The Legacy and Future of Genomic Medicine: From the 15th Annual State of Personalized Medicine Address

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The Personalized Medicine Coalition met in Washington, DC, in May 2023 to commemorate the 20th anniversary of the Human Genome Project’s completion. Eric Green, director of the National Human Genome Research Institute (NHGRI), has been a key contributor to the fields of genomics and personalized medicine for more than three decades. According to Lincoln Nadauld, cofounder and chief executive officer (CEO) of Culmination Bio, Green’s work has “included significant involvement in the Human Genome Project, during which he and his lab pioneered novel approaches for mapping and sequencing the human genome.” Green addressed constituents at the Personalized Medicine Coalition’s 15th Annual State of Personalized Medicine Luncheon to discuss medical advancements bolstered by the success of the genome project. Below, we present a summary of Green’s insights into human genomics and the future of medicine.

Green’s Presentation
Serving as one of 27 organizations that make up the US National Institutes of Health (NIH), the NHGRI represents the young field of genomic research, operating on a relatively modest US$600 million budget. NHGRI was created to lead the NIH’s research in the Human Genome Project, with the stated mission of enabling genomics to reach across biomedical science so that other institutions can prosper from knowledge gained within the field.

Green discussed the origin of the word “genomics,” which was first coined in 1987 and became the title of a scientific journal. Shortly thereafter, the NIH institute known as NHGRI was created to focus on the study and advancement of genomics. Excitement grew throughout the 1980s as the ambitious idea to map the human genome began to capture the imagination of scientists and the public. The project began in 1990 and was completed in 2003, successfully mapping and sequencing the human genome. That achievement set into motion an incredible series of advances that have followed over the past 20 years. The Human Genome Project changed fundamental paradigms about medicine, enabling healthcare providers to move away from population-scale research and focus on personalized therapies using genomic data. Green emphasized that such progress was hard to envision when the project finished 20 years ago. He said, “I don’t think any of us could have contemplate really moving toward significant advances in genomic medicine without having the Human Genome Project in the rearview mirror.”

Scientists have used different definitions for genomic medicine but generally describe it as using personal genetic information to tailor medical care for individual people. Green characterized the Human Genome Project as both a starting and an ending point in advancing the field. He said that the journey toward genomic medicine began with the completion of the Human Genome Project, but that there are numerous steps to prepare for and anticipate to advance genomic medicine further. The journey toward doing so involves multiple institutes, funders, investigators, and countries, requiring people from many disciplines to work together toward a goal that will be defined over decades rather than years.

The Human Genome Project cost about $1 billion to complete. In the past 20 years, scientists have reduced the cost of genome sequencing more than a millionfold to below $1,000 and set an eventual goal of reaching $100. The cost reduction has enabled scientists to sequence millions of human genomes with improved distribution and a greater understanding of variability.

Of particular importance to science and medicine is the notion of a pangenome, which is a collection of high-quality genome sequences that represent the diverse populations around the world. Without a pangenome, researchers do not have an adequate reference to compare with a given individual’s sequence for the purpose of detecting variants. One reference genome cannot represent a complex human population appropriately. The pangenome is an important resource to advance equity in genomics, which Green acknowledged as a problem within the field. “We need to fix this,” he said. “Genomics needs to be equitable. Genomics needs to represent the world’s population. If we don’t do it, not everybody is going to benefit equally.”

Green emphasized NHGRI’s commitment to creating a such a genome, stating that knowledge about variants in isolation is inadequate for healthcare because scientists need to understand the biology that the genome represents and how variation influences that biology.

Increasingly, people can view the functional landscape of the human genome by using a Google Maps–like framework through the Internet where they can freely browse base by base. But according to Green, interpreting 3 billion letters and their incredible biological complexity and choreography is a multigenerational problem. Scientists are striving to advance their understanding of how biological variation influences function because it is important to understand how variation correlates to traits of interest that include physical traits and importantly, disease and health-related traits.

Green discussed scientists’ long-standing interest in using knowledge of human genetics to untangle the complexities of human health and disease. Over the past 20 years, researchers have developed technologies and data resources about variation that increased our understanding of the functional landscape of the human genome. Users can put those tools together and apply them to sophisticated human genetic studies.

Rare diseases are complicated because they often require scientists to identify singular mutated genes, whereas common diseases typically have greater environmental contributions. Nevertheless, when the Human Genome Project began, the mutated genes had been identified for 61 rare diseases. Green emphasized that today, out of the 8,000–9,000 known rare diseases in humans, scientists have identified the mutated gene for almost 6,000. Meanwhile, researchers are starting to understand the genes and pathways involved in disorders such as hypertension, diabetes, and schizophrenia. Thousands of regions in the human genome have been associated statistically with variants that confer risk for specific disorders. Although scientists still need to discover and understand causative variants, they have found clues that were not available 20 years ago.

Green said that when he took over as the director of NHGRI in 2011, his team used the phrase “Genomic Medicine” in the title of its strategic vision. Many people criticized the institute for integrating the idea of medicine too early in the process. But vivid examples now emerge that justify the team’s decision to push the institute toward genomic medicine. Although no grand organizing principle links genomics to medicine, there is sufficient evidence to show a relationship between those fields. In the future, genomics will have regular relevance to medicine.

Cancer genomics are leading the way in medicine and often are the first thing that people envision when they think of medical innovations and genomics. Green said that cancer genomics probably will continue to have the greatest impact on medicine for a long time. He touted the advances that enable medical providers to diagnose tumors by genome analysis, enabling greater diagnostic precision and better access to personalized data that can guide prognostic information and therapeutic options. He also discussed advancements in liquid biopsies and surveillance capabilities that are improving prevention and follow-up for individuals after treatment. Sometimes

The Human Genome Project and its impact on genomic medicine also have had a significant impact on rare-disease diagnostics. Green said that when he began training in pathology, he never expected to see the day when patients could walk into a clinic, have their genomes sequenced, and then receive diagnoses based on those sequences. Such events are now routine in medicine. Green said, “It is now estimated that for rare genetic conditions, upwards of 25,000 people in the United States and probably double that number internationally, are getting their genome sequenced every year.” He said that number will increase significantly, especially for patients with previously unknown genetic conditions.

In neonatal intensive care, many state-of-the-art facilities are implementing rapid genome sequencing. Sequencing capabilities will continue to grow for diagnosing rare diseases. An estimated 5–7 million pregnant individuals are receiving noninvasive prenatal genetic testing worldwide in 2023, making it the most heavily used genomic test by far.

Genomic risk prediction based on polygenic scoring is another exciting highlight, especially in regard to common diseases. NHGRI is investing heavily in developing clear evidence of clinical utility, and Green’s team is optimistic about doing so soon. He said that over the past 20 years, scientific understanding of genomic medicine has grown from vague concepts to clear ideas based on early examples. Nevertheless, scientists are working to overcome some challenges. According to Green, attaining a comprehensive understanding of a patient’s genome sequence remains difficult. Each person has 4–6 million variants, and the research community has yet to achieve a comprehensive understanding of all variants and their clinical significance.

As genomics gains relevance to society, bioethics becomes an important consideration. Until recently, genomics was a separate field from medicine, but genomic medicine has introduced many important discussions about payments, privacy, regulations, and scientific literacy. Ultimately, genomics presents similar obstacles to other scientific advances.

Eric Green is the director of the National Human Genome Research Institute and a leading contributor to genomic research, including the Human Genome Project. (HTTPS//GENOME.GOV).

The Strategic Plan
Many aspects of health and disease have genetic and nongenetic contributions. Green praised his team for contributing genomics expertise to modern medical advancements and praised other experts for bringing nongenomic information that relates to personalized precision medicine.

Part of Green’s responsibility at NHGRI is to envision progress, consider upcoming challenges, and plan for the future. Every eight to 10 years, NHGRI releases a strategic vision to plan for the next few years. The organization began writing its first in 2018 and finished the process during the COVID-19 pandemic.

Green realizes that planning around the entire field of genomics is almost impossible. When he devised strategy for human genomics on behalf of the NIH, his team needed to plan for the part of genomics that they could lead. They performed a self-identity assessment and enacted a new organizational mantra that guided the planning process. Instead of encompassing all of genomics, the team decided to focus its attention on the forefront of genomics specifically. That philosophy came to symbolize NHGRI’s mission, including the product of its two-year strategic planning process, which Nature published in 2020 based on feedback from thousands of people within the scientific community (1). Using that feedback, the NHGRI team identified four major categories of importance that differed from those that it previously had considered. That feedback helped NHGRI’s define its ongoing role at the forefront of genomics.

Four Categories of Importance: The first category identified in NHGRI’s plan comprised the important responsibilities of rearticulating and extending the guiding principles and values of the genomics field.

The team recognized the need to exercise stewardship and maintain responsibility for open-science policies and data standards. The genomics field has a host of ethical, legal, and social implications related to its continuous advancement that need oversight. The field needs people to lead the way in creating policies, ideas, and positions.
The second category regards the need to maintain a reliable foundation for genomics by managing the critical data resources and technologies that stakeholders use. Green emphasized the importance of ensuring that genomics maintains a strong and robust foundation.

The third category addresses barriers that impede progress within the field. Twenty years ago, the largest barrier to genomic progress was the cost of DNA sequencing. Many new barriers have cropped up in the years since that cost has gone down. It is important to address difficulties in genome-editing technologies and DNA-synthesis methods as well as burgeoning issues around implementing genomics in healthcare systems and the complexity of implementation science.

Finally, for NHGRI to lead the forefront of genomics, it must undertake compelling, audacious genomics projects. This is especially true for projects that are outside the scope of other organizations. NHGRI’s strategic plan articulates a number of compelling genomics research projects for Green’s team to consider in the near future.

Reference
1 Green ED, et al. Strategic Vision for Improving Human Health at the Forefront of Genomics. Nature 586, 2020: 683–692; https://doi.org/10.1038/s41586-020-2817-4.

Josh Abbott is an associate editor at BioProcess International and Eric Green, PhD, is director of the National Human Genome Research Institute, 31 Center Drive, Bethesda, MD 20894; 1-301-402-0911; https://www.genome.gov.