Dr. Mandë Holford

Mandë Holford is an associate professor of chemistry at CUNY Hunter College and The CUNY Graduate Center, with scientific appointments at the American Museum of Natural History and Weill Cornell Medicine. Her joint appointments reflect her interdisciplinary research.

Dr. Holford’s research focus is chemical and biological diversity, specifically, investigating venom and venomous organisms as agents of change and innovation in evolution and for therapeutic development in pain and cancer.

She is actively involved in science education, advancing the public understanding of science and science diplomacy. She has received several awards including being named a 2020 Sustainability Pioneer and a 2015 New Champion Young Scientist by the World Economic Forum, and a California Academy of Sciences Fellow. She also received the prestigious Camille Dreyfus Teacher-Scholar Award, an NSF CAREER Award, and was honored as a Breakthrough Women in Science by the Howard Hughes Medical Institute (HHMI) and NPR’s Science Friday. She is cofounder of KillerSnails.com, an award winning EdTech company that uses gaming as a conduit to advance scientific learning in K-12 classrooms. Dr. Holford is a life member on the Council of Foreign Relations and an AAAS Science & Technology Policy Fellow.

• City University of New York (BS, 1997)
• Rockefeller University (PhD, 2003)
• University of Utah (Part of Postdoc, 2005-2008)
• Max Delbruck Center for Molecular Medicine, Germany (Part of Postdoc, 2006-2007)
• Muséum National d’Histoire Naturelle, France (Part of Postdoc, 2005-2008)

• CHEM 29101 Introduction to Research
• CHEM 37700/64100 Biochemistry II
• CHEM 38862 Science and Diplomacy

Research in the Holford Laboratory uses a “mollusks-to-medicine” strategy to discover novel peptides from venomous marine snails that could be used to manipulate cellular physiology pertaining to pain and cancer. Research projects apply inventive tools from chemistry and biology to: (1) investigate the evolution of venom in predatory marine snails, (2) discover disulfide-rich peptides from a venom source, (3) develop high-throughput methods for characterizing structure-function peptide interactions, and (4) deliver novel peptides to their site of action for therapeutic application.

1. Taxonomy, Phylogeny, and Systematics of Venomous Marine Snails

The Tererbridae auger snails are a family of globally distributed predatory marine snails that use venom to subdue their prey. The terebrid species are highly representative of a broad range of feeding strategies, more so than any other venomous marine taxa. We describe the taxonomy, phylogeny and venom diversity of terebrid snails. We produced the first molecular phylogeny of the Terebridae and used it to identify terebrid lineages that used a venom apparatus similar to cone snails to produce bioactive venom peptides (teretoxins).

2. Venomics – Venom Peptide Discovery, Diversification and Evolution

Venom peptides from predatory organisms are a resource for investigating evolutionary processes such as adaptive radiation or diversification and exemplify promising targets for biomedical drug development. Characterization of cone snail venom peptides, conotoxins, has revealed a venom arsenal of bioactive peptides used to investigate physiological cellular function, predator-prey interactions and to develop novel therapeutics. However, venom diversity of other conoidean snails remains poorly understood. We apply a systems biology approach to venomics to discover new bioactive venom peptides and to study venom diversification in terebrids within an evolutionary phylogenetic context.

3. High Throughput Venom Peptide Characterization

Venom peptides are levers that manipulate cell signaling. We are interested in finding new therapies for pain and cancer by creating high throughput methods for screening novel venom peptides. Each venomous marine snail of the family Conoidea can produce hundreds of novel peptides in their venom arsenal. From the breakthrough success of the first commercial venom snail drug ziconotide (Prialt ®) used to treat chronic pain in HIV and cancer patients, we know that these peptides can potentially be used to develop novel therapies for treating human disorders.

4. Venom Peptide Optimization and Drug Delivery

Peptides are promising therapeutic agents, however these natural compounds often need to be optimized to be used successfully as drug compounds. For example, ziconotide (Prialt ®) has a major drawback in that as a peptide drug, its size and complexity prevents its widespread application and a spinal tap is required to deliver it to patients. To address this issue, we are combining chemical and recombinant biology techniques to devise a method for encapsulating venom peptides from marine snails in viral capsids for delivery to their site of action. We are also developing new computational methods for optimizing the function of venom peptides to make them more selective for their molecular targets.

• Kelly P, Napolitano T, Anand P, Ho J, Jabeen S, Kuppan J, Manir S, Holford M. Induced Disassembly of a Virus-Like Particle under Physiological Conditions for Venom Peptide Delivery. ACS Bioconjugate Chem. In Press (2020).
• Cerullo A, Lai TY, Allam B, Baer A, Barnes J, Barrientos A, Deheyn DD, Fudge D, Gould J, Harrington MJ, Holford M, Hung C, Jain G, Mayer G, Medina-Munoz M, Monge J, Napolitano T, Espinosa EP, Schmidt S, Thompson E, Braunschweig AB. Comparative animal mucomics: Inspiration for functional materials from ubiquitous and understudied biopolymers. ACS Biomater. Sci. Eng. 6(10):5377–5398 (2020). doi:10.1021/acsbiomaterials.0c00713
• Anand P, Filipenko P, Huaman J, Lyudmer M, Hossain M, Santamaria C, Huang K, Ogunwobi OO, Holford M. Selective Inhibition of Liver Cancer Cells Using Venom Peptide. Drugs. 17(10):587 (2019). doi:10.3390/md17100587
• Napolitano T, Holford M. Breakthroughs in Venom Peptide Screening Methods to Advance Future Drug Discovery. Protein & Peptide Letters. 25:1137 (2018). doi:10.2174/0929866525666181101103047
• Eriksson A, Anand P, Gorson J, Grijuc C, Hadelia E, Stewart JC, Holford M, Claridge-Chang A. Using Drosophila behavioral assays to characterize terebrid venom-peptide bioactivity.Sci Rep. 8:15276 (2018). doi:10.1038/s41598-018-33215-2
• Verdes A, Anand P, Gorson J, Jannetti S, Kelly P, Leffler A, Simpson D, Ramrattan G, Holford M. From Mollusks to Medicine: A Venomics Approach for the Discovery and Characterization of Therapeutics from Terebridae Peptide Toxins. Toxins. 8(4):117 (2016). doi:10.3390/toxins8040117
• Gorson J, Holford M.Small Packages, Big Returns: Uncovering the Venom Diversity of Small Invertebrate Conoidean Snails. Integr Comp Biol. 56(5):962-972 (2016). doi:10.1093/icb/icw063
• Gorson J, Ramrattan G, Verdes A, Wright ME, Kantor Y, Srinivasan R, Musunuri R, Packer D, Albano G, Qiu WG, Holford M. Molecular Diversity and Gene Evolution of the Venom Arsenal of Terebridae Predatory Marine Snails. Genome Biol Evol. 7(6):1761-78 (2015). doi:10.1093/gbe/evv104
• Puillandre N, Holford M. The Terebridae and teretoxins: Combining phylogeny and anatomy for concerted discovery of bioactive compounds. BMC Chem Biol. 10:7 (2010). doi:10.1186/1472-6769-10-7