Translating Proteomics

Unlike “globular” proteins that adopt stable structures that are relatively easy to analyze, intrinsically disordered proteins adopt many context-dependent shapes. These shapes may drive diverse functions, but they are also difficult to capture and study. This represents a large gap in our understanding of biology, given that most proteins may have intrinsically disordered regions. Thankfully, researchers like Professor Priyanka Joshi, Ph.D., from Georgetown University have devoted themselves to studying intrinsically disordered proteins and are developing new approaches and leveraging new technologies like the Nautilus Voyager™ Platform to discover how their dynamic structures influence biological function. Because intrinsically disordered proteins often aggregate in disease, this work is not only essential to our understanding of biology but may also enable the development of effective biomarkers and treatments for diseases like Alzheimer’s.

Parag interviews Professor Joshi on this episode of Translating Proteomics to discover:

• What intrinsically disordered proteins are
• How intrinsically disordered proteins influence biology and why they’re hard to study
• How the recently announced SEEDS Consortium is studying intrinsically disordered proteins

Chapters:

00:00 – Introduction to Prof. Priyanka Joshi, Ph.D.

04:35 – What are intrinsically disordered proteins (IDPs)?

11:41 – When do intrinsically disordered proteins go bad in disease?

23:02 – Archetypal Intrinsically disordered proteins – c-Myc/Max, p53, and Tau

38:26 – Barriers to solving the problems associated with intrinsically disordered proteins

43:30 – The future of intrinsically disordered protein research and introducing the SEEDS Consortium

Additional resources featured in the episode:

https://pubmed.ncbi.nlm.nih.gov/26923286/

Joshi, Priyanka et al. “A Fragment-Based Method of Creating Small-Molecule Libraries to Target the Aggregation of Intrinsically Disordered Proteins.” ACS combinatorial science vol. 18,3 (2016): 144-53. doi:10.1021/acscombsci.5b00129

Priyanka’s 2016 work developing small-molecule libraries to target IDPs

https://www.georgetown.edu/news/georgetown-and-buck-institute-awarded-up-to-51-7m-to-predict-protein-changes-linked-to-alzheimers-and-some-cancers/

Georgetown University press release covering the SEEDS Consortium

https://investors.nautilus.bio/news-releases/news-release-details/nautilus-measure-proteoforms-driving-alzheimers-disease-and

Nautilus Biotechnology press release covering its involvement in the SEEDS Consortium

Professor Brendan Keating’s lab focuses on “advancing the field of organ transplantation” and employs multiomic techniques to improve outcomes for both allo- (human to human) and xeno- (animal to human) transplantation. He’s using multiomics to better understand the mechanisms of rejection and acceptance with a particular focus on immunologic barriers in cross-species transplantation. Professor Keating joins Translating Proteomics to discuss:

• The current state of transplant medicine including xenotransplantation
• How multiomics is changing transplant medicine
• The future of transplant medicine.

Chapters:

00:00 – Introduction

05:00 - Transplantation Today: Outcomes, Challenges, and the Organ Shortage

10:06 - From Genetics to Multiomics

19:53 - Xenotransplantation deep dive

30:42 - Ten‑Year Vision: Transplants and the Role of Multiomics

Translating Proteomics hosts Parag Mallick and Andreas Huhmer discuss our new Nature Methods paper, “Large-scale single-molecule analysis of tau proteoforms.” This publication describes how the Nautilus Voyager™ Platform can be used to quantify proteoforms derived from the neurodegeneration-associated tau protein. These proteoforms are defined by their unique combinations of post-translational modifications and isoform specific sequences. They may make powerful next-generation biomarkers or drug targets, but few technologies can measure them today.

In the episode, Parag and Andreas discuss:

• What proteoforms are and why it’s critical to study them to understand biology.
• How the Nautilus Voyager™ Platform quantifies proteoforms.
• The key findings from the tau proteoform analyses in the paper.
• Potential applications of these findings.
• The Nautilus Voyager™ Platform as a powerful foundational technology.

Access our video series exploring the paper in more detail.

On the latest episode of the Translating Proteomics podcast, Nautilus VP of Scientific Engagement and proteomics industry expert Sheri Wilcox joins hosts Parag Mallick and Andreas Huhmer for a thought-provoking discussion of their proteomics "hot takes.”

Each “hot take” is a provocative opinion on a topic in proteomics. Specifically, they cover:

• Insufficient biological validation is one of the biggest problems in proteomics.
• Antibody validation remains a distributed, inconsistent, lab-by-lab responsibility, and this model for validation may not be sustainable going forward.
• AI cell models are overhyped.

Check out the episode for deep explorations of each of these hot takes and their potential remedies.

After listening, be sure to let us know whether you agree, disagree, or have your own hot take to share!

Professor Olga Vitek has a deep understanding of statistics, machine learning, and computational biology. She puts her know-how to work to develop computational tools enabling high-quality proteomic analysis and systems biology approaches. She hopes to apply these tools to the quantitative analysis of large-scale mass spectrometry-based investigations and thereby advance our understanding of organismal function. In this episode, Parag and Professor Vitek discuss:

• Why statistics is important for experimental design
• How statistics and AI can help researchers understand biology
• Gaps keeping us from using AI and statistics to their maximum potential in biology

Resources

Statistical methods for studies of biomolecular systems website

• Olga’s personal lab website

Beyond protein lists: AI-assisted interpretation of proteomic investigations in the context of evolving scientific knowledge

• Gyori and Vitek, 2024 discuss how AI can be used to interpret proteomics data and its biological meaning.

A Bayesian Active Learning Experimental Design for Inferring Signaling Networks

• Ness et al., 2018 show how statistical methods can guide the selection of experiments that optimally enhance understanding

Host Parag Mallick chats with Professor Afshin Beheshti who is a Professor of Surgery, Director of the Center for Space Biomedicine, and Associate Director of the McGowan Institute for Regenerative Medicine at the University of Pittsburgh. In addition, Professor Beheshti has a visiting researcher appointment at the Broad Institute of MIT and Harvard and is president of two non-profits – the COVID-19 International Research Team and Kwaai. The latter aims to democratize access to artificial intelligence through the design, construction, and maintenance of a free personal AI called Kwaai.

Professor Beheshti’s research covers a range of topics focused on how circulating mirco RNAs and mitochondria impact health, but this conversation focuses primarily on Professor Beheshti’s work advancing our understanding of how spaceflight impacts biology. We cover:

• How research on spaceflight and biology is done
• Gaps that remain in our understanding of spaceflight and biology
• Omics studies of spaceflight and biology
• How studying spaceflight and biology enhances our understanding of human health more broadly

Resources

Trivedi Institute for Space and Global Biomedicine

• New Institute at the University of Pittsburgh focused on “advancing human health through space-driven innovation”

NASA Open Science Data Repository

• "Provides open access to biological and physical science datasets from spaceflight and ground studies, enabling data reuse for discovery and innovation."

Camera et al., 2024. Agining and putative frailty biomarkers are altered by spaceflight

• Study on molecular biomarkers and frailty phenotypes in space

Overbey et al., 2024. The Space Omics and Medical Atlas (SOMA) and international astronaut biobank

• An “integrated data and sample repository for clinical, cellular, and multi-omic research profiles” from a variety of space missions
• Space Omics and Medical Atlas (SOMA) website

Corti et al., 2024. To boldly go where no microRNAs have gone before: spaceflight impact on risk for small-for-gestational-age infants

• Explores how miRNA signatures of “small-for-gestational-age” are impacted by the space environment

Beheshti et al., 2013. Age and space irradiation modulate tumor progression: implications for carcinogenesis risk

• Some of Professor Beheshti’s early work studying connections between spaceflight and cancer progression.

Kwaai

• Nonprofit "building a no-cost open source Personal AI assistant"

On this episode of Translating Proteomics, Parag and Andreas share their reflections on proteomics developments in 2025 largely inspired by their observations at the World HUPO 2025 conference in Toronto. Whether you agree, disagree, or simply want to share some of your own observations on proteomics, please post your thoughts in the comments.

We look forward to even more exciting developments in 2026!

Chapters

00:00 - 00:35 – Intro

00:36 – 07:00 - Increased focus on applications of proteomics and less on method development

Learn more about One Health from our conversation with Professor Jennifer Geddes-McAlister

https://youtu.be/JFwvTdkb5bw

07:01 – 12:47 - Increase in people talking about the importance of proteoforms

Learn more about proteoforms in our episode featuring proteoform pioneer Professor Neil Kelleher

https://youtu.be/3pPuxVrMxpw

12:47 – 17:26 - An increase in multiomics studies

17:27 – 20:03 - A shift to larger scale proteomics studies

For a great example of a multi-platform comparison study, check out Kirsher et al., 2025

https://www.nature.com/articles/s42004-025-01665-1

20:03 – 25:07 - Increased integration of AI into proteomics workflows

For an example of how proteomics workflows can be modified with multiomic data, check out Suhre et al., 2025

https://www.nature.com/articles/s41588-025-02413-w

25:08 – 30:05 – Recognition of the need to assess quality across proteomics workflows

30:06 – 32:19 – Less of a focus on spatial proteomics this year than in past years

32:20 – 35: 13 - Parag and Andreas share their predictions for 2026

35:14 – End – Outro

On this episode of Translating Proteomics, Parag speaks with Professor Jennifer Geddes-McAlister from the University of Guelph. Professor Geddes-McAlister is an expert at using proteomics to study host-microbe interactions from a systems biology perspective. Her exciting work spans studies of pathogenic fungi all the way to engineering plants to produce pharmaceutics (so-called “molecular pharming"). On top of all that, Professor Geddes-McAlister also founded “Moms in Proteomics” to support and encourage an intentional focus on the inherently unique physical, emotional, and biological commitments of Mothers, and the ensuing balance required to excel within the diverse STEM fields encompassing Mass-Spectrometry-based proteomics.

Dive into this episode to:

• Learn why it’s critical to study hosts, pathogens, and molecular pharming from a systems point of view
• Discover what Professor Geddes-McAlister is excited about for the upcoming Human Proteome Organization (HUPO) conference
• Find out what “Moms in Proteomics” has planned for HUPO

Chapters

00:00 - Intro

01:39 - Professor Geddes-McAlister's initial interest in host-microbe interactions

06:13 - Why it's important to study host-microbe interactions

08:10 - Pathogens vs helpful microbes

10:06 - Thinking about microbes through the lens of "One Health"

14:34 - Why Professor Geddes-McAlister works primarily in proteomics as opposed to other omes

19:44 - Professor Geddes-McAlister's favorite thing that she's learned from the proteome and couldn't learn from the other omes

24:56 - Molecular pharming

29:35 - The need for accessibility in proteomics

34:09 - The need for all-in-one workflows in proteomics

36:08 - HUPO 2025

39:56 - Moms in Proteomics

42:36 - The future of proteomics

43:59 - Outro

Resources

Geddes et al., 2015. Secretome profiling of Cryptococcus neoformans reveals regulation of a subset of virulence-associated proteins and potential biomarkers by protein kinase A

https://pubmed.ncbi.nlm.nih.gov/26453029/

Some of Professor Geddes-McAlister’s early work using proteomics to study pathogenic fungi

Prudhomme et al., 2024. Bacterial growth-mediated systems remodelling of Nicotiana benthamiana defines unique signatures of target protein production in molecular pharming

https://onlinelibrary.wiley.com/doi/10.1111/pbi.14342

Researchers from Professor Geddes-McAlister’s lab use multiomic techniques to discover factors impacting the production of a pharmaceutical in an engineered plant

Woods et al., 2023. A One Health approach to overcoming fungal disease and antifungal resistance

https://wires.onlinelibrary.wiley.com/doi/full/10.1002/wsbm.1610

Review on the importance of incorporating “One Health” principals into efforts to fight pathogenic fungi

Moms in Proteomics website

https://momsinproteomics.ca

Learn all about the Moms in Proteomics initiative and its international community

On this episode of Translating Proteomics, Parag, Andreas, and special guest Don Kirkpatrick answer questions submitted by the Translating Proteomics community. They cover:

• Needs in plasma proteomics
• How proteomics impacts drug development – with special guest Don Kirkpatrick, Ph.D.!
• How lifestyle impacts the proteome
• How the Nautilus Proteome Analysis Platform is impacting tau and Alzheimer’s disease research

References

Shome et al., 2022 - Serum autoantibodyome reveals that healthy individuals share common autoantibodies

https://www.sciencedirect.com/science/article/pii/S2211124722006489

LaBaer Lab paper investigating autoantibody levels in plasma and their relationship to health.

Sylman et al., 2018 - A Temporal Examination of Platelet Counts as a Predictor of Prognosis in Lung, Prostate, and Colon Cancer Patients

https://www.nature.com/articles/s41598-018-25019-1

Mallick lab paper investigating temporal changes in platelets and their associations with cancer biology.

Krönke et al., 2014 - Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells

https://www.science.org/doi/10.1126/science.1244851

Seminal paper describing selective protein degradation caused by lenalidomide.

Fink and Ebert 2015 - The novel mechanism of lenalidomide activity

https://ashpublications.org/blood/article/126/21/2366/34644/The-novel-mechanism-of-lenalidomide-activity

Review of research elucidating the mechanisms of lenalidomide activity

Ndoja et al., 2025 - COP1 Deficiency in BRAFV600E Melanomas Confers Resistance to Inhibitors of the MAPK Pathway

https://www.mdpi.com/2073-4409/14/13/975

Describe links between kinase inhibitor vemurafenib and changes in ETV transcription factor degradation

Song et al., 2022 - RTK-Dependent Inducible Degradation of Mutant PI3Kα Drives GDC-0077 (Inavolisib) Efficacy

https://aacrjournals.org/cancerdiscovery/article/12/1/204/675622/RTK-Dependent-Inducible-Degradation-of-Mutant-PI3K

Use proteomics to discover that inavolisib acts through selective degradation of mutant PI3Kα

Canon et al., 2019 - The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity

https://www.nature.com/articles/s41586-019-1694-1

Covers the development of an inhibitor of KRAS mutant KRAS (G12C).

Schneider et al., 2024 - Feeding gut microbes to nourish the brain: unravelling the diet-microbiota-gut-brain axis

https://www.nature.com/articles/s42255-024-01108-6

Review on the gut-brain axis

Webpage for Johanna Lampe’s Lab at Fred Hutch Cancer Center

https://www.fredhutch.org/en/faculty-lab-directory/lampe-johanna.html

Guseh et al., 2020 - An expanded repertoire of intensity-dependent exercise-responsive plasma proteins tied to loci of human disease risk

https://www.nature.com/articles/s41598-020-67669-0

Work investigating the relationship between exercise, the plasma proteome, and health

Human Proteome Organization (HUPO) webpage with resources focused on proteomics in space

https://hupo.org/Human-Proteomics-at-Extreme-Conditions

Joly et al., 2025 - Large-scale single-molecule analysis of tau proteoforms

https://doi.org/10.1101/2025.06.26.660445

Nautilus preprint using Iterative Mapping of proteoforms to measure tau proteoforms in Alzheimer’s disease and related dementias samples.

On this episode of Translating Proteomics, host Parag Mallick discusses spatial proteomics with special guest Fiona Ginty Ph.D. Fiona is a Senior Principal Scientist in Precision Diagnostics at the GE Healthcare Technology & Innovation Center. She is a leader in the development of spatial proteomics technologies and their application in precision diagnostics and medicine.

Their discussion covers:

· How Fiona began working in spatial proteomics

· Why spatial biology is important

· What the future holds for spatial biology

Chapters:

00:00 – Introduction

01:54 – Fiona’s journey to biology

05:26 – Fiona’s transition to tool development

07:20 – Working at GE Research

11:26 – Identifying the importance of spatial biology

14:43 – How Cell DIVETM works

18:25 – The importance of single cell

23:01 - When Fiona realized the technology worked

28:04 – Spatial biology projects Fiona is excited about

30:08 – Fiona’s role in HuBMAP

36:50 – Learnings from HuBMAP so far

38:35 – The future of spatial proteomics in the clinic

46:56 – Current limits on spatial proteomics

49:56 – Current and future uses of AI in spatial proteomics

53:30 – The most exciting thing Fiona learned in her spatial proteomics journey

56:08 – Outro

Resources:

Method of the Year 2024: Spatial Proteomics

Paper covering the spatial proteomics technology Fiona worked on at GE Healthcare

• Highly multiplexed single-cell analysis of formalin-fixed, paraffin-embedded cancer tissue

HubMAP – Human BioMolecular Atlas Program

Human Tumor Atlas Network

Cell DIVE Multiplex Imaging Solution

Papers discussing what makes colorectal cancer cells undergo apoptosis in response to chemotherapy

• An atlas of inter- and intra-tumor heterogeneity of apoptosis competency in colorectal cancer tissue at single-cell resolution
• Integrated multiplex analysis of cell death regulators in stage II colorectal cancer suggests patients with ‘persister’ cell profiles fail to benefit from adjuvant chemotherapy

Paper discussing how the distance between tumor cells and cytotoxic t-cells correlates to caspase level

• Spatial effects of infiltrating T cells on neighbouring cancer cells and prognosis in stage III CRC patients - Azimi - 2024 - The Journal of Pathology - Wiley Online Library

Paper showing it takes 3 hits from cytotoxic t-cells to kill cancer cells

• Cytotoxic T cells are able to efficiently eliminate cancer cells by additive cytotoxicity | Nature Communications

Paper focused on generating new pathology image patches using AI

• Predicting Breast Cancer Events in Ductal Carcinoma In Situ (DCIS) Using Generative Adversarial Network Augmented Deep Learning Model - PubMed

Acknowledgements

Dr. Ginty wanted to acknowledge the many people she’s worked with on Cell DIVE and as part of HuBMAP. She stresses that these are highly collaborative projects, and just some of the many great team members she's worked with are listed below.

Cell DIVE:

Anup Sood, Sean Dinn, Yunxia Sui, Sanghee Cho, John Graf , Kathleen Bove, Musodiq Bello, Sudeshna Adak, Michael Lazare, Anirban Bhaduri, Thomas Treynor, Dileep Vangasseri, Alberto Santamaria-Pang, Maureen Bresnahan, Micheal Gerdes, Megan Rothman, Colin McCullough, Chris Sevinsky, Liz McDonough, Christine Surrette, Max Seel, Alex Corwin, Bob Filkins, Kevin Kenny, Brion Sarachan, Mike Montalto, Christoph Hergersberg, John Burczak, Jens Rittscher, Steve Zingelewicz, Dr. Sunil Badve (Emory U), Dr. Yesim Gokmen Polar (Emory U), Eli Lilly collaborators

HuBMAP:

Lou Falo (U. Pitt), Arivarasan Karunamurthy (U. Pitt), John Hickey (Duke), Chenchen Zhu (Stanford), Ioannis Vlachos (BIDMC), Liz McDonough (GE HealthCare Technology and Innovation Center [HTIC]), Sammi Abate (GE HealthCare Technology and Innovation Center [HTIC]), Soumya Ghose (GE HealthCare Technology and Innovation Center [HTIC]), Christine Surrette (GE HealthCare Technology and Innovation Center [HTIC]), Dr. Katy Borner (Indiana U)

On this special episode of Translating Proteomics, Parag and Andreas break down the basics of proteomics — perfect for anyone with a background in molecular biology looking to get started in the field.

Seasoned experts: We hope you can share this episode as a teaching tool or to inspire others to explore proteomics.

Parag and Andreas cover the following questions in the episode, and links to additional Nautilus resources can be found below each question.

What is proteomics?

• Blog post – What is proteomics? Techniques, applications, and methods

What are key questions proteomics can answer?

• Blog category – Applications of proteomics

Why is it important to measure the proteome?

• FAQ on the Nautilus Resources page
• Blog post – Genomics vs. proteomics: Two complementary perspectives on life

What can and can't you do with proteomics?

• Translating Proteomics episode – Plasma Proteomics: The Dream and the Nightmare
• Learn how the Nautilus Platform is designed to enable comprehensive broadscale proteomics and targeted proteoform studies

What are key proteomics methods and techniques?

• Blog series – Traditional protein analysis methods
• Blog series – Next-generation proteomics technologies

What are the major pitfalls when doing proteomics?

What are the challenges in proteomic data analysis?

• Translating Proteomics episode – Biology in Space and Time
• Blog post – What is multiomics?

What are people excited about in proteomics?

• Translating Proteomics episode – Poised for a Proteomics Breakthrough
• Translating Proteomics episode - US HUPO 2025 – Key Takeaways, Trends, and Future Directions for Proteomics
• Translating Proteomics episode – Protein Function 201 with Kathryn Lilley
• Blog post – What is single-molecule proteomics?

If you listened to our episode focused on science communication featuring proteomics leaders Ben Orsburn Ph.D. and Ben Neely Ph.D., then you've already heard about their excellent podcast, The Proteomics Show. On The Proteomics Show, they interview researchers in the proteomics community to learn about their motivations, their backstories, and their work. Today, we're sharing an episode of The Proteomics Show where the Bens interview Translating Proteomics host Parag Mallick. Check it out to learn about Parag's journey to proteomics, his efforts advocating for open data sharing, and his work as a professional magician.

After listening, be sure to check out more episodes of The Proteomics Show on their feed where you'll find over 70 interviews with many, many interesting people in the proteomics community. Find their feed here:

https://us-hupo.org/Podcasts

On this episode of Translating Proteomics, hosts Parag Mallick and Andreas Huhmer discuss their recent experience at the 2025 US Human Proteome Organization conference or US HUPO. Their conversation covers:

· The rising use of multiple proteomics platforms

· Advances in multiomics

And

· What they hope to see at the next US HUPO

Chapters:

00:00 – Introduction

01:47 – Things Parag and Andreas were most excited about going into US HUPO

06:19 - Trends Parag observed at US HUPO

· A bifurcation between studies that focused on measuring many proteins and those that focused on a specific biological process

· People increasingly using multiomics to wholistically understanding biology as opposed to a means of comparing the different omes

· A shift to researchers using multiple proteomics platforms

11:44 – The rising prominence of proteoforms at US HUPO

15:50 – The future of proteomics as informed by US HUPO

18:06 – What Parag and Andreas hope to see at the next US HUPO

19:57 - Outro

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 public

Chapters:

00:00 – 03:04 – Intro

03:04 – 07:23 – Why the Bens created "The Proteomics Show"

07:23 – 10:42 – Ways the proteomics show has impacted the Bens’ research

10:42 – 16:44 – Every scientist is interesting!

16:44 – 20:36 – Ways the Bens' communication efforts have changed their research

20:36 – 25:08 – Trends in proteomics

25:08 – 35:34 – Barriers to communication between the proteomics community and others in the life science

34:34-48:34 - Barriers to communication between the proteomics community and the broader public

48:34 - End - Outro

Resources

• The 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 proteomics

Chapters

00:00 – 01:23 – Introduction

01:23 – 03:27 – Proteomics and alcohol fermentation

03:27 – 05:24 – Food properties and their relationship with molecular composition

05:24 – 07: 42 – How can we use proteoforms to improve food quality?

07:42 – 11:49 – Proteomics to aid plant and animal breeding

11:49 – 14:35 – Proteomics, Food Safety, and Food Security

14:35 – 17:05 – Proteomics and food authenticity

17:05 – 20:36 – Proteomics and terroir

20:36 – 22:48 – Proteomics, the microbiome, and health

22:48 – 24:29 – A fun party trick

24:29 – 30:24 – Creating new foods and flavors

30:24 – 34:33 – Designing food for space

34:33 – End – Outro

Resources

The 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 foam

Heat 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 tenderness

Comprehensive 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 bread

Differential 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 reproducible

Chapters

00:00 – 01:20 – Introduction

01:20– 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 reproducibility

05:42 – 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 workflows

11:30 – 14:00 – The need to create repositories of analytical workflows codified in a structured way that AI can learn from

14:00 – 15:24 – A role for dedicated data curators

15:24 – 18:31 – Moving beyond the idea of study endpoints and recognizing data as part of a larger whole

18:31 – 21:32 – How does AI fit into the continuous analysis and incorporation of new datasets

21:32 – 23:36 – The role of AI in helping researchers design experiments

23:36 – 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 tools

27:25 – End – Outro

Resources

Parag’s Gilbert S. Omenn Computational Proteomics Award Lecture

o In this lecture, Parag describes his vision for a more reproducible future in proteomics

Nature Special on “Challenges in irreproducible research”

o A list of articles and perspective pieces discussing the “reproducibility crisis” in research

Why Most Published Research Findings Are False (Ioannidis 2005)

o Article outlining many of the issues that make it difficult to reproduce research findings

Reproducibility Project: Cancer Biology

o eLife initiative investigating reproducibility in preclinical cancer research

Center for Open Science Preregistration Initiative

o Resources for preregistering a hypothesis as part of a study

National Institute of Standards and Technology (NIST)

o US government agency that aims to be “the world’s leader in creating critical measurement solutions and promoting equitable standards.”

MSstats

o Open source software for mass spec data analysis from Bioconductor

National Institute of General Medical Sciences

o US government agency focused on “basic research that increases understanding of biological processes and lays the foundation for advances in disease diagnosis, treatment, and prevention.”

Chan Zuckerberg Initiative – Essential Open Source Software for Science

o CZI program supporting “software maintenance, growth, development, and community engagement for critical open source tools.”

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 trials

Chapters

00:00 – 01:06 – Introduction

01:06 – 06:51 – Proteomics in pre-clinical studies

06:51 – 11:40 – The importance of choosing the right model for preclinical work

11:40 – 17:10 – How proteomics is used in Phase I/II clinical trials

17:10 – 19:29 – Proteomics tools in patient selection

19:29 – 24:33 – Useful information that we get from proteomics that we can’t get from genomics or transcriptomics

24:33 – 28:14 – Proteomics in Phase III clinical trials and picking the best indications of drug efficacy

28:14 – 29:19 - Understanding why clinical trials fail

29:19 – End - Outro

Resources

• The National Cancer Institute’s webpage covering how clinical trials work
• Preprint on the miBrain model - An example of a new in vitro brain model
• Geary et al., 2021 - Discovery and Evaluation of Protein Biomarkers as a Signature of Wellness in Late-Stage Cancer Patients in Early Phase Clinical Trials
• Wasko et al., 2024 - Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer
• The NCI-MATCH trail: Lessons for precision oncology – Report on a large-scale trial using genomic biomarkers to match cancer patients to treatments
• Tumour-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 research
• Proteomics in basic research
• Technology development in proteomics

Synopses 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 proteomics

In this work from Professor Bernhard Kuster’s Lab 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 turnover

As we discussed on a previous episode of Translating Proteomics, genome alterations often fail to faithfully propagate to the proteome. In this work, researchers from the labs of Professor Judith Berman at Tel Aviv University and Professor Markus Ralser 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.

Find the publication here.

Multi-pass, single-molecule nanopore reading of long protein strands

Single-molecule protein sequencing is a long sought after goal of the proteomics field. Nanopore-based sequencers thread single protein molecules through tiny pores imbedded in membranes. Changes in the electrical properties of the pores due to protein threading can theoretically be measured to sequence the threaded proteins. To date, the complex signals coming from full protein molecules cannot be effectively interpreted to determine complete protein sequences. In this work from Professor Jeff Nivala’s lab at the University of Washington, researchers bring the field one step closer to full protein sequencing by showing they can use nanopore-based devices to effectively conduct long reads and identify single amino acid substitutions in repetitive protein sequences with otherwise highly similar readouts. In addition, they develop a method that makes it possible to conduct repeated reads of the same protein molecule and thereby improve read accuracy. They leverage their methodology to show they can design protein barcodes, identify PTMs on otherwise identical protein molecules, and identify traces indicative of particular proteins. While they do not sequence full proteins, these researchers suggest their techniques can be used for proteoform identification and the creation of millions to billions of individually distinguishable barcodes.

Find the publication here.

Additional exciting work in proteomics from 2024

While not discussed in this podcast, Parag and Andreas also loved the papers listed below. Do you have any favorites that aren’t featured here? Please share them in the comments or email them to us at translatingproteomics@nautilus.bio. We can’t wait to hear from you.

Additional favorites from Parag and Andreas:

· Exploring structural diversity across the protein universe with the Encyclopedia of Domains

· Atlas of the plasma proteome in health and disease in 53,026 adults

· Integrating multiplexed imaging and multiscale modeling identifies tumor phenotype conversion as a critical component of therapeutic T cell efficacy

· Brain-wide alterations revealed by spatial transcriptomics and proteomics in COVID-19 infection

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 learning
• How founders are applying AI and machine learning in biotech
• The future of AI and machine learning in biotech

Chapters

00:00 - Introduction

04:37 - How did Vijay and Matt get into AI and ML

07:33 - The importance of structured data, advances in compute, and algorithmic advances in driving the boom in machine learning

18:44 - The Intersection of AI and biology

21:57 - The evolution of biological models

31:55 - The Complexity of biological data

39:42 - Ways founders and biotech startups are using AI

43:25 - Favorite/Impactful applications of AI/ML

47:00 - AI for experimental design

50:13 - The future of AI in bio/health

Resources

• Learn more about Matt McIlwain
• Learn more about Vijay Pande
• Folding at Home
• Learn about various types of machine learning on IBM's website
• Learn about autoencoders on IBM's website
• Learn more about transformers on NVIDIA's blog
• Translating 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 translatingproteomics@nautilus.bio!

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 research
• Recent Alzheimer’s drug approvals
• The 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*

Chapters

00:00 – Introduction

01:54 – Why Sarah began studying Alzheimer’s

03:39 – Current tools and needs for future Alzheimer’s diagnostics

09:52 – Recent drug approvals in the Alzheimer’s space and their relationship to diagnostics

14:26 – 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’s

19:33 – The genetics of Alzheimer’s

22:19 – Novel approaches to identifying and understanding Alzheimer’s pathology

25:54 – Where can proteomics advance Alzheimer’s research?

31:25 – The role of proteomics in Alzheimer’s animal models

34:33 – Sarah’s hopes for the next 10 years of Alzheimer’s research

41:39 - Outro

Resources

Dominant Inherited Alzheimer’s Network (DIAN) trials research updates

o 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 Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer's Disease (Haeberlein et al. 2022)

o Donanemab in Early Symptomatic Alzheimer Disease - The TRAILBLAZER-ALZ 2 Randomized Clinical Trial (Sims et al. 2023)

o 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 Clinical research into a new phospo-tau biomarker that can help physicians more effectively diagnose Alzheimer’s disease

Resurrecting the Mysteries of Big Tau (Fischer and Baas 2021)

o 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 to Alzheimer’s Disease (Hurst et al. 2023)

o Paper linking the NRN1 protein to cognitive resilience in Alzheimer’s

o Nautilus blog post about this paper