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Technological advances have led to drastic improvements in the field of precision medicine, enabling more personalized approaches to treatment. This article explores four leading groups that are overcoming many of the challenges of genomic profiling and precision medicine through their innovative platforms and technologies.
Somatic Genomics
“We have such a tremendous amount of genetic diversity that exists within each of us, and not just between us as individuals,” stated Simon Brunner, Head of Platform at Quotient Therapeutics. “Each cell within us is genetically distinct from one another.” Brunner explained that the extent of this diversity is so significant that the genetic variation within just one organ, like the liver, can surpass the total genetic diversity currently assumed across the entire global population's genomes.
The team at Quotient Therapeutics sought to leverage this somatic diversity to help identify genes under evolutionary pressure in the context of different diseases and provide potential new targets for drug development. These ambitions led to the creation of their aptly named Somatic Genomics platform. Operating through a four-step process, the platform provides direct insights into human pathology. The process works by phenotyping to identify cells of interest, isolating the target cells, genotyping them with high-precision technology, and lastly, employing proprietary algorithms to detect genetic variations significant for therapeutic development.
“We're applying [the platform] exclusively to clinical human samples,” Brunner stated. He noted that the most valuable insights come directly from these settings because unlike mouse models or in vitro organoid models, human samples provide a direct link to human pathological conditions, which is imperative for drug discovery. In addition to these benefits, Brunner sees at least three key advantages that the Somatic Genomics platform has over other genomic approaches. First, it achieves large-scale insights from relatively few patient samples. Additionally, it provides intrinsic validation by linking findings directly to human disease pathology. Finally, the high-resolution data can pinpoint mutations within specific gene domains or amino acid sites, which is essential for developing targeted therapies.
Yet uncovering the diversity needed for these insights is no easy task. To accomplish this, Quotient relies on their NanoSeq (Nanorate sequencing) technology1. Initially developed at the Sanger Institute, NanoSeq provides unprecedented sequencing accuracy and minimizes artifacts introduced during the standard sequencing process. Brunner pointed out that this heightened sensitivity is especially crucial in the study of somatic genomics, where detecting rare mutations is needed for reliable analysis and discovery.
Along with NanoSeq, Quotient’s work is advanced by their extensive genomic database—currently the world's largest database of somatic genomes. Brunner shared that the group is fortunate to work with excellent collaborators and patient donors contributing to research and ensuring high-quality samples. Additionally, Brunner noted that the efforts of Matthew Young and Will Spooner, the team’s veteran in data infrastructure management, have allowed the team to overcome the challenges of managing this vast collection of data.
Recent developments at Quotient include the appointment of Janeta Popovici-Muller as Senior Vice President of Drug Discovery. With her extensive experience, she is set to advance their drug discovery capabilities, with the goal of advancing multiple drugs into clinical trials in the coming years. As for their next steps, Brunner emphasized the importance of linking phenotypes with genotypes through their platform and focusing on the variation within diseased tissues, as well as the impact of somatic mutations on cell health. Furthermore, Brunner shared that exciting new and promising datasets in spatial omics are increasingly becoming integral to their work at Quotient.
HiFi Sequencing in Precision Medicine
Long-read sequencing has become an indispensable tool in the field of precision medicine2,3. Nina Gonzaludo, Pharmacogenomics and Human Leukocyte Antigens Market Development Senior Manager at PacBio, highlighted that their HiFi sequencing technology can read DNA stretches up to 100 times longer than traditional methods, accurately capturing complex genomic regions like repetitive sequences and structural variants. This technology excels at identifying multiple variants on the same allele or DNA strand, known as a haplotype, using just one long read or a contiguous set of long reads. “Some of these complex regions and haplotypes are related to disease risk, drug response, or severity or variability of other clinical symptoms,” stated Gonzaludo.
Due to the high accuracy and longer read lengths, Gonzaludo believes that HiFi sequencing is ideally suited for both comprehensive genomic profiling and building a more complete genome. She further noted that PacBio’s technology can precisely measure changes beyond DNA, including RNA and methylation. Multiomics, the combination of these different modalities, is a promising area of research for the group. “This gives unprecedented insight into biology and disease, and is particularly useful in cases of rare disease, where DNA alone might not be enough to figure out what’s going on,” added Gonzaludo.
Due to its numerous benefits, HiFi sequencing has become prevalent in genomic profiling and precision medicine research, particularly in population-specific genomic studies. Gonzaludo emphasized that large-scale projects and initiatives like the Estonian Biobank, the All of Us Research Program, and the Million Veterans Project have incorporated PacBio’s technology to advance their personalized medicine research efforts. PacBio's impact has also been illustrated through numerous case studies, like recent efforts from the Solve-RD program. In this study, researchers utilized HiFi long-read sequencing to uncover genetic variants in undiagnosed rare disease families, achieving novel diagnoses in 13% of cases and identifying potential disease-causing variants in an additional 4.3% of families4.
Along with their sequencing solutions, PacBio develops the tools needed to analyze these data and draw valuable insights for precision medicine research. Gonzaludo highlighted several of these recent innovations, including tools like Paraphase for resolving paralagous genes and segmental duplications5, and tools like TRGT and TRVZ, designed to help characterize tandem repeat expansions. Other notable developments include targeted sequencing solutions such as the PureTarget repeat expansion panel and enhancements of Twist panels for pharmacogenomics research.
Alongside ongoing enhancements to PacBio’s technology, workflows, ecosystem partners, and software, Gonzaludo anticipates significant advancements emerging from large networks and consortia using their technology. “Groups like HiFiSolves are starting to incorporate HiFi-based genomic profiling into clinical research, and we expect to start seeing major results and impacts from these projects in the near future.”
Insights from the 3D Genome
The way researchers interact with the genome considerably shapes their perspective of it. For instance, wet lab researchers might perceive the genome as a challenging, colorless liquid, whereas bioinformaticians view it as a series of data files filled with sequences and quality scores. It’s also quite common to conceptualize the genome as a linear sequence. In contrast, organizations like
Enhanc3D Genomics specialize in studying the 3D conformation of the genome and extracting insights from non-coding regions of interest. Daniel Turner, Chief Scientific Officer of Enhanc3D Genomics, believes that “the non-coding genome is a relatively untapped resource that we can exploit to improve human health.”
One might wonder why 3D genome organization is so important or how this is involved in improving human health. As Turner emphasized, DNA is not randomly packed in the cell nucleus, but rather strategically folded to regulate gene activity. Its folding can vary across different cell types and conditions, such as healthy versus diseased cells, and this complex interaction and regulation are dependent on the physical proximity facilitated by the folding of DNA, rather than the linear sequence proximity. This makes 3D genome organization an important factor in cellular function, behavior, and disease6.
Conventional approaches to studying the genome, like genome-wide association studies (GWAS), have improved our understanding of genetic factors associated with diseases, but they have fallen short in their ability to link specific variants to actual gene function and disease mechanisms. Enhanc3D Genomics is working to address these gaps through their innovative GenLink3D platform. GenLink3D creates a comprehensive picture of live cell activity, and the bedrock of the platform is the use of Promoter Capture Hi-C, rather than the standard Hi-C, which allows the group to focus on 3D proximity data from the most relevant genomic interactions. Turner noted that this targeted method increases the proportion of on-target reads from 5% in regular Hi-C to 85% in their approach. Their platform also integrates additional -omics data, such as RNA-seq, ATAC-seq, and methylation data.
Through the combination of genomic technologies and computational strategies, Enhanc3D Genomics’ platform has significantly enhanced the capability to identify pertinent genomic interactions within their large datasets. This advancement allows them to effectively “de-orphanize” GWAS variants by linking them to their interacting genes, as well as identifying previously overlooked disease-related genes. These genes can then be classified into druggable classes and investigated for existing drug developments in other disease contexts. This approach offers exciting prospects for discovering new genes associated with diseases that currently have no treatments, repurposing opportunities for existing drugs, and also the ability to stratify patients into those who are more or less likely to respond to a particular treatment with greater power than is offered by the use of traditional polygenic risk scores.
Turner pointed out that their GenLink3D platform is unique because it approaches genomic analysis in a genome-wide, agnostic way. Instead of focusing on specific regions or diseases, it examines overall genomic activity and spatial relationships within different cells. The platform’s scalability allows for the analysis of numerous samples and the development of comprehensive, genome-wide data sets. Although still in the early stages, Enhanc3D Genomics is progressively expanding its technological capabilities. Turner shared that future enhancements will include greater integration of single-cell methodologies and potentially incorporating long-read sequencing technologies.
Patient-Centric Innovation
In addition to leading technology advancements, Matthew Goldberg, M.D., Senior Vice President of Medical at Castle Biosciences, explained that Castle Biosciences prioritizes patients, and their focus is on developing innovative diagnostic tests that address significant unmet clinical needs in several therapeutic areas, such as dermatology, gastroenterology, and mental health. Goldberg emphasized that Castle’s approach is grounded in the real-world clinical questions and challenges faced by patients and their healthcare providers.
Among their offerings, Castle’s DecisionDx-Melanoma and DecisionDx-SCC tests utilize gene expression profiling (GEP) as a method for understanding various types of cancers like melanoma and squamous cell carcinoma. While many traditional methods focus primarily on DNA, GEP analyzes the RNA in tumors to offer insights into the active processes within cells that can improve the prognostic accuracy of current risk stratification approaches. Goldberg noted that this analysis aids clinicians in distinguishing between tumors that look similar histologically but behave differently biologically. This distinction is key to more accurately predicting disease outcomes and personalizing risk-aligned treatment options.
Another key tool in Castle’s collection is TissueCypher, a test designed to better manage Barrett's esophagus. This is a troublesome condition that can potentially lead to esophageal adenocarcinoma. Using a spatial biology platform and a sophisticated AI algorithm, TissueCypher evaluates nine protein biomarkers and seven tissue structures that are used to extract 15 features predictive of progression risk to identify patients who may benefit from more aggressive surveillance or therapeutic intervention. “This is a crystalline example of how the power of spatial biology can be translated to the clinic,” stated Goldberg. “TissueCypher is a well-validated test for gastroenterologists that is being applied in a meaningful way for patient prognosis, enabling risk-aligned treatment.”
Outside of oncology, Castle is making advances in mental health with their comprehensive pharmacogenomic test, IDgenetix. Raymond Lorenz, Associate Medical Director of Pharmacogenomics at Castle Biosciences, shared that IDgenetix combines genetic information with individual lifestyle factors and existing medication regimens to personalize selection of psychiatric medications. The test utilizes an algorithmic platform to merge these diverse data points into a user-friendly report for clinicians. Lorenz explained that IDgenetix is an example of how Castle is integrating various types of data to reduce the trial-and-error approach often associated with psychiatric treatments and streamline the path to remission.
Recent updates from Castle Biosciences include new data presented at the 2023 Psych Congress meeting. Lorenz shared that these new findings show IDgenetix provides 75% more information than traditional pharmacogenomic tests. In addition to this data, Goldberg discussed advancements in dermatology at Castle, emphasizing ongoing research and data supporting the clinical validity and utility of DecisionDx-Melanoma and DecisionDx-SCC. Two recent studies, including a collaboration with the National Cancer Institute and its SEER Program cancer registry, validate DecisionDx-Melanoma’s ability to stratify risk in a large, population-based study, as well as demonstrate its significant impact to inform risk-aligned management, such a surveillance imaging, leading to improved patient outcomes7,8.
Goldberg explained that Castle Biosciences is enhancing its test offerings and expanding into new therapeutic areas like inflammatory skin diseases. As they continue to grow, Goldberg emphasized Castle's commitment to patient care. The team continues to encourage advocacy efforts, and both Goldberg and Lorenz shared their enthusiasm about using their currently available technologies to make a difference in personalized medicine. “It's not a future project,” added Lorenz with excitement. “It's here now; these are technologies that we can use now to actually help our patients.”
Closing Thoughts
While the future looks promising, the dedication and optimism of each of these groups make the current state of precision medicine look even brighter.
References
- Abascal, F., Harvey, L. M. R., Mitchell, E., et al. (2021). Somatic mutation landscapes at single-molecule resolution. Nature, 593(405–410). https://doi.org/10.1038/s41586-021-03477-4
- Mahmoud, M., Huang, Y., Garimella, K., et al. (2024). Utility of long-read sequencing for All of Us. Nature Communications, 15(837). https://doi.org/10.1038/s41467-024-44804-3
- Oehler, J. B., Wright, H., Stark, Z., et al. (2023). The application of long-read sequencing in clinical settings. Human Genomics, 17(73). https://doi.org/10.1186/s40246-023-00522-3
- Steyaert, W., Sagath, L., Demidov, G., et al. (2024). Unravelling undiagnosed rare disease cases by HiFi long-read genome sequencing. medRxiv. https://doi.org/10.1101/2024.05.03.24305331
- Chen, X., Harting, J., Farrow, E., Thiffault, I., Kasperaviciute, D., Hoischen, A., & Eberle, M. A. (2023). Comprehensive SMN1 and SMN2 profiling for spinal muscular atrophy analysis using long-read PacBio HiFi sequencing. The American Journal of Human Genetics, 110(2), 240-250.
- Jerković, I., & Cavalli, G. (2021). Understanding 3D genome organization by multidisciplinary methods. Nature Reviews Molecular Cell Biology, 22(511–528). https://doi.org/10.1038/s41580-021-00362-w
- Bailey, C. N., Martin, B. J., Petkov, V. I., Schussler, N. C., Stevens, J. L., Bentler, S., & Kurley, S. J. (2023). 31-Gene expression profile testing in cutaneous melanoma and survival outcomes in a population-based analysis: a SEER collaboration. JCO Precision Oncology, 7, e2300044.
- Dhillon, S., Duarte-Bateman, D., Fowler, G., et al. (2023). Routine imaging guided by a 31-gene expression profile assay results in earlier detection of melanoma with decreased metastatic tumor burden compared to patients without surveillance imaging studies. Archives of Dermatological Research, 315(8), 2295-2302. https://doi.org/10.1007/s00403-023-02613-6