Expanding the Drug Development Toolkit with Proteomics

On this episode of Translating Proteomics, host Parag Mallick speaks with special guests doctors Ben Neely and Ben Orsburn, leaders in the proteomics community and hosts of “The Proteomics Show” podcast. Their insightful conversation focuses on the role of communication in proteomics and covers:·      Impactful things they’ve learned while hosting The Proteomics Show·      How their communication efforts have changed their research·      Barriers to proteomics becoming more popular in the life sciences and in the broader publicChapters:00:00 – 03:04 – Intro03:04 – 07:23 – Why the Bens created "The Proteomics Show"07:23 – 10:42 – Ways the proteomics show has impacted the Bens’ research10:42 – 16:44 – Every scientist is interesting!16:44 – 20:36 – Ways the Bens' communication efforts have changed their research20:36 – 25:08 – Trends in proteomics25:08 – 35:34 – Barriers to communication between the proteomics community and others in the life science34:34-48:34 - Barriers to communication between the proteomics community and the broader public48:34 - End - OutroResourcesThe Proteomics Show - Ben Neely and Ben Orsburn host this podcast sponsored by the Human Proteomics Organization. On it, they interview proteomics researchers in a “fireside chat” format. Their conversations cover not just the latest research, but also their guests’ motivations, hobbies, and histories. Definitely check it out!News in Proteomics Research - Ben Orsburn's blog on the latest developments in proteomics.Proteomics, the next truly massive investment opportunity - Forbes article on the potential of proteomics.The Magic School Bus Rides Again - Recently rebooted version of The Magic School Bus. Will we see an episode featuring proteomics?

On this episode of Translating Proteomics, hosts Parag Mallick and Andreas Huhmer discuss the many ways proteomics can impact our interactions with food. Some of the topics they touch upon in this wide-ranging conversation include:·      Proteomics and food quality·      Proteomics and food safety·      Developing new kinds of food with proteomicsChapters00:00 – 01:23 – Introduction01:23 – 03:27 – Proteomics and alcohol fermentation03:27 – 05:24 – Food properties and their relationship with molecular composition05:24 – 07: 42 – How can we use proteoforms to improve food quality?07:42 – 11:49 – Proteomics to aid plant and animal breeding11:49 – 14:35 – Proteomics, Food Safety, and Food Security14:35 – 17:05 – Proteomics and food authenticity17:05 – 20:36 – Proteomics and terroir20:36 – 22:48 – Proteomics, the microbiome, and health22:48 – 24:29 – A fun party trick24:29 – 30:24 – Creating new foods and flavors30:24 – 34:33 – Designing food for space34:33 – End – OutroResourcesThe post-translational modification landscape of commercial beers (Kerr et al. 2021)·      Paper looking at the ways post-translational modification differ between different beers and how protein content relates to the properties of foamHeat shock and structural proteins associated with meat tenderness in Nellore beef cattle, a Bos indicus breed (Carvalho et al. 2024)·      Paper looking at the relationship between proteins and meat tendernessComprehensive proteome analysis of bread dicphering the allergenic potential of bread wheat, spelt and rye (Zimmermann et al. 2021)·      Research measuring the levels of allergens in different kinds of breadDifferential proteomic analysis by SWATH-MS unravels the most dominant mechanisms underlying yeast adaptation to non-optimal temperatures under anaerobic conditions·      Study using proteomics to reveal how yeast adapt to growth at different temperatures

On this episode of Translating Proteomics, co-hosts Parag Mallick and Andreas Huhmer of Nautilus Biotechnology discuss the reproducibility crisis in biology and specifically focus on how we can enhance reproducibility in computational proteomics. Key topics they cover include:•               What the reproducibility crisis is•               Factors that make it difficult to replicate multiomics research•               Steps we can take to make biology research more reproducibleChapters 00:00 – 01:20 – Introduction01:20– 03:10 – What is reproducibility in research and why is it important?03:10 – 05:42 – Recent work from the Mallick Lab focused on computational proteomics reproducibility05:42 – 09:32 – Ways to help improve reproducibility in computational proteomics – More detailed documentation, moving beyond papers as our main form of documentation, and ensuring computational workflows are available,09:32 – 11:30 – Why Parag got interested reproducibility – Attempts to build AI layers on top of current workflows11:30 – 14:00 – The need to create repositories of analytical workflows codified in a structured way that AI can learn from14:00 – 15:24 – A role for dedicated data curators15:24 – 18:31 – Moving beyond the idea of study endpoints and recognizing data as part of a larger whole18:31 – 21:32 – How does AI fit into the continuous analysis and incorporation of new datasets21:32 – 23:36 – The role of AI in helping researchers design experiments23:36 – 27:25 – Three things we can do today to increase the reproducibility of computational proteomics experiments:·      Be clear about the stated hypothesis·      Document analyses through workflow engines and containerized workflows·      Advocate for support for funding for reproducibility and reproducibility tools27:25 – End – OutroResourcesParag’s Gilbert S. Omenn Computational Proteomics Award Lectureo   In this lecture, Parag describes his vision for a more reproducible future in proteomicsNature Special on “Challenges in irreproducible research”o   A list of articles and perspective pieces discussing the “reproducibility crisis” in researchWhy Most Published Research Findings Are False (Ioannidis 2005)o   Article outlining many of the issues that make it difficult to reproduce research findingsReproducibility Project: Cancer Biologyo   eLife initiative investigating reproducibility in preclinical cancer researchCenter for Open Science Preregistration Initiativeo   Resources for preregistering a hypothesis as part of a studyNational Institute of Standards and Technology (NIST)o   US government agency that aims to...

On this episode of Translating Proteomics, co-hosts Parag Mallick and Andreas Huhmer of Nautilus Biotechnology discuss how clinical researchers can leverage proteomics for drug development. Some of the themes covered in this episode include:·      Proteomics and pre-clinical models·      How proteomics can drive patient selection·      Choosing the right end points in clinical trialsChapters00:00 – 01:06 – Introduction01:06 – 06:51 – Proteomics in pre-clinical studies06:51 – 11:40 – The importance of choosing the right model for preclinical work11:40 – 17:10 – How proteomics is used in Phase I/II clinical trials17:10 – 19:29 – Proteomics tools in patient selection19:29 – 24:33 – Useful information that we get from proteomics that we can’t get from genomics or transcriptomics24:33 – 28:14 – Proteomics in Phase III clinical trials and picking the best indications of drug efficacy28:14 – 29:19 - Understanding why clinical trials fail29:19 – End - Outro ResourcesThe National Cancer Institute’s webpage covering how clinical trials workPreprint on the miBrain model - An example of a new in vitro brain modelGeary et al., 2021 - Discovery and Evaluation of Protein Biomarkers as a Signature of Wellness in Late-Stage Cancer Patients in Early Phase Clinical TrialsWasko et al., 2024 - Tumour-selective activity of RAS-GTP inhibition in pancreatic cancerThe NCI-MATCH trail: Lessons for precision oncology – Report on a large-scale trial using genomic biomarkers to match cancer patients to treatmentsTumour-selective activity of RAS-GTP inhibition in pancreatic cancer – Study using proteomics to understand mechanisms of resistance to a cancer drug

On this special, year-end episode of Translating Proteomics, hosts Parag Mallick and Andreas Huhmer discuss three of their favorite proteomics publications from 2024. They'll cover one paper in each of the following topic areas:Proteomics in pre-clinical researchProteomics in basic researchTechnology development in proteomicsSynopses of each of the papers can be found below and you can find many more insights in the podcast.Decrypting the molecular basis of cellular drug phenotypes by dose-resolved expression proteomicsIn&nbsp;this work&nbsp;from&nbsp;Professor Bernhard Kuster’s Lab&nbsp;at the Technical University of Munich, researchers assess protein abundance changes that result from treating Jurkat acute T cell leukemia cells with 144 drugs over five drug doses. The researchers use their proteomic data to generate millions of dose response curves for the thousands of proteins measured and discover that the drugs impact many more proteins and pathways than those identified as drug targets. In addition, they checked how 7 of the drug treatments impacted the transcriptome and found there was often discordance between impacts at the mRNA level and the protein level. This works highlights the many ways drugs can impact biological systems and suggests that similar studies will help researchers understand the effects of drug treatments and may even aid in the development of more effective or more specific therapies.Find the publication here.Natural proteome diversity links aneuploidy tolerance to protein turnoverAs we discussed on a&nbsp;previous episode of Translating Proteomics, genome alterations often fail to faithfully propagate to the proteome. In&nbsp;this work, researchers from the labs of&nbsp;Professor Judith Berman&nbsp;at Tel Aviv University and&nbsp;Professor Markus Ralser&nbsp;at the Charité - Universitätsmedizin Berlin, investigate the means through which yeast strains adapt to chromosome gains or losses (aneuploidy). They assess the concordance between changes in mRNA and protein expression in aneuploid yeast that were either found in nature or generated in the lab. The researchers observed dosage compensation, a tendency to return to expression levels associated with normal chromosome numbers, for both mRNAs and proteins expressed on aneuploid chromosomes. However, dosage compensation was much stronger at the protein level than the mRNA level and even stronger at the protein level in naturally aneuploid strains compared to lab-generated strains. This work suggests that multiomics efforts are necessary to determine the effects of genomic alterations. In addition, the authors find that protein degradation, as observed through increased ubiquitination, increased turnover of proteins encoded in aneuploid chromosomes, and the up regulation of the proteasome complex, is a key means of dosage compensation. Finally, because the naturally aneuploid strains achieved a higher level of dosage compensation than the lab-generated strains, the authors suggest there has been selection for natural aneuploid strains that down-regulate proteins causing detrimental effects.<a...

Parag Mallick discusses the role of AI and machine learning in biotech with special guests Vijay Pande from Andreessen Horowitz and Matt McIlwain from Madrona Venture Group. Their fascinating conversation covers:Advances that have enabled biotech to make use of AI and machine learningHow founders are applying AI and machine learning in biotechThe future of AI and machine learning in biotechChapters00:00 - Introduction04:37 - How did Vijay and Matt get into AI and ML07:33 - The importance of structured data, advances in compute, and algorithmic advances in driving the boom in machine learning18:44 - The Intersection of AI and biology21:57 - The evolution of biological models31:55 - The Complexity of biological data39:42 - Ways founders and biotech startups are using AI43:25 - Favorite/Impactful applications of AI/ML47:00 - AI for experimental design50:13 - The future of AI in bio/healthResourcesLearn more about Matt McIlwainLearn more about Vijay PandeFolding at HomeLearn about various&nbsp;types of machine learning&nbsp;on IBM's websiteLearn about&nbsp;autoencoders&nbsp;on IBM's websiteLearn more about&nbsp;transformers&nbsp;on NVIDIA's blogTranslating Proteomics Episode 6 - The Future of AI in Biomedicine

Do you have a question you'd like answered on a future episode of Translating Proteomics? Send it to [email protected]!On this episode of Translating Proteomics, host Andreas Huhmer discusses advances in Alzheimer’s research with special guest and Curie Bio Drug Maker in Residence, Sarah DeVos Ph.D. Their conversation focuses on:The impact of molecular diagnostics on Alzheimer’s researchRecent Alzheimer’s drug approvalsThe future of Alzheimer’s research*Small edit on Sarah's background - She did her graduate work at Washington University in St. Louis and a Postdoc at Massachusetts General Hospital*Chapters00:00 – Introduction01:54 –&nbsp;Why Sarah began studying Alzheimer’s03:39 – Current tools and needs for future Alzheimer’s diagnostics09:52 – Recent drug approvals in the Alzheimer’s space and their relationship to diagnostics14:26 – Is it possible to develop biomarkers that detect Alzheimer’s at its earliest stages?16:36 – What is limiting the development of new Alzheimer’s biomarkers?17:51 – The DIAN trials and learnings from studying dominantly inherited Alzheimer’s19:33 – The genetics of Alzheimer’s22:19 – Novel approaches to identifying and understanding Alzheimer’s pathology&nbsp;25:54 – Where can proteomics advance Alzheimer’s research?31:25 – The role of proteomics in Alzheimer’s animal models34:33 – Sarah’s hopes for the next 10 years of Alzheimer’s research41:39 - OutroResourcesDominant Inherited Alzheimer’s Network (DIAN) trials research updateso&nbsp;&nbsp;&nbsp;In the DIAN trials, researchers work with families to study various clinical and basic science aspects of dominantly inherited Alzheimer’s disease.Amyloid plaque reducing clinical trials:o&nbsp;&nbsp;&nbsp;Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer's Disease (Haeberlein et al. 2022)o&nbsp;&nbsp;&nbsp;Donanemab in Early Symptomatic Alzheimer Disease - The TRAILBLAZER-ALZ 2 Randomized Clinical Trial (Sims et al. 2023)o&nbsp;&nbsp;&nbsp;Lecanemab in Early Alzheimer’s Disease (Van Duck et al. 2022)Blood Biomarkers to Detect Alzheimer Disease in Primary Care and Secondary Car (Palmqvist et al. 2024)o&nbsp;&nbsp;&nbsp;Clinical research into a new phospo-tau biomarker that can help physicians more effectively diagnose Alzheimer’s diseaseResurrecting the Mysteries of Big Tau (Fischer and Baas 2021)o&nbsp;&nbsp;&nbsp;Review covering a potentially neuro-protective form of tau called “Big tau”Integrated Proteomics to Understand the Role of Neuritin (NRN1) as a Mediator of Cognitive Resilience...

Do you have a question you'd like answered on a future episode of Translating Proteomics? Send it to [email protected]!On this episode of Translating Proteomics, hosts Parag Mallick and Andreas Huhmer of Nautilus Biotechnology discuss the challenges and opportunities of plasma proteomics. Their conversation focuses on:·&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Why blood plasma may be a good source of protein biomarkers·&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Current methodologies and pitfalls in plasma proteomics·&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The path forward for plasma proteomicsWhat is Plasma Proteomics?For those who are new to this topic,&nbsp;plasma&nbsp;is the liquid portion of the blood distinct from fractions containing red and white blood cells. Given the relatively non-invasive ways physicians can collect patient plasma, and the blood’s intimate association with tissues throughout the body, plasma is potentially an excellent source of&nbsp;protein biomarkers. Yet, it is quite difficult to measure the levels of all plasma proteins because their concentrations span over&nbsp;12 orders of magnitude. This episode features an in-depth discussion of the ways plasma proteomics efforts have and have not lived up to the promise of biomarker discovery and what we can do to advance plasma biomarker discovery efforts in the future.Chapters00:00 – 01:01 – Intro01:02 – 4:55 – What is the promise of plasma proteomics?04:55&nbsp;&nbsp;– 07:23 – Is the plasma proteome really the best source of biomarkers?07:23 – 10:16 – How do proteins get into the blood and what are the implications for biomarker discovery?10:16 – 13:59 – Is it clear that proteins are the best candidates for blood biomarkers?13:59 – 19:57 – Advances in and the future of comprehensive plasma proteomics19:57 – 22:31 – Pros and cons of fractionating the plasma proteome to discover biomarkers22:31 – 28:14 – Progress in identifying multiomic plasma biomarkers and the path forward28:14 – End – OutroResourcesNano-omics: nanotechnology-based multidimensional harvesting of the blood-circulating cancerome (Gardner et al. 2022)o&nbsp;&nbsp;&nbsp;Review from focused on the development multiomics liquid biopsiesMulticompartment modeling of protein shedding kinetics during vascularized tumor growth&nbsp;(Machiraju et al. 2020)o&nbsp;&nbsp;&nbsp;Work from Parag’s Lab investigating tumor protein sheddingSimulation of the Protein-Shedding Kinetics of a Fully Vascularized Tumor&nbsp;(Frieboes et al. 2015)o&nbsp;&nbsp;&nbsp;Tumor protein shedding work from Parag’s LabMathematical model identifies blood biomarker-based early cancer detection strategies and limitations (Hori and Gambhir et al. 2011)o&nbsp;&nbsp;&nbsp;Study modeling how much protein could be shed and detected from different size tumors<a href="https://pubmed.ncbi.nlm.nih.gov/12488461/" rel="noopener noreferrer"...

Do you have a question you'd like answered on a future episode of Translating Proteomics? Send it to [email protected]!Proteins adopt a wide variety of functions depending upon factors like their location in the cell, their modifications, and the biomolecules they interact with. While many of us may have been taught that single genes produce single proteins that have single functions, protein function is far more dynamic than that. In this episode of Translating Proteomics, Nautilus Co-Founder and Chief Scientist Parag Mallick sits down with University of Cambridge Professor and proteomics expert Kathryn Lilley to discuss our evolving understanding of protein function. They cover:How they came to realize protein function is more complex than one gene, one enzyme, one functionFactors that give rise to the dynamic complexity of protein function including proteoforms, protein localization, and moonlightingSteps we can take to better understand and teach others about the complexities of protein functionResearch diving into the complexities of protein functionResearch from the Beltrao Lab using bioinformatics techniques to identify functional phosphosites (Ochoa et al. 2020)Work from the Lilley Lab integrating techniques to investigate ome-wide localization of both&nbsp;RNA and protein (Villanueva et al. 2024)Lilley Lab preprint investigated protein localization changes in a cancer cell line as a result of ionizing radiation treatment (Christopher et al. 2024).Collaborative work with the Lundberg Lab mapping subcellular proteomics (Thul et al. 2017).Additional protein function resourcesMoonProt&nbsp;- A database for moonlight proteins from Professor Constance Jeffrey's LabTranslating Proteomics Episode 5 - Why the Biology Surrounding Biology's Central Dogma is Wrong

Do you have a question you'd like answered on a future episode of Translating Proteomics? Send it to [email protected]!In our Translating Proteomics episode titled "Harnessing Proteoforms to Understand Life's Complexity", Parag and Andreas discussed why&nbsp;proteoforms&nbsp;are important in a theoretical sense. In this episode, Parag sits down with Northwestern University Professor and proteoform pioneer,&nbsp;Neil Kelleher&nbsp;to dive deep into the biology of proteoforms. They cover:What proteoforms areExamples of the importance of proteoformsThe scale of and technological advances needed to meet the challenges of proteoform biology.Some examples of the power of proteoforms covered in this episodeRecent work from Neil's lab showing blood proteoforms can help predict liver transplant success (Melani et al. 2022).Work form Ying Ge's lab showing changes in troponin proteoforms correlate with varying degrees of heart disease (Zhang et al. 2011).The&nbsp;BioTyper&nbsp;- a mass spectrometry-based device that can identify different kinds of microbes.Additional proteoform resourcesThe Human Proteoform Atlas webpagePublication describing The Human Proteoform Atlas (Hollas et al. 2022)Publication discussing how many human proteoforms there are (Aebersold et al. 2018)Animation - Proteoform Analysis on the Nautilus Proteome Analysis Platform