Huntington's Disease and the Nature of Science

Huntington's Disease and the Nature of Science

Learning Objectives

• Provide examples of the following concepts from unit one to the study and current understanding of Huntington's disease (HD): observation, inference, pattern, process, natural experiment, association study, comparison study, physical model, conceptual model, and explanation.

• Identify two patterns from the history of research on HD and explain why they are best described as patterns and not processes.

• Compare and contrast the two types of models that have been used to advance understanding of the processes underlying HD.

• Build a conceptual model that uses observations, inferences, patterns, processes, models, and studies to explain why Huntington's disease occurs in some individuals and not others.

• Explain why single types of explanations such as downward looking or functional explanations cannot adequately account for phenomena such as HD.

Introduction to Huntington's Disease

• Huntington's disease (HD) is a rare illness affecting hundreds of thousands globally.

• Understanding HD requires familiarity with scientific thinking and problem-solving.

• The history of HD illustrates how researchers and clinicians work to understand and explain deadly diseases.

Early Scientific Work: George Huntington's Observations

• The first scientific work on HD can be traced to the late nineteenth century on Long Island.

• George Huntington, as a young boy, shadowed his physician father and observed families with a unique illness characterized by abnormal involuntary movements, behavioral and psychiatric symptoms, and cognitive changes.

• Doctor Huntington observed intergenerational patterns of the illness within families.

• This led him to infer that the illness might be inherited genetically.

• Huntington's insights were built upon careful observations and the broader patterns they formed.

• In 1872, Doctor Huntington published a paper describing his observations.

Key Observable Features Characterized by Doctor Huntington

• Late onset of the illness in midlife.

• Inferred hereditary nature of the illness.

• Inevitable progression to dementia.

• Dramatic and often devastating psychiatric symptoms, including depression, impulsivity, aggression, and other behavioral changes.

• Doctor Huntington grouped his observations into patterns: motor/physical symptoms, emotional/behavioral symptoms, and cognitive symptoms.

• His work made progress in documenting a pattern, but it did not include an explanation for the patterns.

Natural Experiment: The Venezuelan Community

• In the 1960s, a unique situation in Venezuela known as a natural experiment was documented.

• In 1963, Doctor Americo Negrete described a community on the shores of Lake Maracaibo region in Venezuela with an extremely high concentration of inhabitants with Huntington's.

• This natural experiment turned out to be crucial for medical research.

• In 1972, details about this unique community were presented, which helped lead to the discovery of a genetic mutation for Huntington's disease, confirming Doctor George Huntington's inference from a hundred years ago that the illness had a genetic basis.

Nancy Wexler's Research in Venezuela

• Critical field research in the Venezuelan community was directed by Doctor Nancy Wexler.

• The community had the highest incidence of Huntington's in the world.

• Wexler and her team studied families in the Lake Maracaibo region.

• In 1993, Nancy's team at Columbia University discovered the genetic abnormality responsible for HD, a stutter at the top of chromosome four.

• This discovery became an important part of the work to identify the genes that make up our DNA, the landmark human genome project.

• Most of the research in Venezuela involves documenting observations and patterns in the community in order to develop models that could be used to explain the causes of the illness.

Pedigree Analysis

• Pedigrees were used to document the appearance of illness over generations.

• These patterns served as models of heredity.

• Pedigrees led to inferences about the mechanisms responsible for transmission.

• Blood samples were collected from individuals included in the pedigrees to compare genetic and illness patterns.

• The Venezuelan field research led to the localization of a region of interest on chromosome four in 1983.

• The genetic mutation was identified in 1993.

• The HD gene (allele) was found to have too many CAG repeats in the DNA.

• These extra CAGs coded for too much glutamine, leading to an abnormally long protein product.

Association Studies

• Association studies investigated the relationship between the size of the mutation and the age of onset of the disease.

• An association study demonstrated that there is a relationship between the CAG repeat length and the age of onset of illness.

• With increasing repeat lengths of the genetic mutation, a decreasing age of onset of illness occurred.

• There were also factors influencing age of onset, not just mutation.

Mutation Repeat Ranges and Phenotypes

• A normal allele has a repeat length of less than 26 repeats.

• A narrow range from 27 to 35 repeats is described as a mutable normal allele.

• A very narrow range from 36 to 39 repeats has reduced penetrance.

• In genetic counseling, patients usually have either less than 26 or more than 40 repeats.

Comparison Studies

• Comparison studies compared brain samples from autopsies of individuals who died of Huntington's disease to the brains of individuals who died of other non-neurological causes.

• Scientists found patterns of difference in the caudate nucleus region of the brain.

• The caudate nucleus is marked with a "c" in the normal brain, and on the HD patient brain, a flattening occurs.

Caudate Volume Loss

• Caudate volume loss was observed with age and disease duration.

• In normal aging, caudate volume is between 8 and 9 milliliters from age 20 to age 65.

• In Huntington's patients, there is a slight decrease in caudate volume compared to normal aging individuals even fifteen years before diagnosis or onset of motor signs.

• By diagnosis at age 45, the caudate volumes reduce at around six, and around fifteen years of illness towards the bottom, the caudate volume is around four milliliters.

• Comparisons between normal and diseased brains show that the disease duration is associated with caudate volume loss.

Models of Huntington's Disease

• Physical and conceptual models help scientists integrate information and propel understanding forward.

Physical Models: Mouse Models

• Mouse models of HD are used to advance understanding of the illness.

• Scientists cloned the HD gene and transplanted it into mice.

• The mice developed an accelerated form of the disease.

Conceptual Models

• Conceptual models of illness are critical and complementary to physical models.

• Conceptual models of movement disorder circuits in Huntington's disease versus controls in individuals with a different movement disorder, Parkinson's disease were developed.

• These models help scientists build explanations for patients' symptoms.

• They integrate data from many different sources and help to advance understanding of the illnesses.

• They can be tested and modified using experiments, and they can be used to guide clinical intervention.

• Conceptual models illustrate the motor circuits in normal individuals, individuals with Parkinson's disease, and HD individuals.

• The same brain structures are involved in all three models, but there are varying adjustments in the relative excitatory and inhibitory activity in the motor circuits due to changes.

• The models help to explain how a mutation causes physical symptoms.

Comprehensive Understanding of Huntington's Disease

• HD is an autosomal dominant genetic disorder.

• Affected people typically present in each generation.

• An affected person has a 50% chance of passing on the affected gene to a child.

• A gene called Huntington or HTT on chromosome four contains a triplet repeat, where nucleotides c, a, and g are repeated 10 to 35 times in a row in most people.

• In people with Huntington's disease, this repeat goes on for 36 or more times in a row.

• CAG codes for the amino acid glutamine, so people with Huntington's disease will have 36 or more glutamines in a row in the Huntington protein.

• HD is a polyglutamine disease.

• The mutated protein aggregates within the neuronal cells of the caudate and the putamen of the basal ganglia, causing neuronal cell death.

• Cell death might be related to excitotoxicity, which is excessive signaling of these neurons, which leads to high intracellular calcium.

• The expanded CAG repeats not only affect the Huntington protein; they also affect DNA replication itself.

• DNA polymerase can accidentally add extra CAGs when copying the HTT gene.

• The more repeats that are added, the more unstable it gets.

• The expansion of the originally inherited gene means that a child of a parent with HD can inherit even more CAG repeats than the parent did.

• The higher the number of repeats in the protein, the earlier the age when a person starts having symptoms; this is called anticipation.

• Repeats of 27 to 35 CAG's can expand occasionally; these are called premutation alleles since they don't cause the disease, but they're set up for developing a mutation of 36 or more CHGs.

• Repeat expansion happens way more in the production of sperm than of eggs.

• HD basically has a 100% penetrance, meaning that in this case, if they have 36 or more repeats, they have the disease.

• Even repeats of 27 to 35 CAG's can expand occasionally.

• The test for HD, which counts the number of CHG repeats, is really good at determining whether Huntington's disease will develop in an at-risk video.

Biological Explanations of Huntington's Disease

• Comprehensive biological explanation requires integrating multiple types of explanations: upward looking, downward looking, and backward looking.

Downward Looking Explanations

• Seek the underlying causes at a smaller scale.

• Neurons are cells that contain proteins.

• Proteins are encoded by alleles.

• Alleles differ due to mutations.

• The mutation with greater than forty CAG repeats is the cause.

Upward Looking Explanations

• Differences in the brain can be used to explain many of the features of patients.

• Disruption of circuits in the brain explains the chorea movements, the depression, the extreme irritable outbursts, and ultimately the health, reproduction, and survival of an individual with Huntington's.

Backward Looking Explanations

• The presence of an allele in a patient is explained in most cases by the inheritance of an allele from a parent.

• The pattern of inheritance in pedigrees can be explained by the parental genotypes.

• Using Mendel's laws, we can predict the probability of an inheritance of an allele.

• Backward looking explanations involve the genetic history of a lineage.

Learning Objectives

• Provide examples of the following concepts from unit one to the study and current understanding of Huntington's disease (HD): observation, inference, pattern, process, natural experiment, association study, comparison study, physical model, conceptual model, and explanation. Elucidate how each of these concepts plays a role in the progression of understanding HD, from initial observations to current treatments.

• Identify two patterns from the history of research on HD and explain why they are best described as patterns and not processes. Discuss the differences between patterns and processes in scientific inquiry and apply this distinction to the research history of HD.

• Compare and contrast the two types of models that have been used to advance understanding of the processes underlying HD. Explain the strengths and limitations of physical and conceptual models in studying complex diseases like HD.

• Build a conceptual model that uses observations, inferences, patterns, processes, models, and studies to explain why Huntington's disease occurs in some individuals and not others. Detail the steps involved in constructing this model and how each component contributes to explaining the etiology of HD.

• Explain why single types of explanations such as downward looking or functional explanations cannot adequately account for phenomena such as HD. Discuss the necessity of integrating multiple perspectives to comprehensively understand diseases like HD.

Introduction to Huntington's Disease

• Huntington's disease (HD) is a rare, neurodegenerative disorder affecting hundreds of thousands globally. It is characterized by a combination of motor, cognitive, and psychiatric symptoms, significantly impacting the quality of life for affected individuals and their families.

• Understanding HD requires familiarity with scientific thinking and problem-solving. Grasping the scientific method, data interpretation, and critical analysis are essential for comprehending the complexities of HD research and clinical management.

• The history of HD illustrates how researchers and clinicians work to understand and explain deadly diseases. The collaborative efforts of scientists and clinicians across various disciplines have led to significant advancements in understanding the genetic basis, pathophysiology, and potential therapeutic targets for HD.

Early Scientific Work: George Huntington's Observations

• The first scientific work on HD can be traced to the late nineteenth century on Long Island. This marked the beginning of formal scientific inquiry into the disease.

• George Huntington, as a young boy, shadowed his physician father and observed families with a unique illness characterized by abnormal involuntary movements (chorea), behavioral and psychiatric symptoms, and cognitive changes. Huntington's early exposure to the disease sparked his lifelong interest in understanding its nature and inheritance.

• Doctor Huntington observed intergenerational patterns of the illness within families. He noted that the disease consistently appeared across generations, suggesting a hereditary component.

• This led him to infer that the illness might be inherited genetically. Huntington hypothesized that a specific gene or genes might be responsible for transmitting the disease from parents to offspring.

• Huntington's insights were built upon careful observations and the broader patterns they formed. His ability to synthesize observations into meaningful patterns allowed him to make groundbreaking contributions to our understanding of HD.

• In 1872, Doctor Huntington published a paper describing his observations. This publication served as the foundation for future research and clinical understanding of Huntington's disease.

Key Observable Features Characterized by Doctor Huntington

• Late onset of the illness in midlife (typically between 30 and 50 years of age). This delayed onset posed challenges for early diagnosis and family planning.

• Inferred hereditary nature of the illness. Huntington recognized that the disease consistently appeared across generations, suggesting a genetic basis.

• Inevitable progression to dementia. Huntington observed that cognitive decline was a common feature of the disease, ultimately leading to severe dementia in affected individuals.

• Dramatic and often devastating psychiatric symptoms, including depression, impulsivity, aggression, and other behavioral changes. Huntington noted that psychiatric symptoms could significantly impact patients' quality of life and social interactions.

• Doctor Huntington grouped his observations into patterns: motor/physical symptoms, emotional/behavioral symptoms, and cognitive symptoms. This categorization helped to organize the complex manifestations of the disease and facilitate further study.

• His work made progress in documenting a pattern, but it did not include an explanation for the patterns. Huntington's observations laid the groundwork for future research aimed at uncovering the underlying causes and mechanisms of Huntington's disease.

Natural Experiment: The Venezuelan Community

• In the 1960s, a unique situation in Venezuela known as a natural experiment was documented. This community provided a rare opportunity to study the disease in a concentrated population.

• In 1963, Doctor Americo Negrete described a community on the shores of Lake Maracaibo region in Venezuela with an extremely high concentration of inhabitants with Huntington's. The high prevalence of HD in this community made it an invaluable resource for genetic research.

• This natural experiment turned out to be crucial for medical research. The Venezuelan community allowed researchers to trace the inheritance patterns of HD and collect biological samples for genetic analysis.

• In 1972, details about this unique community were presented, which helped lead to the discovery of a genetic mutation for Huntington's disease, confirming Doctor George Huntington's inference from a hundred years ago that the illness had a genetic basis. This discovery revolutionized our understanding of HD and paved the way for genetic testing and counseling.

Nancy Wexler's Research in Venezuela

• Critical field research in the Venezuelan community was directed by Doctor Nancy Wexler. Wexler's leadership and dedication were instrumental in unraveling the genetic mysteries of HD.

• The community had the highest incidence of Huntington's in the world. This concentration of cases allowed researchers to study the disease in a systematic and comprehensive manner.

• Wexler and her team studied families in the Lake Maracaibo region. They meticulously documented clinical and genealogical data to identify the genetic basis of HD.

• In 1993, Nancy's team at Columbia University discovered the genetic abnormality responsible for HD, a stutter at the top of chromosome four. This breakthrough provided a definitive genetic marker for HD and opened new avenues for research and treatment.

• This discovery became an important part of the work to identify the genes that make up our DNA, the landmark human genome project. The identification of the HD gene contributed to the broader understanding of human genetics and disease.

• Most of the research in Venezuela involves documenting observations and patterns in the community in order to develop models that could be used to explain the causes of the illness. These models helped to integrate genetic, clinical, and epidemiological data to provide a comprehensive understanding of HD.

Pedigree Analysis

• Pedigrees were used to document the appearance of illness over generations. These genealogical charts helped to visualize the inheritance patterns of HD within families.

• These patterns served as models of heredity. Pedigrees provided evidence of autosomal dominant inheritance, where each affected individual typically has an affected parent.

• Pedigrees led to inferences about the mechanisms responsible for transmission. By analyzing pedigrees, researchers could infer that a single dominant gene was responsible for HD.

• Blood samples were collected from individuals included in the pedigrees to compare genetic and illness patterns. These samples allowed for the identification of genetic markers associated with HD.

• The Venezuelan field research led to the localization of a region of interest on chromosome four in 1983. This marked a significant step towards pinpointing the exact location of the HD gene.

• The genetic mutation was identified in 1993. This discovery provided a definitive genetic test for HD and enabled predictive testing for at-risk individuals.

• The HD gene (allele) was found to have too many CAG repeats in the DNA. The expansion of CAG repeats was identified as the causative mutation for HD.

• These extra CAGs coded for too much glutamine, leading to an abnormally long protein product. The elongated glutamine sequence in the huntingtin protein causes it to misfold and aggregate, leading to neuronal dysfunction and cell death.

Association Studies

• Association studies investigated the relationship between the size of the mutation and the age of onset of the disease. These studies sought to determine if there was a correlation between the number of CAG repeats and the age at which individuals developed HD symptoms.

• An association study demonstrated that there is a relationship between the CAG repeat length and the age of onset of illness. The study found that longer CAG repeat lengths were associated with earlier disease onset.

• With increasing repeat lengths of the genetic mutation, a decreasing age of onset of illness occurred. This inverse correlation between CAG repeat length and age of onset is a hallmark of HD.

• There were also factors influencing age of onset, not just mutation. Environmental factors, genetic modifiers, and epigenetic mechanisms can also influence the age at which symptoms appear.

Mutation Repeat Ranges and Phenotypes

• A normal allele has a repeat length of less than 26 repeats. Individuals with fewer than 26 CAG repeats are not at risk of developing HD.

• A narrow range from 27 to 35 repeats is described as a mutable normal allele. These individuals are not affected by HD but have an increased risk of transmitting an expanded allele to their offspring.

• A very narrow range from 36 to 39 repeats has reduced penetrance. Some individuals with 36-39 CAG repeats may develop HD later in life, while others may not develop symptoms at all.

• In genetic counseling, patients usually have either less than 26 or more than 40 repeats. Genetic testing provides clear results for the majority of individuals, allowing for informed decision-making regarding family planning and medical management.

Comparison Studies

• Comparison studies compared brain samples from autopsies of individuals who died of Huntington's disease to the brains of individuals who died of other non-neurological causes. These studies aimed to identify structural and biochemical differences in the brains of HD patients.

• Scientists found patterns of difference in the caudate nucleus region of the brain. The caudate nucleus is particularly vulnerable to the effects of HD, showing significant atrophy and neuronal loss.

• The caudate nucleus is marked with a "c" in the normal brain, and on the HD patient brain, a flattening occurs. This flattening is a characteristic feature of HD and can be visualized using neuroimaging techniques.

Caudate Volume Loss

• Caudate volume loss was observed with age and disease duration. The progressive loss of caudate volume correlates with the progression of motor and cognitive symptoms in HD.

• In normal aging, caudate volume is between 8 and 9 milliliters from age 20 to age 65. This provides a baseline for comparison when assessing caudate volume in HD patients.

• In Huntington's patients, there is a slight decrease in caudate volume compared to normal aging individuals even fifteen years before diagnosis or onset of motor signs. This suggests that neurodegenerative changes may begin years before clinical symptoms become apparent.

• By diagnosis at age 45, the caudate volumes reduce at around six, and around fifteen years of illness towards the bottom, the caudate volume is around four milliliters. This progressive decline in caudate volume reflects the ongoing neurodegeneration in HD.

• Comparisons between normal and diseased brains show that the disease duration is associated with caudate volume loss. This emphasizes the importance of early diagnosis and intervention to slow the progression of the disease.

Models of Huntington's Disease

• Physical and conceptual models help scientists integrate information and propel understanding forward. These models provide frameworks for organizing and interpreting complex data related to HD.

Physical Models: Mouse Models

• Mouse models of HD are used to advance understanding of the illness. These animal models allow researchers to study the effects of the HD mutation in a controlled environment.

• Scientists cloned the HD gene and transplanted it into mice. This allowed for the creation of mice that express the mutant huntingtin protein.

• The mice developed an accelerated form of the disease. These mice exhibit motor, cognitive, and psychiatric symptoms similar to those seen in human HD patients.

Conceptual Models

• Conceptual models of illness are critical and complementary to physical models. These models provide a framework for understanding the complex interactions between genes, environment, and disease.

• Conceptual models of movement disorder circuits in Huntington's disease versus controls in individuals with a different movement disorder, Parkinson's disease were developed. These models help to explain the specific motor symptoms seen in HD patients.

• These models help scientists build explanations for patients' symptoms. By integrating data from various sources, these models provide a comprehensive understanding of the disease.

• They integrate data from many different sources and help to advance understanding of the illnesses. These models incorporate genetic, clinical, neuroimaging, and pathological data to provide a holistic view of HD.

• They can be tested and modified using experiments, and they can be used to guide clinical intervention. Conceptual models are dynamic and can be updated as new information becomes available.

• Conceptual models illustrate the motor circuits in normal individuals, individuals with Parkinson's disease, and HD individuals. These models highlight the specific disruptions in neural circuitry that lead to motor dysfunction in HD.

• The same brain structures are involved in all three models, but there are varying adjustments in the relative excitatory and inhibitory activity in the motor circuits due to changes. This illustrates how changes in neuronal activity can lead to different movement disorders.

• The models help to explain how a mutation causes physical symptoms. By linking the genetic mutation to disruptions in neural circuitry, these models provide a mechanistic understanding of HD.

Comprehensive Understanding of Huntington's Disease

• HD is an autosomal dominant genetic disorder. This means that a person only needs to inherit one copy of the mutated gene to develop the disease.

• Affected people typically present in each generation. HD does not skip generations, ensuring that in most cases each generation has an affected person.

• An affected person has a 50% chance of passing on the affected gene to a child. Genetic counseling can help families understand the risks of inheriting HD.

• A gene called Huntington or HTT on chromosome four contains a triplet repeat, where nucleotides c, a, and g are repeated 10 to 35 times in a row in most people. This is the normal range of CAG repeats in the HTT gene.

• In people with Huntington's disease, this repeat goes on for 36 or more times in a row. This expansion of CAG repeats is the causative mutation for HD.

• CAG codes for the amino acid glutamine, so people with Huntington's disease will have 36 or more glutamines in a row in the Huntington protein. The elongated glutamine sequence causes the huntingtin protein to misfold and aggregate.

• HD is a polyglutamine disease. This refers to a class of neurodegenerative diseases caused by the expansion of CAG repeats in various genes.

• The mutated protein aggregates within the neuronal cells of the caudate and the putamen of the basal ganglia, causing neuronal cell death. These aggregates disrupt neuronal function and lead to the characteristic symptoms of HD.

• Cell death might be related to excitotoxicity, which is excessive signaling of these neurons, which leads to high intracellular calcium. Excitotoxicity can trigger a cascade of events that lead to neuronal damage and death.

• The expanded CAG repeats not only affect the Huntington protein; they also affect DNA replication itself. The expanded repeats can interfere with DNA replication and repair processes.

• DNA polymerase can accidentally add extra CAGs when copying the HTT gene. This can lead to further expansion of the CAG repeat length.

• The more repeats that are added, the more unstable it gets. Longer CAG repeat lengths are associated with earlier disease onset.

• The expansion of the originally inherited gene means that a child of a parent with HD can inherit even more CAG repeats than the parent did. This phenomenon is known as anticipation.

• The higher the number of repeats in the protein, the earlier the age when a person starts having symptoms; this is called anticipation. Anticipation can make it difficult to predict the age of onset in subsequent generations.

• Repeats of 27 to 35 CAG's can expand occasionally; these are called premutation alleles since they don't cause the disease, but they're set up for developing a mutation of 36 or more CHGs. These individuals are at risk of transmitting an expanded allele to their offspring.

• Repeat expansion happens way more in the production of sperm than of eggs. This means that HD is more likely to expand when inherited from the father.

• HD basically has a 100% penetrance, meaning that in this case, if they have 36 or more repeats, they have the disease. However, the age of onset can vary depending on the number of CAG repeats and other genetic and environmental factors.

• Even repeats of 27 to 35 CAG's can expand occasionally. This highlights the instability of these premutation alleles.

• The test for HD, which counts the number of CHG repeats, is really good at determining whether Huntington's disease will develop in an at-risk video. Genetic testing provides a definitive diagnosis for HD and allows for predictive testing in at-risk individuals.

Biological Explanations of Huntington's Disease

• Comprehensive biological explanation requires integrating multiple types of explanations: upward looking, downward looking, and backward looking. This interdisciplinary approach is essential for fully understanding the complexities of HD.

Downward Looking Explanations

• Seek the underlying causes at a smaller scale. This involves examining the molecular and cellular mechanisms that contribute to the disease.

• Neurons are cells that contain proteins. HD is a disease that primarily affects neurons in the brain.

• Proteins are encoded by alleles. The huntingtin protein is encoded by the HTT gene.

• Alleles differ due to mutations. The HD mutation is an expansion of CAG repeats in the HTT gene.

• The mutation with greater than forty CAG repeats is the cause. This mutation leads to the production of a toxic huntingtin protein.

Upward Looking Explanations

• Differences in the brain can be used to explain many of the features of patients. This involves examining how changes in brain structure and function lead to the symptoms of HD.

• Disruption of circuits in the brain explains the chorea movements, the depression, the extreme irritable outbursts, and ultimately the health, reproduction, and survival of an individual with Huntington's. These symptoms are all linked to specific changes in brain circuitry.

Backward Looking Explanations

• The presence of an allele in a patient is explained in most cases by the inheritance of an allele from a parent. HD is an autosomal dominant genetic disorder.

• The pattern of inheritance in pedigrees can be explained by the parental genotypes. By analyzing pedigrees, we can trace the inheritance of HD within families.

• Using Mendel's laws, we can predict the probability of an inheritance of an allele. Mendel's laws provide a framework for understanding the inheritance of genetic traits.

• Backward looking explanations involve the genetic history of a lineage.