Genes, Chromosomes, and Disease: From Simple Traits, to Complex Traits, to Personalized Medicine Genes, Chromosomes, and Disease
From Simple Traits, to Complex Traits, to Personalized Medicine
Preface
The science of genetics began in 1900 with the independent rediscovery of Mendel’s 1866 paper by Carl Correns and Hugo de Vries. Until the middle of the nineteenth century, blending theories of inheritance prevailed, but it became clear to Charles Darwin and his cousin Francis Galton that the hereditary elements must be particulate to provide the kind of variation upon which natural selection could work. Each of them proposed a particulate theory of inheritance, but the particles had to be hypothetical as the architecture of the cell and its different components were only beginning to reveal themselves to the curious eye. By 1900, a great deal was known about cell structure. In particular, chromosomes had been identified and Walther Flemming, a German scientist, had characterized their behavior in cell division (mitosis). Another German scientist, Theodor Boveri, provided evidence that chromosomes of the germ cell lineage provided continuity between generations. And in 1902, an American graduate student, Walter Sutton, connected chromosomes with genes, in a classic paper. Thomas Hunt Morgan and his associates obtained experimental proof of the chromosome theory using the fruit fly Drosophila as a model. Working with Drosophila in his Fly Room at Columbia University, Morgan and his colleagues would elucidate many of the most important principles of Mendelian genetics.
In England, William Bateson became Mendel’s great advocate. One would have thought such advocacy unnecessary except that, just about the time of Mendel’s rediscovery, Francis Galton had come up with a model of inheritance, which he called his Ancestral Theory. Particularly in Great Britain, there was much controversy in the first decade of the twentieth century between Galton’s supporters and Bateson. The Mendelians finally won out. In the course of these heated exchanges, Bateson became aware of the work of an English doctor, Archibald Garrod. Garrod was studying a disease called alkaptoneuria that caused the urine to blacken. His results suggested to Bateson that a recessive gene mutation might be involved. Bateson entered into a correspondence with Garrod, who in 1902 published a paper titled “The Incidence of Alkaptoneuria: A Study in Chemical Individuality.” And with that paper, Garrod made the first connection between a human disease and a gene.
The aim of this book is to provide an overview of the relationship between genes and disease, what can be done about these diseases, and the prospects for the future as we enter the era of personalized medicine. The first three chapters deal with diseases that are simple in the sense that they result because of single gene mutations. Chapter 1, “Hunting for disease genes,” considers the pedigree and its use in deciphering human genetic diseases and, at the end, the question of how many genetic diseases there are in the context of the structure of the human genome and the genes it contains. Chapter 2, “How genetic diseases arise,” is about how the process of mutation gives rise to genetic defects, but also about how this same process has produced millions of tiny genomic changes called single nucleotide polymorphisms (SNPs). Most SNPs have little or no effect on the individual, but they are of major importance to those who desire to investigate genetic diseases, particularly complex ones. People with and without a genetic disease can be compared to see if any of these SNPs can be associated with specific diseases. The chapter also considers what happens when mistakes occur in partitioning chromosomes properly to sperm and eggs. Chapter 3, “Ethnicity and genetic disease,” examines the reasons why some diseases are more prevalent in some races and ethnic groups than others and explains why this has nothing to do with race or ethnicity per se.
The second group of three chapters considers genetically complex diseases. Chapter 4, “Susceptibility genes and risk factors,” is about genetic risk factors and diseases like type 2 diabetes, coronary disease, and asthma, where the environment also plays an important role. In each case, there are single gene mutations that can cause the disease. These disease mutations are considered in some detail as they show how certain single gene changes can lead to complex diseases. However, people with these single gene changes only represent a small fraction of those suffering from the disease. In most people who suffer from asthma, have type 2 diabetes, or are susceptible to coronary disease, there is a complex interplay between a variety of genetic risk factors and the environment. Unraveling these interactions is a work in progress.
Chapter 5, “Genes and cancer,” discusses cancer, a large collection of different genetic diseases. What they all have in common is the propensity for uncontrolled growth. It has only been possible to work out the many different genetic pathways that lead to cancer because of basic research in cell biology. This has provided the necessary background information on how the normal pathways themselves are organized. The topic of cancer genetics is so vast that select examples have been chosen to illustrate several different points concerning the disease. For example, cervical cancer shows how viruses sometimes act as causative agents of cancer. The greatly increased frequency of lung cancer in recent years illustrates that decades can elapse between the exposure of a tissue or organ to carcinogens, in this case those present in cigarette smoke, and the appearance of the disease.
Like type 2 diabetes or coronary disease, schizophrenia and bipolar disease are genetically complex, as discussed in Chapter 6, “Genes and behavior.” There have been many false alarms in identifying susceptibility genes for these and other behavioral conditions—the gay gene controversy comes to mind. But there have also been some notable successes. The chapter begins by recounting the history of the “warrior gene.” This odd gene has been implicated in a wide variety of bad or risk-taking behaviors.
Chapter 7, “Genes and IQ: an unfinished story,” deals with a subject whose relevance may not seem apparent initially. The reader may rightly ask what on earth this topic has to do with disease. The answer is that not only do quite a number of genetic diseases affect IQ, but in the first half of the last century, the presumption that “feeblemindedness” was inherited was the basis for involuntary sterilizations, particularly of women, in many states in the United States, Scandinavia, and Nazi Germany. To this day, there are those who argue that IQ differences between races and classes are largely genetic in nature and, therefore, explain certain alleged inferiorities.
For better or worse, it seems likely that IQ and related tests will be used to measure intelligence for a long time because they yield numbers and numbers are easier for most people to deal with than descriptions. Take wine, for instance. All that business about tasting like black cherries with a hint of cinnamon loses out to Robert Parker’s numbering system. However, his scale is so compressed, between the high 80s and 100, that a Bordeaux wine that rates 96 can command a far greater price than one that Parker grades as 90. IQ scores, in contrast, are not compressed and follow the pleasing shape of the bell curve. Furthermore, IQ does measure something that relates to what we would call intelligence. Most would agree that the cognitive powers of children with Down syndrome are qualitatively different from those of ordinary children. This difference is captured in IQ distributions for children suffering from Down syndrome and children without this affliction. In both cases, IQs are normally distributed, but the upper end of the Down distribution overlaps with the lower end of the distribution for children who do not have the disease. However, the data on the heritability of IQ rest on shaky underpinnings. They largely depend on comparing the IQs of less than 200 pairs of identical twins reared apart and the assumption that the environments in which these twins were reared are not correlated.
Having dealt at length with genetic diseases, the next question is what to do about them. Chapter 8, “Preventing genetic disease,” discusses prevention as the most desirable outcome, particularly for the most severe genetic diseases, but how do we accomplish this? Suppose a man and woman in their late thirties get married and want to have a child while it is still possible. They have a relatively high risk of giving birth to a child with Down syndrome. What should they do? A good place to begin is to initiate a discussion with a genetic counselor. Should amniocentesis or chorionic villus sampling predict the birth of a Down child, the counselor can be helpful in explaining in a nondirective way the options open to the couple. They themselves will have to decide whether the pregnancy should continue or whether to terminate it. Or suppose another couple knows that they may give birth to a Tay-Sachs child. The couple has the choice of initiating the pregnancy and aborting the fetus if it has Tay-Sachs or planning to have a healthy baby following in vitro fertilization and preimplantation genetic diagnosis. This permits the doctor to implant embryos that will not develop into Tay-Sachs babies although some of them may be carriers of the mutant gene. The procedure is not fail-safe, however, and multiple rounds of in vitro fertilization may be required. Moreover, these procedures are costly and the couple may have ethical or religious reasons for not opting either for abortion or in vitro fertilization.
Specific treatments need to be devised for each genetic ailment and many such diseases are not treatable, as explained in Chapter 9, “Treating genetic disease.” The first line of defense for diseases like phenylketoneuria is newborn screening. If left untreated, the disease causes a rapid loss of cognition and a precipitous drop in IQ. Fortunately, if a phenylketoneuric infant is given a special diet shortly after birth, these cognitive declines can be avoided. All the states have mandatory newborn screening for this disease and many others where early intervention can make all the difference. Treatment of some genetic diseases involves administering an enzyme that is missing because of the genetic defect. This sort of therapy is often very expensive and it must be continued for life.
Then there is gene therapy. After 20 years of trying, it is fair to say that, despite all the hype that accompanied gene therapy, particularly in the beginning, gene therapy has delivered very little except in the case of a couple of diseases where the immune system has been rendered nonfunctional. In these cases, insertion of a copy of the normal gene into certain bone marrow stem cells has proven effective. We hope that this heralds the beginning of a new era for gene therapy, possibly in combination with stem cells, a topic that is hardly discussed in this book. The main reason that this book has practically nothing to say about embryonic or adult stem cells is that, despite very encouraging results with mouse models, we have no idea how this technology is going to play out in humans. In fact, the first approved clinical trial got under way late in 2010. We hope that the disappointments that have plagued gene therapy will not also arise in the case of stem cells, but only time will tell.
Today, drugs are being developed to target specific mutational defects for cystic fibrosis and other genetic diseases, as described in Chapter 10, “The dawn of personalized medicine.” It has also become clear that certain drugs are effective with people with one genetic background, but not another. Gene testing companies are measuring genetic risk for complex diseases like type 2 diabetes, and genome sequencing will soon cost around $1,000, making it affordable for a lot of people. With regard to their own genomes, the problem for most people will be an overload of information. What are they to do with it? How are they to weigh it? How much do they really want to know? We have entered the era of personalized medicine, an era in which most of us are going to need some guidance. Before proceeding to discuss the array of topics that are the subject of this book, a word about the diverse ways in which human genetic diseases are named is in order.
Genetic diseases are named in various ways. Most commonly, they bear the names of their discoverers. Down syndrome, for instance, is named for its discoverer, John Langdon Down, a nineteenth-century British physician. Sometimes the name is descriptive—sickle cell anemia comes to mind. The red blood cells of people with this disease do sickle. Sometimes the names are misleading or hard to understand. Why would anyone name a disease that can cause profuse bleeding hemophilia? Only Count Dracula would appreciate that. Or thalassemia. What’s that about? It’s a disease like sickle cell disease, but its name refers to the sea in Greek. The reason for this odd name is that this disease was once prevalent around the rim of the Mediterranean. Sometimes diseases are named quite specifically for the function they perturb. G6PD refers to a common alteration that results in a deficiency of the enzyme glucose-6-phosphate dehydrogenase.
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