Our Genes, Our Choices

How Genotype and Gene Interactions Affect Behavior

David Goldman

• Publisher: Academic Press
• Year: 2012
• ISBN:
  9780123972019
• Topic: Biological Sciences
• Subtopic: Genetics & Genomics
• Index: Biological Sciences

Our Genes, Our Choices: How Genotype and Gene Interactions Affect Behavior — First Prize winner of the 2013 BMA Medical Book Award for Basic and Clinical Sciences — explains how the complexity of human behavior, including concepts of free will, derives from a relatively small number of genes, which direct neurodevelopmental sequence. Are people free to make choices, or do genes determine behavior? Paradoxically, the answer to both questions is "yes, " because of neurogenetic individuality, a new theory with profound implications.

Author David Goldman uses judicial, political, medical, and ethical examples to illustrate that this lifelong process is guided by individual genotype, molecular and physiologic principles, as well as by randomness and environmental exposures, a combination of factors that we choose and do not choose.

Written in an authoritative yet accessible style, the book includes practical descriptions of the function of DNA, discusses the scientific and historical bases of genethics, and introduces topics of epigenetics and the predictive power of behavioral genetics.

• First Prize winner of the 2013 BMA Medical Book Award for Basic and Clinical Sciences
• Poses and resolves challenges to moral responsibility raised by modern genetics and neuroscience
• Analyzes the neurogenetic origins of human behavior and free will
• Written by one of the world's most influential neurogeneticists, founder of the Laboratory of Neurogenetics at the National Institutes of Health

Chapter 1

The Neurogenetic Origins of Behavior

“

”

Transliterated as “Timshel”: Thou mayest choose

Genesis, Chapter 4, verse 16

Is the human will free? Do genes determine behavior? Paradoxically, the answer to both questions is “yes”. A new theory of behavior based on neurogenetic individuality has profound implications for conceptions of self, social expectations, ethics and justice.

This book begins with a challenge to free will from my research. The discovery: “2B or not 2B?” involves a gene “knockout” of the human HTR2B gene, which encodes a receptor for the neurotransmitter serotonin. Serotonin is involved in many aspects of behavior including emotion and impulse control. The severely functional receptor variant causes some people to be impulsive, even to the extent of committing senseless murders. Remarkably, it is found in at least 100,000 people in the Finnish population, but as a “founder mutation” has so far only been observed in individuals who are of Finnish ancestry. Yet, while the inherited variant was a “necessary” factor in the impulsive murders that I and my partners in research studied, the gene alone was insufficient to explain the heinous behavior. In understanding why the carriers of the receptor gene variant became murderers, “2B or not 2B?” was not the only question. The context of the gene, for example male sex and drunkenness, also mattered.

All human qualities, including those that are sublime, creative and adaptive, and those that are seemingly mundane, destructive and maladaptive, are ultimately emergent from the expression of a “message in a molecule”. That molecule is DNA. DNA is an information molecule – a polymer in which information is encoded. For example, our DNA contains some 25,000 genic protein-coding regions. However, DNA is ultimately only a chemical that is now fairly easy to synthesize in the laboratory. The total DNA of a bacterium was recently made in a laboratory, and it is probably only a matter of time and motivation before someone synthesizes the whole genome of a more complex creature – even a human. Also, because of the tools now available to study DNA and the ability to study its effects in powerful contexts, including in animal models in which genes are knocked out, the science of genetics has now achieved what seemed impossible only a few years ago. We have demonstrated the causal connection, and not just the correlation, between single genetic variants and complex human behaviors. As will be shown, this reductionistic explanation of human behavior is only in its infancy, and complicated by many difficulties and some false leads.

With some 25,000 protein building blocks and probably an equal number of regulatory RNA molecules, and even allowing for variations in structure, how is it possible that the DNA message can encode a human brain, with its 10¹⁵ (one billion×one million) connections? How, based on the DNA code, can a brain build itself? Is it possible that the complexity of human behavior, and even free will, can be derived from the chemistry of DNA? As will be proposed, the answer lies in the way that this relatively small complement of genes directs a developmental sequence that continues throughout life and that is guided by principles, stochastic in countless details and always completely individual.

Pathways from neurobiology to complex behavior, and the ability of “things we cannot control” to shape behavior, are illustrated by sex. Why do men and women behave as if from different planets and, beyond the effects of culture, how are we to understand the origins of variations in sexual behavior of sex-specific behaviors ranging from attachment, to aggression, to homosexuality? Is there a “gay gene”? Why is there a genetics of sexual behavior and how can we understand the diversity, or even perversity, of human sexual behavior? A clue is that in other animals there are sex genes and several have been identified, although in the human the identity of these genes is yet unknown. What are the implications for choice and conceptions of personal freedom that people are born male, female, or gay, or that a switch in the function of a single gene can cause a fish to stop acting like a female, and start acting like a male?

Despite the complexity, and using methods that can find the needles hidden in the genetic haystack, I and other neurogeneticists have identified the first genes that predict cognitive and emotional differences, and sometimes the same gene can have countervailing effects on both. The ability of genes to predict behavior is explained by example, as are the limitations and nuances, which include gene by environment interaction. The genetic variants identified so far are not strongly predictive of behavior and their value should not be oversold, as has already been done. Yet they are of explanatory value, and foreshadow the discovery of additional variants that must account for the heritability of human behavioral characteristics.

The new science of gene by environment interaction is explored via genes that can lead to depression, anxiety, impulsivity and even suicide. For example, genes predispose some people to be resilient “warriors” and others to be less resilient and pain resistant but sometimes cognitively advantaged “worriers”.

The findings in this relatively young science of behavior genetics are not without controversy, as would be expected. However, there appear to be several solid examples of genetic variations that affect behavior, and also affect what the brain is doing during behavior, as is now observable with brain imaging, which is a window on the activity of the brain. By imaging the regional structure, activity and chemistry of the brain, for the first time the basis of the effects of these behaviorally important genes has been understood. Also, their predictive effects on brain function itself is much stronger than on overtly manifested behaviors. Several genes with weak effects on anxiety and emotion have strong effects on brain responses to emotional challenges. Two genes that influence cognition have strong effects on brain activity while people are asked to perform cognitive tasks that challenge specific parts, and neuronal networks, of the brain.

This book is concerned with the neurogenetic origins of behavior and with the possibilities and limits of genetic behavioral prediction; however, it is unavoidable that these discoveries would be connected to conceptions of self and freedom. Is it sufficient to treat people “as if” they have free will? I argue that it is not. The “as if” stance is inherently inconstant, setting the stage for the easy erosion of individual autonomy whenever situational ethics dictate that it is more expedient to treat people as slaves to causality. Compatabilism is the philosophical position that determinism and free will can be reconciled. However, I would also take issue with Daniel Dennett’s compatabilistic formulation, which holds a dependency on culture, “morality memes”, and child upbringing, and even the idea that to have free will one must believe in free will or be disabled as a chooser. All are metastable foundations. As will be discussed, individual and group autonomy are the vital bases of moral ethics, for example as applied in the conduct of human research, where these are foundational principles. However, are these principles divined from a philosophical or practical calculus or are they inherent to human nature? Are they suppositions, in which case any system of moral ethics may define humans otherwise, or are they parameters based upon observation?

I will argue that individual free will, and by extension the autonomy of groups of people, are parameters whose existence can be derived from the inheritance of cognitive structures and variation in these structures due to developmental neuroadaptation. Returning to the question of whether choice can emerge from a brain shaped by genetic and environmental determinants, a conception of neurogenetically determined free will is unveiled that at first seems paradoxical if we are only wading in the shallows of neurogenetics, where the focus naturally gravitates to how genes and environments influence the behavior of groups of people. A deeper analysis reveals that each human, including an identical twin, is neurogenetically individual, and that brain development unfolds stochastically throughout life in a way that makes each of us a unique and ultimately self-determined entity. As a consequence, each of us is also unpredictable, but it is not this unpredictability that represents freedom. Our freedom is bound to our individuality, which is partly the product of neurogenetic determinism, which is itself bound to the ways the human genome, and brain, were shaped by evolution, and that would include the random events that altered humankind’s evolutionary path. Freedom does not consist of randomness: philosophers such as Robert Kane and Daniel Dennett are correct to emphasize that free will does not originate in quantum randomness. However, our brains capitalize on randomness as raw material for the development of our individuality. Dennett has warned that we should not look too closely at our mental activities or we may discover that we have no selves. Coming at the problems of self and free will from a neurogenetic perspective, I am contending that it is these biological parameters that define our individual, free selves. As we solidify our understanding of genetic and environmental predictors, behavioral prediction inevitably improves – we can better anticipate the responses of any particular person, be they neuroscientist or philosopher or someone intrigued by their musings – but whether or not someone may guess our choices, we may choose.

Chapter 2

The Jinn in the Genome

Outline

Fifteen Minutes of Fame

Some Famous Geneticists, and Why they are Famous

The Jinn of Knowledge and the Jinn of Technology

Revolutions in Culture and Evolution of Genes

Genes, Brain and Individuality

The Neurogenetics of Determinism and Freedom

Fifteen Minutes of Fame

In 2002 I helped to conceive “Our Genes/Our Choices”, a Public Broadcasting series that explored ethical and legal choices created by the genome revolution. Topics of these Fred Friendly seminars included genetic reproductive decisions and genetic privacy. Our session, “Genes, Choices and the Law”, was adeptly moderated by Charles Ogletree, a well-known Harvard Law Professor. The scenario involved an alcoholic accused of a crime, and a genetic test result that might be mitigating. I was the geneticist with a predictive test. My molecular geneticist partner on hand was Dean Hamer, already celebrated for having discovered the “gay gene” (more on that later). Little did I know what I was getting into, and as they say, my 15 minutes went by so fast. Seated on my left was my “boss”, Francis Collins, who later indeed became Director of the National Institutes of Health. On my right was Justice Stephen Breyer. Other superstars included lawyer Nadine Strossen and journalist Gwen Ifil. Representing the defendant was Johnny Cochran.

The case was a puzzle in genetics and the law. Can genes predict behavior? Should predictive tests be used and if so how? What about genetic tests that could stigmatize groups of people? If a judge rules that evidence can be introduced that a gene influenced criminal behavior, would identification of this genetic link in a chain of causality influence our ability to convict someone, or modify the penalty? Several people including Dean Hamer suggested that I write a book about genes and behavior. However, at that time (and while Dean was writing another) I was grappling with a foundational issue with which the puzzle of genetic prediction is bound. This was the problem of determinism and free will, and the implications of inborn genetic determinants for behavioral choice. If I had not made up my own mind, what business did I have trying to change someone else’s? Eight years later, I thought I might be ready to attempt a new synthesis on human choice, based on a concept of neurogenetically determined behavioral individuality.

Some Famous Geneticists, and Why they are Famous

As has been well chronicled, the draft sequence of the human genome was published in 2001 by two rival groups, a corporation led by Craig Venter and a government consortium led by Francis Collins, who co-discovered the cystic fibrosis gene and who at that time directed the Human Genome Institute. Because the race for the sequence ended in a virtual dead heat, it was appropriate that both were honored by President Clinton in a Rose Garden ceremony. However, as Francis Collins observed, completion of the draft sequence was only the end of the beginning, bringing us to the starting line of a much longer race to understand how the genome works, and to prevent and cure diseases. The advances keep coming. Last year, Craig synthesized the complete genome of a bacterium. This in-laboratory duplication of nature underlines the fact that all life on Earth, and its complex variations, is ultimately based on the expression of complex chemicals: DNA and RNA, and those chemicals are increasingly open to measurement and manipulation. Beyond its biomedical applications, knowledge of the human genome may enable us to answer some of the most fundamental questions as to what humanity is and to what peaks it might lift itself, by its own bootstraps. If genetics can never provide all the answers, it can at least do what science does best, which is to facilitate the asking of better questions and new questions. Also, as will be discussed in some detail, genetics properly applied has a nearly unique ability to establish causal connections, and not just correlations, between the molecular level of the DNA code and people’s most complex attributes, including their behavior.

James Watson, who with Francis Crick won the Nobel Prize in Physiology and Medicine for deciphering the structure of DNA, conceived the Human Genome Project. Watson recognized the critical importance of genethics, and as Director of the Human Genome Institute he therefore set aside a fixed percentage of the funding for the ethical and policy implications of genomics research. This ELSI (Ethical, Legal and Social Implications) program has had a lasting and pervasive impact on the thinking of human geneticists, in part because many, including me, participated in symposia it sponsored. From the beginnings of human genomics research, scientists grappled with the societal implications with some important practical results including the passage of GINA, a federal law that will make it more difficult to discriminate on the basis of genetic information, as will be discussed in more depth in Chapter 9.

However, it is also fair to say that the impact of genetic knowledge and of the powerful new tools that implement it remains a work in progress for the scientific community and has scarcely been appreciated by the public at large. As the leading edges of genomic knowledge and technology rapidly advance and science becomes more specialized, it becomes more difficult for generalists to make accurate assessments, and to some extent experts are being asked to predict the future. For example, will stem cells made from adult tissues suffice for transplantation medicine, and in what time frame and at what costs? The important advances in genetics are coming from scientists with very widely varying goals, perspectives and backgrounds. Some are human geneticists and some are not. Some are physicians and some are unfamiliar with medicine. Some have had direct involvement in the medicolegal side of genetics and others not. The public and the scientists advancing frontiers of knowledge will repeatedly be presented with new ethical puzzles created by new capabilities. Making wise use of the knowledge will require a continuing reevaluation and readjustment of mindset, and the input of many voices.

The Jinn of Knowledge and the Jinn of Technology

Everyone is aware that there has been a genome revolution, but probably all but a few visionaries and writers of science fiction underestimate the implications. By studying our own genomes – the genetic blueprints of our lives – humanity picked up a lamp and two powerful forces were released. They wait expectantly, and we should be very careful what we ask of them. Unlike “real” jinns, they are at large in the world and answer to no one master. Genomics knowledge and tools are available in any country. We cannot assume that the decisions we make will determine how these tools are used elsewhere, but we can influence those decisions by word and deed.

The jinn of knowledge is the linear sequence of the human genome discovered by the Human Genome Project, and soon we will have much of the genome’s three- and four-dimensional depth – its variation between individuals and populations, and its complex regulation including the unfolding of the DNA-encoded developmental programs that enable us to develop from a single cell into a complex organism. The jinn of technology is the ability to rapidly, accurately and cheaply measure any genome and its functional outputs. Applying the new technology and the template of genomic knowledge, we shift our level of evaluation of personhood to the level of molecular predictors. Obviously, this molecular view of the person is particularly potent prena...

Table of contents

• Cover Image
• Table of Contents
• Title
• Copyright
• A Note on Gene and Protein Symbols
• Foreword
• Preface
• About the Author
• Chapter 1. The Neurogenetic Origins of Behavior
• Chapter 2. The Jinn in the Genome
• Chapter 3. 2B or Not 2B?
• Chapter 4. Stephen Mobley and His X-Chromosome
• Chapter 5. Dial Multifactorial for Murder
• Chapter 6. Distorted Capacity I
• Chapter 7. Distorted Capacity II
• Chapter 8. Inheritance of Behavior and Genes “For” Behavior
• Chapter 9. The Scientific and Historic Bases of Genethics
• Chapter 10. The World is Double Helical
• Chapter 11. The Stochastic Brain
• Chapter 12. Reintroducing Genes and Behavior
• Chapter 13. Warriors and Worriers
• Chapter 14. How Many Genes Does it Take to Make a Behavior?
• Chapter 15. The Genesis and Genetics of Sexual Behavior
• Chapter 16. Gene By Environment Interaction
• Chapter 17. The Epigenetic Revolution
• Chapter 18. DNA on Trial
• Chapter 19. Parents and Children
• Chapter 20. Summing Up Genetic Predictors of Behavior
• Suggested Reading
• List of Figures
• Glossary
• Index