Since the days of Hippocrates, medicine has gradually shifted from treating a patient’s symptoms to treating underlying mechanisms of disease. Early physicians had a very limited armamentarium, and the few effective remedies they possessed were focused on specific symptoms such as pain or fever. For example, an ancient Greek or medieval physician would attempt to treat an appendicitis patient for fever and abdominal pain, which would prove useless for correcting the underlying cause of the patient’s symptoms. Today, physicians and surgeons understand the underlying pathophysiology and remove the appendix surgically or treat the infection with antibiotics, usually resulting in recovery.

However, for many more complex disease processes, determining disease etiology and translating this knowledge to effective cures have remained challenging. Cancer is one example of this problem. While the underlying pathophysiology is better understood – one does not treat a lung cancer patient’s dyspnea alone – the primary treatments in many cases are still essentially focused on a disease’s effects, that is, uncontrolled proliferation and growth, rather than the underlying genetic etiology. The same is true of diseases such as multiple sclerosis where the majority of treatments target the uncontrolled immune attack on the central nervous system rather than the underlying cause of this aberrant response to self-antigens.

This quest to understand the fundamental pathophysiology of a disease in order to better treat it has been hampered by the heterogeneity of most disease processes. Some patients with colon cancer will undergo treatment and have a complete recovery; others with the same stage and grade will progress to metastatic disease and die. While for many cancers, there are clinical and/or pathological factors that are associated with prognosis, in most cases, the predictive power of these data is insufficient to guide specific treatment decisions. Consequently, for many diseases, patients with an aggressive form of the disease will be recommended the same treatment as patients with an indolent form of the disease, resulting in undertreatment of the aggressive disease and overtreatment of the indolent disease. The realization that our current approach to the diagnosis and treatment of many complex diseases is hampered by a lack of understanding of disease heterogeneity, and disease molecular pathogenesis leads to the concept of personalized medicine – that the design of treatments should incorporate understanding of the molecular pathogenesis of a patient’s disease, so that each patient’s personalized treatment regimen can target the specific aberrant molecular pathways driving each patient’s disease process.

Genetics and Disease

While the basic concepts of genetics date from the time of Gregor Mendel, the idea that genetic alterations can cause disease is more recent. The link between genetics and human disease was firmly established in the early twentieth century by Victor McKusick, the ‘father of medical genetics,’ and others. Early work in applying genetic methods to human disease was hindered by technically difficult methods with extremely low throughput. For example, Bishop et al. identified the src gene in normal avian DNA by creating a radioactive complementary strand and then measuring its ability to adhere to pooled DNA from various species. While this identified the gene as present in normal genomes, it gave no information as to mutations, or even location within the genome. Others used cytogenetic methods to identify chromosomal rearrangements in diseases such as acute promyelocytic leukemia (APL) or non-small-cell lung cancer (NSCLC). While cytogenetic methods were effective in identifying large-scale chromosomal rearrangements, they are not able to detect point mutations or other subtle, small-scale genetic changes that do not cause grossly visible chromosomal changes.

The Sanger sequencing method of DNA sequencing was initially developed in the late 1970s. This method originally developed by Frederick Sanger and colleagues uses a pool of labeled nucleotides to randomly terminate DNA synthesis from a template. This produces a pool of oligonucleotides of various lengths, each with a particular label at its end – by sorting the fragments by length, one can deduce the sequence of segments of DNA. A series of technical advances in the early 1980s enabled automation of Sanger sequencing, which significantly increased assay throughput and played an important role in the Human Genome Project (HGP).

The HGP started in the early 1990s and was completed in the early 2000s. The HGP was funded by the DOE and NIH, with the goal of understanding the genetic makeup of the human species by constructing a haploid reference genome. The project began in 1990 and a draft sequence of the Human Genome was published in 2000, with a more complete working draft completed 2003. In 1998, J. Craig Venter and Celera Genomics launched a privately funded effort to sequence the human genome. Celera and HGP scientists published details of draft sequences in February 2001 in Science and Nature. In total, the HGP-funded project was reported to have cost $3 billion dollars, while the Celera-led effort cost ~$300 million dollars.

After completion of the initial drafts of the human genome, subsequent projects in human genomics were able to utilize a high-quality reference genome, which dramatically increased the speed, accuracy, and cost-efficiency of human genome resequencing. At the same time, sequencing technologies progressed dramatically, with the development and widespread adoption of massively parallel ultra-high-throughput ‘next-generation’ sequencing platforms in the late 2000s. Increasing attention was now focused on the sequencing of germline and somatic tissues across large collections of human samples to gain insights into the genetic etiology of human disease. Next-generation sequencing has revolutionized the field of medical genetics and the efficiency with which clinicians and researchers can identify the underlying genetic cause of rare, genetic inherited disease. In parallel with this work, there has been a great deal of interest in characterizing the genomes of somatic tissues; in particular, the characterization of cancer genomes. Several large-scale projects (including the International Cancer Genome Consortium and The Cancer Genome Atlas Research Network) have begun to characterize thousands of cancer genomes from all major cancers. Further, genomic research expanded from focusing primarily on the coding portion of the genome (representing < 5% of the genome) to studying the role of noncoding transcribed genomic regions in human health and disease (e.g., miRNAs and lincRNAs), as well as the role of chromatin biology and epigenetics.

Detailed understanding of human genomes has great potential to improve medical care but many have been disappointed by the slow rate of progress since the completion of the HGP. However, modern genomic approaches have led to significant advances in the diagnosis and treatment of human diseases. For hundreds of rare, inherited Mendelian disorders, exome and whole genome sequencing have led to the identification of causative genetic variants. For genetic diseases affecting somatic tissues (such as cancer), detailed genomic characterization of patient cancer samples has led to the identification of new disease subtypes and the development of therapies to target genetic alterations in specific cancer subtypes. The amount of ongoing work in this emerging area of ‘personalized genomic cancer medicine’ is vast, read more about two illustrative examples, APL and NSCLC, which demonstrate the key approaches, successes, and challenges of applying genomics and concepts of personalized medicine to the diagnosis and treatment of disease in the article The Human Genome Project and Personalized Medicine here.

This excerpt was taken from the article The Human Genome Project and Personalized Medicine by M.M. Hefti and A.H. Beck. The article discusses the role of the Human Genome Project in enabling studies into the genetic etiology of disease, it examines notable examples where this genetic knowledge has led to improved personalized treatments and finally, major challenges to the field of personalized medicine as well as new opportunities afforded by the rapid decrease in the costs of genome sequencing. Read More Here.

The article is taken from the dynamic reference Pathobiology of Human Disease, which provides the definitive knowledge on morphologic, experimental, and molecular pathology. View the table of contents here.