEAVOR THE CREATION OF KNOWLEDGE As scientists, we draw from the work of those whe Over the years, a generally accepted pro came before us, using other scientists'work as a foun- conducting research has evolved. This process involves dation for our own. We build on and extend previous examining the existing literature, identifying an impor observations and, it is hoped, contribute something to tant question, and formulating a research plan. Often, those who will come after us. The information pre- new experimental pathways are launched when one I. NEUROSCIENCI
10 1. FUNDAMENTALS OF NEUROSCIENCE I. NEUROSCIENCE protein. These essential aspects of certain proteins account for a small number of brain diseases that can be linked to mutations in a single gene, such as Huntington’s Disease (see Chapter 31). Second, though compiling this draft inventory represents a stunning technical achievement, there remains the enormously daunting task of determining, for example, where in the brain’s circuits specifi c genes normally are expressed, and how that expression pattern may be altered by the demands of illness or an unfriendly environment. That task, at present, is one for which there are as yet no tools equivalently as powerful as those used to acquire the fl ood of sequence data with which we are now faced. This stage has been referred to as the end of “naïve reductionism.” In the fall of 2005, a six-nation consortium of molecular biologists announced the next phase of genomic research. The new focus will be toward refi ning the initial inventories to compare whole genomes of healthy and affected individuals for a variety of complex genetic illnesses (the HapMap project). Complex genetic diseases, such as diabetes mellitus, hypertension, asthma, depression, schizophrenia, and alcoholism, arise through the interactions of multiple short gene mutations that can increase or decrease one’s vulnerability to a specifi c disease depending on individual life experiences. Ultimately, as the speeds of genome sequencing improve still further and the cost is reduced, it may be possible to predict what diseases will be more likely to affect a given person, and predict the lifestyle changes that person could undertake to improve his or her opportunities to remain healthy. In order to benefi t from the enormously rich potential mother lode of genetic information, next we must determine where these genes are expressed, what functions they can control, and what sorts of controls other gene products can exert over them. In the nervous system, where cell–cell interaction is the main operating system in relating molecular events to functional behavioral events, discovering the still-murky properties of activity-dependent gene expression will require enormous investment. NEUROSCIENCE TODAY: A COMMUNAL ENDEAVOR As scientists, we draw from the work of those who came before us, using other scientists’ work as a foundation for our own. We build on and extend previous observations and, it is hoped, contribute something to those who will come after us. The information presented in this book is the culmination of hundreds of years of research. To help acquaint you with some of this work, we have described many of the key experiments of neuroscience throughout the book. We also have listed some of the classic papers of neuroscience and related fi elds at the end of each chapter, and invite you to read some of them for yourselves. The pursuit of science has not always been a communal endeavor. Initially, research was conducted in relative isolation. The scientifi c “community” that existed at the time consisted of intellectuals who shared the same general interests, terminology, and paradigms. For the most part, scientists were reluctant to collaborate or share their ideas broadly, because an adequate system for establishing priority for discoveries did not exist. However, with the emergence of scientifi c journals in 1665, scientists began disseminating their results and ideas more broadly because the publication record could be used as proof of priority. Science then began to progress much more rapidly, as each layer of new information provided a higher foundation on which new studies could be built. Gradually, an interactive community of scientists evolved, providing many of the benefi ts that contemporary scientists enjoy: Working as part of a community allows for greater specialization and effi ciency of effort. This not only allows scientists to study a topic in greater depth but also enables teams of researchers to attack problems from multidisciplinary perspectives. The rapid feedback and support provided by the community help scientists refi ne their ideas and maintain their motivation. It is this interdependence across space and time that gives science much of its power. With interdependence, however, comes vulnerability. In science, as in most communities, codes of acceptable conduct have evolved in an attempt to protect the rights of individuals while maximizing the benefi ts they receive. Some of these guidelines are concerned with the manner in which research is conducted, and other guidelines refer to the conduct of scientists and their interactions within the scientifi c community. Let us begin by examining how new knowledge is created. THE CREATION OF KNOWLEDGE Over the years, a generally accepted procedure for conducting research has evolved. This process involves examining the existing literature, identifying an important question, and formulating a research plan. Often, new experimental pathways are launched when one
RESPONSIBLE CONDUCT scientist reads with skepticism the observations and lished in peer-reviewed journals ultimately follow the interpretations of another and decides to test their verbal communications. Such publications are not metimes especially at the beginning of simply a means to allow the authors to advance as "descriptive, for example, determining the struch professionals(although they are important in that of a protein or the distribution of a neurotransmitter of the advancement of science. As we have already n brain. Descriptive initial research is essential to the stated, science depends on sharing information, subsequent inductive phase of experimentation, the replicating and thereby validating experiments, and movement from observations to theory, seasoned with the en movin ng forward to solve the next problem. wisdom and curiosity. Descriptive experiments are Indeed, a scientific experiment, no matter how spec- valuable both because of the questions that they tacular the results, is not completed until the results attempt to answer and because of the questions that are published. More likely, publication of"spectacu their results allow us to ask. Information obtained lar"results will provoke a skeptical scientist into from descriptive experiments provides a base of doing an even more telling experiment, and knowl knowledge on which a scientist may draw to develop edge will evolve hypotheses about cause and effect in the phenomenon under investigation. For example, once we identify the distribution of a particular transmitter within the brain or the course of a pathway of connections through RESPONSIBLE CONDUCT descriptive work, we may then be able to develop a theory about what function that transmitter or Although individuals or small groups may perform pathway serves. experiments, new knowledge is ultimately the product Once a hypothesis has been developed, the of the larger community. Inherent in such a system is researcher then has the task of designing and perform- the need to be able to trust the work of other scien- ing experiments that are likely to disprove that hypoth- tists--to trust their integrity in conducting and report esis if it is incorrect. This is referred to as the deductive ing research. Thus, it is not surprising that much phase of experimentation, the movement from theory emphasis is placed on the responsible conduct of o observation. Through this paradigm the neuroscien- research tist seeks to narrow down the vast range of alternative Research ethics encompasses a broad spectrum of explanations for a given phenomenon. Only after behaviors. Where one draws the line between sloppy attempting to disprove the hypothesis as thoroughly science and unethical conduct is a source of much as possible may scientists be adequately assured that debate within the scientific community. Some acts their hypothesis is a plausible explanation for the phe- are considered to be so egregious that despite per nomenon under investigation sonal differences in defining what constitutes ethical A key point in this argument is that data may only behavior, the community generally recognizes certain lute proof of its validity. In part, this is because the These unambiguously improper activities consist of constraints of time, money, and technology allow a fabrication, falsification, and plagiarism: Fabrication scientist to test a particular hypothesis only under a refers to making up data, falsification is defined as limited set of conditions. Variability and random altering data, and plagiarism consists of using another chance may also contribute to the experimental results. persons ideas, words, or data without attribution. Consequently, at the end of an experiment, scientists Each of these acts significantly harms the scientific generally report only that there is a statistical probabil community ity that the effect measured was due to intervention Fabrication and falsification in a research paper rather than to chance or variabilit taint the published literature by undermining its Given that one can never prove a hypothesis, how integrity. Not only is the information contained in do"facts"arise? At the conclusion of their experi- such papers misleading in itself, but other scientists ments, the researchers' first task is to report their find- may unwittingly use that information as the founda- ings to the scientific community. The dissemination of tion for new research. If, when reported, these subse- research findings often begins with an informal pres- quent studies cite the previous, fraudulent publication, entation at a laboratory or departmental meeting the literature is further corrupted. Thus, through a ventually followed by presentation at a scientific domino-like effect one paper may have a broad nega- neeting that permits the rapid exchange of informa- tive impact on the scientific literature. Moreover, tion more broadly. One or more research articles pub- when fraud is discovered, a retraction of the paper L NEUROSCIENCE
I. NEUROSCIENCE scientist reads with skepticism the observations and interpretations of another and decides to test their validity. Sometimes, especially at the beginning of a new series of experiments, the research plan is purely “descriptive,” for example, determining the structure of a protein or the distribution of a neurotransmitter in brain. Descriptive initial research is essential to the subsequent inductive phase of experimentation, the movement from observations to theory, seasoned with wisdom and curiosity. Descriptive experiments are valuable both because of the questions that they attempt to answer and because of the questions that their results allow us to ask. Information obtained from descriptive experiments provides a base of knowledge on which a scientist may draw to develop hypotheses about cause and effect in the phenomenon under investigation. For example, once we identify the distribution of a particular transmitter within the brain or the course of a pathway of connections through descriptive work, we may then be able to develop a theory about what function that transmitter or pathway serves. Once a hypothesis has been developed, the researcher then has the task of designing and performing experiments that are likely to disprove that hypothesis if it is incorrect. This is referred to as the deductive phase of experimentation, the movement from theory to observation. Through this paradigm the neuroscientist seeks to narrow down the vast range of alternative explanations for a given phenomenon. Only after attempting to disprove the hypothesis as thoroughly as possible may scientists be adequately assured that their hypothesis is a plausible explanation for the phenomenon under investigation. A key point in this argument is that data may only lend support to a hypothesis rather than provide absolute proof of its validity. In part, this is because the constraints of time, money, and technology allow a scientist to test a particular hypothesis only under a limited set of conditions. Variability and random chance may also contribute to the experimental results. Consequently, at the end of an experiment, scientists generally report only that there is a statistical probability that the effect measured was due to intervention rather than to chance or variability. Given that one can never prove a hypothesis, how do “facts” arise? At the conclusion of their experiments, the researchers’ fi rst task is to report their fi ndings to the scientifi c community. The dissemination of research fi ndings often begins with an informal presentation at a laboratory or departmental meeting, eventually followed by presentation at a scientifi c meeting that permits the rapid exchange of information more broadly. One or more research articles published in peer-reviewed journals ultimately follow the verbal communications. Such publications are not simply a means to allow the authors to advance as professionals (although they are important in that respect as well). Publication is an essential component of the advancement of science. As we have already stated, science depends on sharing information, replicating and thereby validating experiments, and then moving forward to solve the next problem. Indeed, a scientifi c experiment, no matter how spectacular the results, is not completed until the results are published. More likely, publication of “spectacular” results will provoke a skeptical scientist into doing an even more telling experiment, and knowledge will evolve. RESPONSIBLE CONDUCT Although individuals or small groups may perform experiments, new knowledge is ultimately the product of the larger community. Inherent in such a system is the need to be able to trust the work of other scientists—to trust their integrity in conducting and reporting research. Thus, it is not surprising that much emphasis is placed on the responsible conduct of research. Research ethics encompasses a broad spectrum of behaviors. Where one draws the line between sloppy science and unethical conduct is a source of much debate within the scientifi c community. Some acts are considered to be so egregious that despite personal differences in defi ning what constitutes ethical behavior, the community generally recognizes certain research practices as behaviors that are unethical. These unambiguously improper activities consist of fabrication, falsifi cation, and plagiarism: Fabrication refers to making up data, falsifi cation is defi ned as altering data, and plagiarism consists of using another person’s ideas, words, or data without attribution. Each of these acts signifi cantly harms the scientifi c community. Fabrication and falsifi cation in a research paper taint the published literature by undermining its integrity. Not only is the information contained in such papers misleading in itself, but other scientists may unwittingly use that information as the foundation for new research. If, when reported, these subsequent studies cite the previous, fraudulent publication, the literature is further corrupted. Thus, through a domino-like effect one paper may have a broad negative impact on the scientifi c literature. Moreover, when fraud is discovered, a retraction of the paper RESPONSIBLE CONDUCT 11
1. FUNDAMENTALS OF NEUROSCIENCE provides only a limited solution, as there is no guar- plines with regard to what is considered to be appro- antee that individuals who read the original article priate behavior. For example, students in neuroscience will see the retraction. Given the impact that just one usually coauthor papers with their advisor, who typi fraudulent paper may have, it is not surprising that cally works closely with them on their research. In the integrity of published literature is a primary contrast, students in the humanities often publish ethical concern for scientists papers on their own even if their advisor has made Plagiarism is also a major ethical infraction. Scien- a substantial intellectual contribution to the work tific publications provide a mechanism for establishing reported. Within a discipline, the definition of accept priority for a discovery. As such, they form the cur- able practices may also vary from country to country rency by which scientists earn academic positions, Because of animal use regulations, neuroscientists in gain research grants to support their research, attract the United Kingdom do relatively little experimental tudents, and receive promotions. Plagiarism denies work with animals on the important topic of stress, he original author of credit for his or her work. This whereas in the United States this topic is seen as an hurts everyone: The creative scientist is robbed of appropriate area of study so long as guidelines are credit, the scientific community is hurt by the disincen- followed to ensure that discomfort to the animals is tive to share ideas and research results, and the indi- minimized. vidual who has plagiarized-like the person who has The definition of responsible conduct may change fabricated or falsified data-may well find his or her over time. For example, some protocols that were once career ruined performed on human and animal subjects may no In addition to the serious improprieties just longer be considered ethical. Indeed, ethics evolve described, which are in fact extremely rare, a variety alongside knowledge. We may not currently be able to of much more frequently committed"misdemeanors" know all of the risks involved in a procedure, but as in the conduct of research can also affect the scientific new risks are identified (or previously identified risks community. Like fabrication, falsification, and plagia- refuted), we must be willing to reconsider the facts and rism, some of these actions are considered to be adjust our policies as necessary. In sum, what is con- unethical because they violate a fundamental value, sidered to be ethical behavior may not always be such as honesty. For example, most active scientists obvious, and therefore we must actively examine what believe that honorary authorship--listing as an author is expected of us as scientists someone who did not make an intellectual contribu- Having determined what is acceptable practice, we tion to the work-is unethical because it misrepre- then must be vigilant. Each day neuroscientists are sents the origin of the research. In contrast, other faced with a number of decisions having ethical impli unethical behaviors violate standards that the scien cations most of them at the level of misdemeanors tific community has adopted. For example, although Should a data point be excluded because the apparatus it is generally understood that material submitted to might have malfunctioned? Have all the appropriate a peer-reviewed journal as part of a research manu- references been cited and are all the authors appropri script has never been published previously and is not ate? Might the graphic representation of data mislead under consideration by another journal, instances of the viewer? Are research funds being used efficiently? retraction for dual publications can be found on Although individually these decisions may not signifi- occasion cantly affect the practice of science, cumulatively they can exert a great effect. Scientific Misconduct Has Been Formally In addition to being concerned about the integrity Defined by U.S. Governmental Agencies of the published literature, we must be concerned with our public image. Despite concerns over the level of The serious misdeeds of fabrication, falsification, federal funding for research, neuroscientists are among nd plagiarism generally are recognized throughout the privileged few who have much of thei the scientific community. These were broadly recog- funded by taxpayer dollars. Highly pr ublicized scan- nized by federal regulations in 1999 as a uniform dals damage the public image of our profession and standard of scientific misconduct by all agencies hurt all of us who are dependent on continued public funding research. What constitutes a misdemeanor is support for our work. They also reduce the public less clear, however, because variations in the defini- credibility of science and thereby lessen the impact tions of accepted practices are common. There are that we can expect our findings to have. Thus, for our several sources of this variation. Because responsible own good and that of our colleagues, the scientific conduct is based in part on conventions adopted by a community, and the public at large, we must strive to field, it follows that there are differences among disci- act with integrit . NEUROSCIENCI
12 1. FUNDAMENTALS OF NEUROSCIENCE I. NEUROSCIENCE provides only a limited solution, as there is no guarantee that individuals who read the original article will see the retraction. Given the impact that just one fraudulent paper may have, it is not surprising that the integrity of published literature is a primary ethical concern for scientists. Plagiarism is also a major ethical infraction. Scientifi c publications provide a mechanism for establishing priority for a discovery. As such, they form the currency by which scientists earn academic positions, gain research grants to support their research, attract students, and receive promotions. Plagiarism denies the original author of credit for his or her work. This hurts everyone: The creative scientist is robbed of credit, the scientifi c community is hurt by the disincentive to share ideas and research results, and the individual who has plagiarized—like the person who has fabricated or falsifi ed data—may well fi nd his or her career ruined. In addition to the serious improprieties just described, which are in fact extremely rare, a variety of much more frequently committed “misdemeanors” in the conduct of research can also affect the scientifi c community. Like fabrication, falsifi cation, and plagiarism, some of these actions are considered to be unethical because they violate a fundamental value, such as honesty. For example, most active scientists believe that honorary authorship—listing as an author someone who did not make an intellectual contribution to the work—is unethical because it misrepresents the origin of the research. In contrast, other unethical behaviors violate standards that the scientifi c community has adopted. For example, although it is generally understood that material submitted to a peer-reviewed journal as part of a research manuscript has never been published previously and is not under consideration by another journal, instances of retraction for dual publications can be found on occasion. Scientifi c Misconduct Has Been Formally Defi ned by U.S. Governmental Agencies The serious misdeeds of fabrication, falsifi cation, and plagiarism generally are recognized throughout the scientifi c community. These were broadly recognized by federal regulations in 1999 as a uniform standard of scientifi c misconduct by all agencies funding research. What constitutes a misdemeanor is less clear, however, because variations in the defi nitions of accepted practices are common. There are several sources of this variation. Because responsible conduct is based in part on conventions adopted by a fi eld, it follows that there are differences among disciplines with regard to what is considered to be appropriate behavior. For example, students in neuroscience usually coauthor papers with their advisor, who typically works closely with them on their research. In contrast, students in the humanities often publish papers on their own even if their advisor has made a substantial intellectual contribution to the work reported. Within a discipline, the defi nition of acceptable practices may also vary from country to country. Because of animal use regulations, neuroscientists in the United Kingdom do relatively little experimental work with animals on the important topic of stress, whereas in the United States this topic is seen as an appropriate area of study so long as guidelines are followed to ensure that discomfort to the animals is minimized. The defi nition of responsible conduct may change over time. For example, some protocols that were once performed on human and animal subjects may no longer be considered ethical. Indeed, ethics evolve alongside knowledge. We may not currently be able to know all of the risks involved in a procedure, but as new risks are identifi ed (or previously identifi ed risks refuted), we must be willing to reconsider the facts and adjust our policies as necessary. In sum, what is considered to be ethical behavior may not always be obvious, and therefore we must actively examine what is expected of us as scientists. Having determined what is acceptable practice, we then must be vigilant. Each day neuroscientists are faced with a number of decisions having ethical implications, most of them at the level of misdemeanors: Should a data point be excluded because the apparatus might have malfunctioned? Have all the appropriate references been cited and are all the authors appropriate? Might the graphic representation of data mislead the viewer? Are research funds being used effi ciently? Although individually these decisions may not signifi - cantly affect the practice of science, cumulatively they can exert a great effect. In addition to being concerned about the integrity of the published literature, we must be concerned with our public image. Despite concerns over the level of federal funding for research, neuroscientists are among the privileged few who have much of their work funded by taxpayer dollars. Highly publicized scandals damage the public image of our profession and hurt all of us who are dependent on continued public support for our work. They also reduce the public credibility of science and thereby lessen the impact that we can expect our fi ndings to have. Thus, for our own good and that of our colleagues, the scientifi c community, and the public at large, we must strive to act with integrity
SUMMARY SUMMARY Committee on the Conduct of Science( 1995). On Being a Scientist, nd Ed. National Academy Press, National Academy of Sciences, Washington, DC. You are about to embark on a tour of fundamental Cowan, W M. and Kandel, E R (2001). Prospects for i neuroscience. Enjoy the descriptions of the current psychiatry. JAMA 285, 594-600 state of knowledge, read the summaries of some of the Day,, R. A(1994)."How to Write and Publish a Scientific Paper classic experiments on which that information is based, Greengard, P(2001). The neurobiology of slow synaptic transmis- and consult the references that the authors have drawn sion. Science294,1024-1030 on to prepare their chapters. Think also about the Kandel, E R and Squire, L R (2000). Neuroscience: Breaking down ethical dimensions of the science you are studying- scientific barriers to the study of brain and mind. Science 290, your success as a professional and the future of our Kuhn, T.S.(1996). The Structure of Scientific Revolutions, "3rd Ed field depend on it Univ. of Chicago Press, Chicago. Popper, K.R.(1969)."Conjectures and Refutations: The Growth of References Scientific Knowledge, "3rd Ed. Routledge and K. Paul, London Shepherd, G M.(2003). The Synaptic Organization of the Brain. Aston-Jones, G, Cohen, J. D.(2005). An integrative theory of locus Oxford Uni. Press. New York. coeruleus-norepinephrine function: Adaptive gain and optim Swanson, L. (2000). What is the brain? Trends Neurosci. 23, performance. Annu. ReD. Neurosci. 28, 403-45050 519-527 Boorstin, D.J(1983).The Discoverers. Random House, New York Cherniak, C(1990). The bounded brain: Toward quantitative neu- anatomy. Cog. Neurosci. 2, 58-68 Floyd E bloom L NEUROSCIENCE
I. NEUROSCIENCE SUMMARY You are about to embark on a tour of fundamental neuroscience. Enjoy the descriptions of the current state of knowledge, read the summaries of some of the classic experiments on which that information is based, and consult the references that the authors have drawn on to prepare their chapters. Think also about the ethical dimensions of the science you are studying— your success as a professional and the future of our fi eld depend on it. References Aston-Jones, G., Cohen, J. D. (2005). An integrative theory of locus coeruleus-norepinephrine function: Adaptive gain and optimal performance. Annu. Rev. Neurosci. 28, 403–45050. Boorstin, D. J. (1983). “The Discoverers.” Random House, New York. Cherniak, C. (1990). The bounded brain: Toward quantitative neuroanatomy. J. Cog. Neurosci. 2, 58–68. Committee on the Conduct of Science (1995). “On Being a Scientist,” 2nd Ed. National Academy Press, National Academy of Sciences, Washington, DC. Cowan, W. M. and Kandel, E. R. (2001). Prospects for neurology and psychiatry. JAMA 285, 594–600. Day, R. A. (1994). “How to Write and Publish a Scientifi c Paper,” 4th Ed. Oryx Press, Phoenix, AZ. Greengard, P. (2001). The neurobiology of slow synaptic transmission. Science 294, 1024–1030. Kandel, E. R. and Squire, L. R. (2000). Neuroscience: Breaking down scientifi c barriers to the study of brain and mind. Science 290, 1113–1120. Kuhn, T. S. (1996). “The Structure of Scientifi c Revolutions,” 3rd Ed. Univ. of Chicago Press, Chicago. Popper, K. R. (1969). “Conjectures and Refutations: The Growth of Scientifi c Knowledge,” 3rd Ed. Routledge and K. Paul, London. Shepherd, G. M. (2003). “The Synaptic Organization of the Brain.” Oxford Uni. Press, New York. Swanson, L. (2000). What is the brain? Trends Neurosci. 23, 519–527. Floyd E. Bloom SUMMARY 13