Artificial intelligence (AI) is not a new technological development. The idea of intelligent machines has been popular for several centuries. The term “artificial intelligence” was coined by John McCarthy for a workshop at Dartmouth College in 1955 (1), and this workshop is considered the birthplace of AI research. Modern AI owes much of its existence to an earlier paper by Alan Turing (2), in which he proposed the famous Turing Test to determine whether a machine could exhibit intelligent behavior equivalent to—or indistinguishable from—that of a human.
The explosive growth in all things AI over the past few years has evoked strong reactions from the general public. At one end of the spectrum, some people fear AI and refuse to use it—even though they may have unwittingly been using a form of AI in their work for years. At the other extreme, advocates embrace all aspects of AI, regardless of potential ethical implications. Finding a middle ground is not always easy, but it’s the best path forward to take advantage of the improvements in efficiency that AI can bring, while still being cautious about widespread adoption. It’s worth noting that AI is a broad, general term that covers a wide range of technologies (see sidebar).
For life science researchers, AI has the potential to address many common challenges; a previous post on this blog discussed how AI can help develop a research proposal. AI can help with everyday tasks like literature searches, lab notebook management, and data analysis. It is already making strides on a larger scale in applications for lab automation, drug discovery and personalized medicine (reviewed in 3–5). Significant medical breakthroughs have resulted from AI-powered research, such as the discovery of novel antibiotic classes (6) and assessment of atherosclerotic plaques (7). A few examples of AI-driven tools and platforms covering various aspects of life science research are listed here.
Identifying Inflammasome Inhibitors: What’s Missing The NLRP3 inflammasome is implicated in a wide range of diseases. The ability to inhibit this protein complex could provide more precise, targeted relief to inflammatory disease sufferers than current broad-spectrum anti-inflammatory compounds, potentially without side effects.
Studies of NLRP3 inflammasome inhibitors have relied on cell-free assays using purified NLRP3. But cell-free assays cannot assess physical engagement of the inhibitor and target in the cellular micro-environment. Cell-free assays cannot show if an NLRP3 inhibitor enters the cell, binds the target and how long the inhibitor binding lasts.
Cell-based assays that interrogate the physical interaction of the NLRP3 target and inhibitor inside cells are needed.
In our third and final installment of the Promega qPCR Grant Recipient blog series, we highlight Dr. Sabrina Alves dos Reis, a trained immunotherapy researcher. Her work has focused on developing tools for more accessible cancer therapies using CAR-T cells. Here, we explore Dr. Alves dos Reis’ academic and scientific journeys, highlight influential mentorship and foreshadow her plans for the Promega qPCR grant funds.
Dr. Alves dos Reis’ career began with a strong affinity for biology. As an undergraduate student, she pursued a degree in biological science, where she developed a foundational understanding for designing and developing research projects. As her passion for science heightened, she decided to continue her journey in science, culminating in a PhD at the Fundação Oswaldo Cruz Institute in Rio de Janeiro, Brazil. Her research projects focused on the unexplored territory of adipose tissue as a site for Mycobacterium leprae—or leprosy bacillus—infection. She mentioned that this work piqued her curiosity for improving immunotherapies and laid the foundation for her future in cancer research.
Mitogen-activated protein kinases (MAPKs) are a large family of proteins that regulate diverse cellular functions in eukaryotes, including gene expression, proliferation, differentiation and apoptosis (1). MAPK signaling pathways typically include three sequentially activated kinases, and these pathways are triggered in response to extracellular stimuli, such as cytokines, mitogens, growth factors and oxidative stress (1). Ultimately, the signal is transmitted to the nucleus, with the activation of a specific transcription factor that modulates the expression of one or more genes.
Among MAPK pathways, the RAS-RAF-MEK-ERK signaling pathway has been studied extensively. Mutations in RAS family proteins and resultant dysregulation of the signaling pathway are implicated in a variety of cancers. Therefore, this pathway is a popular target for anticancer drug development.
Monitoring and quantifying drug-target binding in a live-cell setting is important to bridging the gap between in vitro assay results and the phenotypic outcome, and therefore represents a crucial step in target validation and drug development (1). The NanoBRET™ Target Engagement (TE) assay is a biophysical technique that enables quantitative assessment of small molecule-target protein binding in live cells. This live-cell target engagement assay uses the bioluminescence resonance energy transfer (BRET) from a NanoLuc® luciferase-tagged target protein and a cell-permeable fluorescent tracer that reversibly binds the target protein of interest. In the presence of unlabeled test compound that engages the target protein, the tracer is displaced, and a loss of BRET signal is observed. Due to the tight distance constraints for BRET, the signal measured is specific to the target fused to NanoLuc® luciferase.
Promega offers over 400 ready-to-use assays for multiple target classes, including kinases, E3 ligases, RAS, and many others. For targets that do not have an existing NanoBRET™ TE assay, Promega offers NanoBRET™ dyes, NanoLuc® cloning vectors, and NanoBRET™ detection reagents to develop novel NanoBRET™ TE assays.
One critical component in the development of novel NanoBRET™ TE assay is the creation of the cell-permeable fluorescent tracers (NanoBRET™ tracers) against the target protein of interest. The tracers are bifunctional, consisting of a NanoBRET™-compatible fluorophore and a target-binding moiety connected by a linker. While the NanoBRET™ 590 dyes have demonstrated consistently robust cell permeability and optimal spectral overlap with NanoLuc® for BRET, a ligand capable of binding to the target protein of interest needs to be identified to generate a NanoBRET™ tracer.
What Are DNA-Encoded Libraries?
DNA-Encoded Libraries, (DELs), have emerged as powerful tools for discovering small molecule ligands to target proteins of interest at an unprecedented scale. . owing to the ability of a DEL to enable the synthesis of larger libraries of compounds and to target proteins without any prior structural knowledge of the proteins or their ligands (2). Because each member of a DEL contains a DNA barcode and a small molecule separated by a linker, DEL is primed for discovering leads within therapeutic modalities that rely on bifunctional chemistry, such as proteolysis targeting chimeras (PROTACs). Since NanoBRET™ tracers are also bifunctional, ligands identified from DEL selections could serve as ideal candidates for developing novel NanoBRET™ tracers that can enable NanoBRET™ TE assays for new targets.
Our cells, and the DNA they contain, are under constant attack from external factors such as ionizing radiation, ultraviolet light and environmental toxins. Internal cellular processes can also generate metabolites, such as reactive oxygen species, that damage DNA. In most cases, DNA damage results in permanent changes to DNA molecules, including DNA mismatches, single-strand breaks (SSBs), double-strand breaks (DSBs), crosslinking, or chemical alteration of bases or sugars. If left unchecked, DNA damage can cause genome instability, mutations and aberrant transcription, and oncogenic transformation.
Fortunately, our cells have also evolved multiple pathways to repair damaged DNA, collectively known as the DNA damage response (DDR). The type of repair mechanism depends on the nature of the damage, and whether the damage occurs in mitochondrial or nuclear DNA. These mechanisms have been reviewed extensively (1,2). Recently, considerable attention has focused on pathways for repairing SSBs and DSBs, mediated by the ADP-ribosylating enzyme known as poly (ADP-ribose) polymerase 1, or PARP-1.
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