Progress, Pioneers and Process

The following sections are included:

• Preface
• Acknowledgements
• Contents

The following sections are included:

• Early History
• Endoplasmic Reticulum
• Discovery of Lysosomes and their Functions
• Endosomes and the Endosomal Pathway
• Autophagy Pathways
• Autophagy Lysosome and mTORC1 in Regulation of Metabolism
• Mitochondria and their Functions
• Peroxisomes
• References

The following sections are included:

• Early History
• Separation of Proteins and Studies of Structure
• Protein Functions, Domains, and Folding
• Insulin Protein, Insulin Receptor, and Insulin Gene
• Different Forms of Diabetes
• Aberrant Fusion Proteins
• Identification of New Proteins and their Functions in the Post-genomic Era
• Post-translational Modification of Proteins
• Multiprotein Complexes
• Metalloproteins, Iron and Copper Metabolism, and Related Diseases
• Protein Interactions
• References

In this chapter I will explore early descriptions of a number of relatively rare Mendelian conditions that are now well known. I will also describe some of the steps made in exploring the molecular pathogenesis of these diseases. Discoveries in these disorders have led to approaches to therapy. Importantly, the insights gained through these molecular studies have served to guide explorations in other Mendelian diseases.

The clinical features of several of the diseases discussed below were documented in the 19th century or early in the 20th century, and several of the conditions were described as being inherited. However, the introduction of concepts of Mendelian genetics to clinical medicine came only in 1909, largely through the efforts of William Bateson (1909) (see also Rushton, 2017).

The following sections are included:

• Progression of Approaches
• Genetic Variation in Health and in Disease
• Evidence for Polygenic Factors in Disease Determination
• Genomic Copy Number Variants
• Population Genetics Following Availability of the Complete Human Genome Sequence
• Genome Analysis in Individuals and Identification of Pathogenic Changes
• Large-scale Structural Genomic Changes and Clinical Genomic Testing
• Recent Insights into Regulation of Gene Expression
• The Three-dimensional Genome
• Epigenetics and Epigenomics
• Eukaryotic Gene Transcription
• Messenger RNA Translation
• The Microbiome
• References

The following sections are included:

• Early Biochemistry and the Inborn Errors of Metabolism Concepts
• Gowland Hopkins
• Fölling and the Discovery of Phenylketonuria
• Newborn Screening
• Tetrahydrobiopterin and Biological Activity of Phenylalanine Hydroxylase
• Evolving Concepts of PKU Management
• Progress in Diagnosis and Treatment of Other Inborn Errors of Metabolism
• Mitochondrial Dysfunction and Clinical Diseases
• Mitochondrial Maintenance Defects and Depletion Syndromes
• Nuclear DNA Mutations That Lead to Disrupted Mitochondrial Function
• Mitochondrial Haplotypes
• Disease-causing Mutations in Mitochondrial DNA
• Additional Approaches to Therapy of Mitochondrial Diseases
• Progress in Diagnosis and Treatment of Lysosomal Storage Diseases
• Important Transcription Factor for Lysosomal Biogenesis
• Autophagy and Its Relevance to Metabolism
• Diseases Due to Defects in Peroxisome Function
• Complex Common Diseases and Metabolism
• Metabolic Syndrome
• Metabolomics
• References

The following sections are included:

• Regulatory Elements, Developmental Biology, and Evolution
• Hox Genes
• Investigations of Birth Defects in Humans and Named Syndromes
• Congenital Heart Malformations
• Orofacial Clefts, Cleft Lip, and Cleft Palate
• Congenital Diaphragmatic Hernia
• Analysis of Segmental Genomic Defects through Microarray Studies
• Deciphering Developmental Disorders Study
• Craniofacial Development and Defects
• Neural Tube Defects Including Spina Bifida
• Developmental Defects Due to Epigenetic Machinery Impairments
• Malformations of Brain Development
• Signaling Pathway Defects Leading to Congenital Malformation Syndromes
• Defects in Multiprotein Complex Components and Overlapping Phenotypes
• Postzygotic (Somatic) Mutations and Congenital Malformations
• References

The following sections are included:

• Phosphorylation
• Signal Transduction Science
• G Protein-coupled Receptors
• Cell Membranes and Receptors
• Signaling Pathways
• Sarcoma Virus Studies Provide Insights into Intracellular Signaling
• Further Studies on Oncogenes and Tumorigenesis
• The Phosphoinositide Pathway and Calcium Signaling
• Neurotransmitters, Receptors, and Downstream Signaling
• Postsynaptic Density and Signaling
• References

The following sections are included:

• Progress in Understanding Humoral Immunity
• Monoclonal Antibodies
• Innate and Cellular Immune System
• Diseases Attributed to Aberrant Immune Reactivity
• Landmark Discoveries That Made Clinical Transplantation a Viable Therapy
• Matching and Discovery of the Major Histocompatibility Complex
• Immunosuppressant Drugs
• Autoimmune Diseases
• Genetic and Environmental Factors in Autoimmune Diseases
• Multiple Sclerosis
• Systemic Lupus Erythematosus
• Rheumatoid Arthritis
• Guillain-Barre Syndrome
• Immune System-based Therapies for Cancer
• References

I introduce this chapter with a summary of an outstanding analysis of the hallmarks of cancer. Insights into factors that lead to cancer have been obtained over the years, through studies on environmental exposures that lead to cancer, and through studies on familial cancer and hereditary cancer predisposition. Further insights into germline and developmental factors related to cancer risk have been obtained through studies on pediatric cancer. Over the past 70 years many researchers and clinicians have carried out studies that have elucidated alterations in genomes and genes that lead to cancer. Information has also been gathered on immunological mechanisms that play a role in cancer.

Even as we celebrate advances in medicine and honor those who assiduously work toward more progress in the field, it is important to keep in mind that there are gaps in progress that need to be addressed. A few examples are presented in this chapter.

Over the past few decades intense studies have been carried out on genetic factors and on molecular and structural alterations that underlie late-onset neurodegenerative diseases. The rationale for in-depth genetic and molecular studies in neurodegenerative diseases is to obtain insights into the pathogenic processes in these disorders, to facilitate early diagnosis of such conditions, and to work toward defining disease-modifying therapies.

In this chapter, gene therapy, use of nucleotides in antisense therapy, and gene editing will each be discussed in separate sections.

The goal of this chapter is to summarize aspects of current approaches to medical care and several exciting new aspects of diagnosis and treatment. Discussed in this chapter are concepts of personalized medicine and learning health systems. In addition, aspects of targeted therapies, cell therapies, gene therapy, and new approaches to cancer diagnosis and therapy are briefly presented; several of these topics were presented in more detail in other chapters. The chapter ends with discussion of 21st century approaches to psychiatric disorders.

The following section is included:

• Index