Bioethics, Genetics and Sport

Silvia Camporesi, Mike McNamee

• Publisher: Routledge
• Year: 2018
• ISBN:
  9781317485384
• Edition: 1
• Topic: Medicine
• Subtopic: Ethics in Medicine

Advances in genetics and related biotechnologies are having a profound effect on sport, raising important ethical questions about the limits and possibilities of the human body. Drawing on real case studies and grounded in rigorous scientific evidence, this book offers an ethical critique of current practices and explores the intersection of genetics, ethics and sport.

Written by two of the world's leading authorities on the ethics of biotechnology in sport, the book addresses the philosophical implications of the latest scientific developments and technological data. Distinguishing fact from popular myth and science fiction, it covers key topics such as the genetic basis of sport performance and the role of genetic testing in talent identification and development. Its ten chapters discuss current debates surrounding issues such as the shifting relationship between genetics, sports medicine and sports science, gene enhancement, gene transfer technology, doping and disability sport.

The first book to be published on this important subject in more than a decade, this is fascinating reading for anyone with an interest in the ethics of sport, bioethics or sport performance.

PART I

Genethics, Sports Medicine and Sports Science

1

The nature of genetics and its place in medicine and sport

1.1 Introduction

The aim of this chapter is to introduce the reader to key concepts in genetics and to the methodological approaches in the study of the genetic bases of sport performance. Genetic science and technology plays a key role in sport medicine and, hype notwithstanding, genomic science has made significant strides towards understanding the genetic pathways to sport excellence.

Casual use of the word ‘genetics’ can be confusing since it can be used in a variety of contexts, notably (i) genetic testing to test the predisposition to injury and response to training; (ii) whole genome sequencing of athletes to understand the genetic basis of sport performance; (iii) genetic testing to predict potential (talent identification and development); (iv) genetic technologies to enhance athletic performance. In each of these contexts, the use of genetics raises a plethora of ethical and epistemic issues, which we will discuss in turn in the following chapters. It may be helpful, however, if before exploring these complex issues we introduce some key terms that are integral to the debates concerning the use of genetics in sports.

Everything starts from our DNA. DNA stands for deoxyribonucleic acid. The iconic double-helix structure was unravelled by James Watson, Francis Crick, Maurice Wilkinson and Rosalind Franklin, at King’s College London in 1951.¹ It is formed by four different nitrogen bases (adenine (A), thymine (T), cytosine (C) and guanine (G)) that bind in sequence and make a single DNA strand. Each base binds to its complementary base (A to T and C to G) to form a double stranded DNA. During replication the two strands open up and one copies itself to form another complementary strand that contains the same amount of genetic information. In these two strands all the genetic information – the blueprint of the information to codify for a member of a certain species – is included. Each triplet of bases codifies for an amino acid, one of the building blocks of proteins.

Genetics is a matter of genes, of course. However, what is a gene is not such an easy question; on the contrary, it is a philosophical question (Fox Keller 2000; Morange 2001; Nowotny et al. 2011)! One of the most important findings of molecular genetics is that the idea of a gene as a simple causal agent is not valid. The sequence of DNA that is referred to as a ‘gene’ has meaning only within a specific context, which determines its expression and function. That is why a single gene may have different effects depending on the context in which it is located (cellular context, environmental context, individual context, etc.). The human genome has about 21,000 genes and over 3 billion nitrogen base pairs, but note that of these 3 billion base pairs, only 5% are encoding regions, i.e. codify for proteins (Krebs et al. 2014). The remaining 95% used to be called until the early 2000s ‘junk DNA’, but it is now recognised that the term was a misnomer and is known that it plays a fundamental physiological role, especially in regulating the rate of gene expression. It is estimated that only 0.1% of the genome varies between individuals of the human species (see Chapter 10 for a discussion). For the purposes of this book, a gene is usually considered to be a specific region of the genome whose DNA sequence encodes for a discrete biological entity, usually a protein, but as we will repeat often throughout this volume, genes are not the only means of inheritance in the human species. As Jablonka and Lamb (2014) have identified, there are at least three other levels that determine the inheritance of traits: the epigenetic level (methylation and other modifications on the DNA that affect its function and expression and are passed down to future generations); and the behavioural and symbolic inheritance system, which together form what we usually refer to as ‘culture’. Although we cannot enter into the philosophy of biology discussion of the different modes of inheritance in H. Sapiens, this volume is based on a strong premise that rejects any type of genetic determinism and exceptionalism.

By ‘genome’, we refer to the entire genetic material that is transmitted to the next generation. In the human species, it is for the most part encoded in the DNA sequence contained in the nucleus, although we have a small number of genes in the mitochondria organelles, which if mutated are responsible for some types of neurodegenerative diseases (hence, the mitochondrial replacement therapies approved by the UK Parliament in February 2015: Wolf et al. 2015).

Chromosomes are nothing other than discrete, compact units of the genome where DNA molecules are organised and that carry many genes. The human species has 23 pairs of chromosomes (each chromosome of the same pair is called homologous), which become unpacked during cellular division. There are two main types of cellular division: meiosis, the cellular division which takes place during sexual reproduction, and mitosis, the normal type of cellular division. With the word ‘karyotype’ we refer to the entire chromosomal complement of a cell or species, in the case of the human species, 23 pairs, XX for women, XY for men. A karyotypic analysis is typically performed during prenatal screening to establish the absence of chromosomal disorders, of which the most common is trisomy 21 or Down Syndrome (in which there are three rather than two copies of chromosome 21).

Each gene can occur in several possible forms, known as ‘alleles’. In human beings, there typically are two alleles for each gene, one of which is located on each chromosome and one of which is inherited from each parent. For each gene, an individual can be homozygous, meaning having two identical alleles (either of the most common variant copy of the gene, or of the less common copy of the gene), or heterozygous, meaning having one allele of the most common copy and the other of the less common copy of the gene. Individuals are said to be heterozygous when they have different alleles at a particular locus, and homozygous when they have the same allele at corresponding loci on the homologous chromosome.

Traits that are controlled by a single gene are said to be ‘monogenic’. In genetics, monogenetic traits are a minority, and result from modifications in a single gene. Common monogenic diseases are cystic fibrosis, thalassaemia, sickle-cell anaemia, Tay-Sachs, fragile X syndrome and Huntington’s diseases. Monogenic diseases, although rare, affect millions of people worldwide. They are divided in three categories: dominant (a trait that needs to have only one mutated copy of DNA to appear phenotypically), recessive (a trait that needs to have two mutated copies of the gene to appear phenotypically) or X-linked (meaning that the gene causing the trait or the disorder is located on the X chromosome, leading to male/female differences in expressions, as females carrying two copies of the gene usually are healthy carriers of the disorder but do not normally express the symptoms, e.g. Duchenne muscular dystrophy).

‘Haplotype’ is a term that is used to refer to the particular combination of alleles in a defined region of a chromosome, while ‘linkage’ refers to the (probabilistic) tendency of genes to be inherited together as a result of their location on the same chromosome; it is measured by the percentage recombination between loci (see whole genome linkage studies below).

Penetrance refers to the extent to which a genetic variant has an effect on individuals who carry it. In practice it is measured as the proportion of individuals that carry the mutated copy of the gene and express the phenotype (it is an indication of the ‘strength’ of the expression of the gene).

We refer to heritability as ‘the proportion of the phenotypic variation in a trait of interest, measured in a given studied population and in a given environment, that is statistically co-varying with genetic differences (however measured) among individuals in the same population’ (Kaplan 2015). Heritability is defined operationally as the ratio of variation due to differences between genotypes to the total phenotypic variation for a character or trait in a population. It is a measure commonly used in twin studies in behavioural genetics.

Note that heritability is a technical notion which often gets misunderstood. One should never conclude from the mere fact that a trait is heritable that it is genetically determined. Errors of reductionism and bio-determinism occur in statements such as ‘Intelligence is 60% genetic and 40% environmental’, or ‘scientists have found that athletic excellence is x% genetic and y% environmental’ and so on and so forth (see Chapter 10 for a discussion). ‘Heritability is not a measure of “how genetic” a trait is. For heritability to make any sense at all as a statistic, the trait in question must vary in the population in question’ (Kaplan 2015). It is important to distinguish familiality from heritability. Traits are familial if members of the same family share them, for whatever reason. Traits are heritable only if the similarity arises from shared genotypes.²

The term genotype refers to the genetic constitution of an organism, and is commonly found in opposition to phenotype, which refers instead to the appearance of an organism, resulting from the interactions of its genetic constitutions with the environment. We will often refer to genotype/phenotype interactions over the course of this book.

Another important concept in genetics, one that we will encounter often in this book in our discussion of the genetic basis of sport performance, is that of single nucleotide polymorphism (SNP), by which we refer to variations at the level of a single base pair in the DNA. These can be changes in a single base pair, deletions or insertions. When a variant appears in less than 1% of the population, it is generally considered a mutation (usually, with some health impact); when it is greater than 1%, it is generally considered a SNP. If the variations affect more than one base pair they are called polymorphisms, not SNPs. In that case there is a higher chance that there will be some effect on the phenotype.

1.2 Approaches to investigating the genetic bases of sport performance

Many, though not all, factors that are relevant for sport performance can be measured and quantified, such as body composition, aerobic power and muscle strength. Not all sports, however, are amenable to comprehensive quantitative measures of sport performance. Popular sports such as running, swimming and cycling are quantified by way of distance times. For many other sports, such as volleyball, tennis, rugby, football/soccer and gymnastics, among others, performance is not simply measured quantitatively; rather excellence is measured from a qualitative standpoint. John William Devine has developed a conceptualisation of the relevant types of sporting excellence in sport and how doping can be a threat to such relevant excellences (Devine 2010). This is only one reason why genotype–phenotype relationships are difficult to establish, and is something that must always be borne in mind when considering the results of association studies between traits that are alleged to be critical for success in this or that sport (Guilherme et al. 2014).

Although research into the genetic basis of sport performance has blossomed only in the last 15 years,³ early studies date back to the end of the 1960s and the first research concerning the applications of genetics in sport. Those early studies concerned mostly the phenotypic characteristics of athletes, were focused on structural traits and were based on the statistical analysis of a given phenotype in the population studied. An example was the work carried out in 1968 during the Olympics in Mexico (De Garay et al. 1974). The purpose of the De Garay study was to test whether there was any association between participation in the Olympic Games and allelic variation in single-gene blood systems (Sawczuk et al. 2011, 254). The phenotypic variability they determined was the basis for studying the influence of genes on individual characteristics of the human body (ibid., 252).

In the early 1970s and throughout the 1980s, several studies into the effects of genetics on athletic performance were conducted. The main approach was based on twin and family aggregation studies. Klissouras and colleagues performed the first study on twins (39 pairs of twins) aimed at elucidating the correlations between genetics and adaptation to maximal effort. Their study concluded that ‘there appears to be a significant resemblance in functional adaptability as measured by maximal oxygen intake between identical twins, whereas there is a divergence between non-identical twins’ (Klissouras et al. 1973, 272) and paved the way for a spate of studies aimed at estimating the percentage contribution of genetic factors to common performance-relevant variables, such as bone density, muscle fibre type distribution, anaerobic capacities and so on. This enabled the identification of the levels of heritability of different complex traits. One of the most important projects of the last 25 years aimed at elucidating the role of genes in sport is the HERITAGE family study (the acronym derives from ‘health, risk factors, exercise training and genetics’), commenced in 1992 and carried out until 2004 (Bouchard et al. 2000). The HERITAGE study demonstrated a variable degree of heritability for the different measurable aspects of sport performance, between 31% and 78%. Nevertheless, these early studies did not provide information about particular genes. The first polymorphism (ACE gene, more below) was identified only in 1998. Since then more than 200 SNPs have been identified; however, only about 20 have been replicated in subsequent studies and only one (alpha actinin gene) has been demonstrated to have a functional counterpart through animal studies (Pitsiladis et al. 2013).

There are several caveats that need to be pointed out concerning these studies if we are to proceed to a proper evaluation of them for our ethical discussion. To start with, it is important to note that although more than 200 polymorphisms have been identified, only about 20 of them have been identified in athletes. Many studies have failed to replicate the results, and we still know very little concerning how genes interact with each other and with environmental factors (Guth and Roth, 2013). This caveat is true for genetic science more generally, and is not merely valid for the more specific field investigating the genetic basis of sport performance. Moreover, as noted above, there are many traits related to sport performance that cannot, or cannot easily, be quantified.

There are three main approaches to investigate the genetic basis of sport performance (Guilherme et al. 2014). The first approach relies on candidate genes association studies, where a candidate allele is correlated with a targeted performance-relevant trait. These studies work in the following way: first, a physiological rationale to investigate a particular gene as a ‘candidate’ in the genetic basis of sport performance is established, based on what is known about the function of the protein codified by the gene. Then an association study is carried out – of which there can be different types. The first type of association study, the simplest, compares the frequency of genotypes in a cohort of controls (non-athletes) versus athletes, or compares a given intervention (e.g. exercise training or diet) between genotype groups (in this case the association studies are called ‘longitudinal studies’). If the association study determines a statistically relevant significance for the candidate gene (or, better, allele), that needs then to be confirmed in another study that looks at how that particular allele affects protein expression, and how this affects the phenotype. This first step to establish an association between a ‘candidate gene’ and elite athletic status is not sufficient to accept a polymorphism as valid, and often associations found in a study are not replicated in subsequent studies. This limitation is very important to bear in mind when assessing the claims made by direct-to-consumer ...