Comment

Most of the world’s diseases have been forgotten by commercial drug development. Patient advocacy groups must look to new types of partnerships to develop therapies.

For Nature Biotechnology’s 30th anniversary, our editors look back at a few of their favorite papers published in the past decade.

To apparently little effect, Nature Biotechnology has been commenting on the oddly unscientific ways of biotech for 30 years. Revisiting the exasperation and occasional ridicule of this journal’s editorials, this Comment explores how populist and commercial lobbies have sidetracked regulations — in particular, those for genetically modified organisms and biosimilars. In a lesson germane in today’s political climate, re-establishing a rational path rapidly may reduce the damage.

Site-directed nuclease (SDN) classification into SDN-1, SDN-2 and SDN-3 outcomes is used for regulating genome-edited plant products in some countries. This reductive categorization system fails to cover the breadth of genome editing technologies developed over the past decade and their rapidly approaching commercial use. Here, we argue that, in the context of plant breeding, regulations should focus on the characteristics of the genome editing outcome, rather than specific methods used in the development process. Such a science-based, outcome-focused regulatory approach would future-proof the risk-proportionate oversight of plant breeding innovations and enable a more efficient delivery of improved crop varieties amidst growing concerns of climate change and evolving pests and diseases.

The potential use of in vitro gametogenesis (IVG) as a reproductive technology could redefine parentage, including the possibility of bipaternal parentage, raising hopes for those who have infertility or desire reproductive autonomy. However, IVG is not yet feasible for human reproduction, and substantial hurdles must be overcome if it is to become a clinical reality. This Comment outlines the major technical limitations of IVG and argues for public engagement in shaping the future directions of IVG research.

As pressure mounts globally on drug pricing and development cost continues to rise, clinicians and translational scientists in biotech, academia and biopharma companies are re-evaluating when, where and how to launch early clinical programs. These initial patient data become critical to de-risk development programs and allow developers to deploy their limited time and resources on the most promising drugs. We evaluate four fundamental shifts in drug development that appear to be unfolding and may well become critical to future global biopharma success: use of large-scale high quality cohort studies, sponsor-driven investigator-initiated trials, the integration of affordable artificial intelligence with extensive high quality data registries, and China’s focus on precision medicine. —

Immunotherapy is at an inflection point. After three decades of accelerating progress, immunotherapy is entering the realm of in vivo engineering. This Comment discusses the potential of in vivo engineering in addressing challenges met by ex vivo engineering efforts. Per a recent workshop organized by the National Institutes of Health, we highlight progress, the platform technologies fueling it, and elements of a road map and challenges ahead.

Our understanding of the genetic mechanisms underlying rare diseases has rapidly advanced over the past decade, largely because of technological innovations. Yet clinical practice still has a strong monogenic focus, leaving many individuals undiagnosed. This Comment outlines how technological advances such as long-read sequencing should be adopted to increase multivariant testing in the clinic.

The Synthetic Yeast Genome Project (Sc2.0) set out to redesign and chemically synthesize an entire eukaryotic genome. This Comment summarizes the design- and construction-related defects revealed during the construction of 16 synthetic chromosomes, and the solutions applied, drawing out the key biological and technical insights that will inform future genome-scale engineering.

Transformer-based large language models are gaining traction in biomedical research, particularly in single-cell omics. Despite their promise, the application of single-cell large language models (scLLMs) remains limited in practice. In this Comment, we examine the current landscape of scLLMs and the benchmark studies that assess their applications in various analytical tasks. We highlight existing technical gaps and practical barriers, and discuss future directions toward a more accessible and effective ecosystem to promote the applications of scLLMs in the biomedical community.

Genome editing technology is evolving fast, and many labs worldwide are generating crop plants with improved traits. If transgenes were used to generate the edits, foreign DNA must be effectively removed by outcrossing. After an evaluation of various technologies, we show that long-read whole-genome sequencing (WGS) is at present the only reliable approach to confirm the absence of foreign DNA. We suggest using long-read WGS before requesting exemption from classification as genetically modified organisms and provide a guide for interpreting WGS data.

The COP16 decision established a multilateral mechanism for digital sequence information (DSI) benefit-sharing. This Comment brings together insights from academia and commercial DSI researchers to assess what has been accomplished so far, identify remaining challenges and describe elements under discussion to support collective goals.

A vast landscape of ‘undruggable’ cancer targets remains beyond the reach of conventional therapeutic agents. Recent advances in artificial intelligence (AI), however, are challenging this paradigm. Synthesizing insights from a Cancer Moonshot workshop, we argue that systemically addressing the undruggable target space with AI requires a new conceptual framework. We highlight the failure of current target taxonomies and the need for benchmarking datasets, and re-evaluate clinical validation for novel AI-driven modalities.

Platform-based approaches for gene-editing therapies could markedly improve development efficiency, reduce costs and increase access for patients with rare diseases. Although gene editing has shown remarkable clinical success for a small number of Mendelian disease indications, broader adoption faces substantial hurdles. We propose strategies to overcome these challenges through modular platforms for nonclinical and chemistry, manufacturing and controls (CMC) data reuse, risk-based manufacturing quality, and streamlined umbrella clinical trials for regulatory efficiency and accelerated approval.

A new model for quantifying the impact of capital investments in life science interventions could help investors, policymakers and healthcare stakeholders to assess, monitor and optimize the societal impact of their investments.

23andMe’s bankruptcy serves as a moment of reflection for the direct-to-consumer (DTC) genomics industry. We analyzed 23andMe financial data and business practices to reveal the factors behind the fall of the company, once valued at US $6 billion and now being considered for acquisition by Regeneron for merely $250 million. Key challenges faced by 23andMe in monetizing its genomic data reveal that this information, at least in a typical DTC setting, is simply not worth that much.

Producing goods, such as foods and fuels, with minimal environmental impacts is urgently needed. Although advances in bioproduction are promising, there is often a noticeable gap in our understanding of whether and where new processes can compete with existing methods on an economic and environmental basis. Transparent lower bound calculations from basic principles highlight potential benefits of producing foods, but not fuels, from electro-microbial production of biomass.

Synergizing advances in artificial intelligence with mathematical modeling will improve our ability to computationally predict immunotherapy outcomes.

Spatial omics technologies offer insights into the organization of cellular and molecular components and their interactions within the tumor ecosystem. Overcoming the key challenges to integrating these advances into routine clinical practice will help unlock new treatment options for patients receiving cancer immunotherapy.

The identification of novel targets together with technological advances is transforming our ability to effectively modulate the tumor microenvironment.