Genomic Medicine-Progress, Pitfalls, and Promise

Abstract

In the wake of the Human Genome Project (HGP), strong expectations were set for the timeline and impact of genomics on medicine-an anticipated transformation in the diagnosis, treatment, and prevention of disease. In this Perspective, we take stock of the nascent field of genomic medicine. In what areas, if any, is genomics delivering on this promise, or is the path to success clear? Where are we falling short, and why? What have been the unanticipated developments? Overall, we argue that the optimism surrounding the transformational potential of genomics on medicine remains justified, albeit with a considerably different form and timescale than originally projected. We also argue that the field needs to pivot back to basics, as understanding the entirety of the genotype-to-phenotype equation is a likely prerequisite for delivering on the full potential of the human genome to advance the human condition.

Figure 1.. Genomic medicine throughout the human lifecycle.

There are many modalities for genomics to have an impact on clinical care, with entry points for application that span the human lifecycle from conception to death.

Figure 2.. Past milestones and future grand challenges for genome sciences and genomic medicine.

A) A timeline on selected milestones in the progression of the genome sciences (top) and genomic medicine (bottom). B) A selection of future grand challenges for the genome sciences (top) and genomic medicine (bottom). Contents of Figure 2. The following bullet items will occupy the four quadrants of Figure 2, and are included here to allow for reference formatting.

Quadrant 1 (genome sciences, selected milestones)

1. 2002 First successful GWAS (Ozaki et al., 2002)

2. 2004 Completion of Human Genome Project (International Human Genome Sequencing Consortium, 2004)

3. 2005 Emergence of next generation DNA sequencing (Margulies et al., 2005; Shendure et al., 2005)

4. 2005 Emergence of cost-effective genome-wide genotyping arrays (Gunderson et al., 2005)

5. 2005 First draft of the HapMap (The International HapMap Consortium, 2005)

6. 2014 Achievement of the $1,000 genome

7. 2018 Emergence of the UK Biobank, a population-scale cohort (Bycroft et al., 2018)

8. Maturation of human genome-wide polygenic risk scores (Khera et al., 2018)

Quadrant 2 (genomic medicine, selected milestones)

1. 2004 Demonstration of NSCLC mutation-specific efficacy of gefitinib, a EGFR kinase inhibitor (Lynch et al., 2004; Paez et al., 2004).

2. 2008 NGS of cell-free DNA for non-invasive screening of fetal aneuploidy (Chiu et al., 2008; Fan et al., 2008)

3. 2009 NGS for Mendelian disease gene discovery and diagnosis (Choi et al., 2009; Hoischen et al., 2010; Ng et al., 2009)

4. 2011 Demonstration of efficacy of ivacaftor, a mutation-specific drug for cystic fibrosis (Ramsey et al., 2011)

5. 2012 Rapid WGS for genetic disease diagnosis in neonatal ICUs (Saunders et al., 2012)

6. 2013 Demonstration that ~25% of probands with suspected genetic disease could be diagnosed by exome sequencing (Saunders et al., 2012; Yang et al., 2013)

7. 2017 Case reports of successful gene therapy for sickle cell anemia, hemophilia (Rangarajan et al., 2017; Ribeil et al., 2017)

8. 2017 First-in-human testing of immunotherapy against sequencing-defined patient-specific neoantigens (Ott et al., 2017; Sahin et al., 2017)

Quadrant 3 (genome sciences, grand challenges)

1. A spatiotemporally resolved molecular atlas of all human cell types, throughout the lifecycle, and in both health and disease.

2. A comprehensive catalog of common genetic variants in which all human populations, as well as all classes of genetic variation, are well represented

3. A “telomere-to-telomere” ungapped reference representation of the human genome

4. A functionally validated catalog of human regulatory elements, annotated with the gene(s) that they regulate and the cellular, developmental, and/or disease contexts in which they are active

5. The definitive identification of causal variants & genes for thousands of GWAS associations

6. A comprehensive understanding of the genetic basis of all Mendelian disorders

7. A basic understanding of the primary function(s) of every human gene

8. Algorithms that can accurately predict the consequences of arbitrary genetic variants at the molecular/cellular level

Quadrant 4 (genomic medicine, grand challenges)

1. A database of whole genome sequences for at least 0.1% of living humans, integrated with electronic medical records and other phenotypes, and broadly accessible for research

2. The routine use of exome or genome sequencing to diagnose the vast majority of suspected cases of Mendelian disease

3. The routine use of genome-wide genotyping and polygenic risk scores for common disease risk prediction

4. The generation of catalogs of clinically meaningful functional scores for all possible SNVs in all “clinically actionable” genes

5. The routine use of exome or genome sequencing to guide cancer treatment, including for patient-specific immunotherapy

6. The successful exploitation of cell-free DNA for early (or at least earlier) detection of common cancers

7. Algorithms that can accurately predict the consequences of arbitrary genetic variants at the organismal level

Figure 3.. Exponential growth in genomic testing.

We show estimates of number of individuals that have been received genetic testing in the form of direct-to-consumer microarrays (DTC) and non-invasive prenatal testing (NIPT) (left) and whole genome sequencing (WGS) (right) as a function of time. For NIPT, estimates are based on (Chiu et al., 2008; Fan et al., 2008; Liu et al., 2018; Yuzuki). For DTC and WGS, estimates are from Illumina (personal communication), with estimates of WGS are based on equivalents of 30X coverage.

Figure 4.

Future Grand Challenges for Genome Sciences and Genomic Medicine A selection of future grand challenges for the genome sciences (left) and genomic medicine (right).