Michael Keiser, PhD

Assistant Professor
Institute for Neurodegenerative Diseases
+1 415 502-7651

Our lab investigates how small molecules perturb protein target networks to biological and therapeutic effect. In a forward polypharmacology campaign, we are using machine learning and computational methods such as the Similarity Ensemble Approach (SEA) to infer new combinations of targets underlying compound-induced phenotypes in cells and broader model systems. Thinking of each target as a musical note, we predict and test entire chords at a time via chemical-genetic epistasis experiments in models of complex diseases such as neurodegeneration.

These systems pharmacology inquiries tell us where current understanding of drug action is weak, and because we use human pharmacology to mine for mechanisms, we can apply the therapeutic chords we find directly to the prediction of patient drug responses, adverse drug reactions, and personalized medicine.

Publications: 

Stress testing reveals gaps in clinic readiness of image-based diagnostic artificial intelligence models.

NPJ digital medicine

Young AT, Fernandez K, Pfau J, Reddy R, Cao NA, von Franque MY, Johal A, Wu BV, Wu RR, Chen JY, Fadadu RP, Vasquez JA, Tam A, Keiser MJ, Wei ML

Adding Stochastic Negative Examples into Machine Learning Improves Molecular Bioactivity Prediction.

Journal of chemical information and modeling

Cáceres EL, Mew NC, Keiser MJ

383 Assessing deep learning artefact bias using global saliency.

Journal of Investigative Dermatology

J. Pfau, A.T. Young, M. Wei, M.J. Keiser

902 Assessing performance of deep neural networks used for image classification by stress testing.

Journal of Investigative Dermatology

A.T. Young, J. Pfau, M.J. Keiser, M. Wei

Learning Molecular Representations for Medicinal Chemistry.

Journal of medicinal chemistry

Chuang KV, Gunsalus LM, Keiser MJ

Validation of machine learning models to detect amyloid pathologies across institutions.

Acta neuropathologica communications

Vizcarra JC, Gearing M, Keiser MJ, Glass JD, Dugger BN, Gutman DA

Artificial Intelligence in Dermatology: A Primer.

The Journal of investigative dermatology

Young AT, Xiong M, Pfau J, Keiser MJ, Wei ML

Zebrafish behavioural profiling identifies GABA and serotonin receptor ligands related to sedation and paradoxical excitation.

Nature communications

McCarroll MN, Gendelev L, Kinser R, Taylor J, Bruni G, Myers-Turnbull D, Helsell C, Carbajal A, Rinaldi C, Kang HJ, Gong JH, Sello JK, Tomita S, Peterson RT, Keiser MJ, Kokel D

Interpretable classification of Alzheimer's disease pathologies with a convolutional neural network pipeline.

Nature communications

Tang Z, Chuang KV, DeCarli C, Jin LW, Beckett L, Keiser MJ, Dugger BN

Adversarial Controls for Scientific Machine Learning.

ACS chemical biology

Chuang KV, Keiser MJ

The Psychiatric Cell Map Initiative: A Convergent Systems Biological Approach to Illuminating Key Molecular Pathways in Neuropsychiatric Disorders.

Cell

Willsey AJ, Morris MT, Wang S, Willsey HR, Sun N, Teerikorpi N, Baum TB, Cagney G, Bender KJ, Desai TA, Srivastava D, Davis GW, Doudna J, Chang E, Sohal V, Lowenstein DH, Li H, Agard D, Keiser MJ, Shoichet B, von Zastrow M, Mucke L, Finkbeiner S, Gan L, Sestan N, Ward ME, Huttenhain R, Nowakowski TJ, Bellen HJ, Frank LM, Khokha MK, Lifton RP, Kampmann M, Ideker T, State MW, Krogan NJ

THE USE OF CONVOLUTIONAL NEURAL NETWORKS TO QUANTIFY AMYLOID PLAQUES IN POSTMORTEM HUMAN BRAIN.

Alzheimer's & Dementia

Kangway Chuang, Ziqi Tang, Michael Keiser, Laurel Beckett, Charlie S. DeCarli, Lee-Way Jin, Brittany N. Dugger

Predicted Biological Activity of Purchasable Chemical Space.

Journal of chemical information and modeling

Irwin JJ, Gaskins G, Sterling T, Mysinger MM, Keiser MJ

Evolutionarily Conserved Roles for Blood-Brain Barrier Xenobiotic Transporters in Endogenous Steroid Partitioning and Behavior.

Cell reports

Hindle SJ, Munji RN, Dolghih E, Gaskins G, Orng S, Ishimoto H, Soung A, DeSalvo M, Kitamoto T, Keiser MJ, Jacobson MP, Daneman R, Bainton RJ

A Simple Representation of Three-Dimensional Molecular Structure.

Journal of medicinal chemistry

Axen SD, Huang XP, Cáceres EL, Gendelev L, Roth BL, Keiser MJ

Zebrafish behavioral profiling identifies multitarget antipsychotic-like compounds.

Nature chemical biology

Bruni G, Rennekamp AJ, Velenich A, McCarroll M, Gendelev L, Fertsch E, Taylor J, Lakhani P, Lensen D, Evron T, Lorello PJ, Huang XP, Kolczewski S, Carey G, Caldarone BJ, Prinssen E, Roth BL, Keiser MJ, Peterson RT, Kokel D

Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach.

The lancet. Psychiatry

Ruderfer DM, Charney AW, Readhead B, Kidd BA, Kähler AK, Kenny PJ, Keiser MJ, Moran JL, Hultman CM, Scott SA, Sullivan PF, Purcell SM, Dudley JT, Sklar P

Leveraging Large-scale Behavioral Profiling in Zebrafish to Explore Neuroactive Polypharmacology.

ACS chemical biology

McCarroll MN, Gendelev L, Keiser MJ, Kokel D

Prediction and validation of enzyme and transporter off-targets for metformin.

Journal of pharmacokinetics and pharmacodynamics

Yee SW, Lin L, Merski M, Keiser MJ, Gupta A, Zhang Y, Chien HC, Shoichet BK, Giacomini KM

In Silico Prediction of Drug Side Effects.

Antitargets and Drug Safety

Michael J. Keiser

Systems pharmacology augments drug safety surveillance.

Clinical pharmacology and therapeutics

Lorberbaum T, Nasir M, Keiser MJ, Vilar S, Hripcsak G, Tatonetti NP

In silico molecular comparisons of C. elegans and mammalian pharmacology identify distinct targets that regulate feeding.

PLoS biology

Lemieux GA, Keiser MJ, Sassano MF, Laggner C, Mayer F, Bainton RJ, Werb Z, Roth BL, Shoichet BK, Ashrafi K

Large-scale prediction and testing of drug activity on side-effect targets.

Nature

Lounkine E, Keiser MJ, Whitebread S, Mikhailov D, Hamon J, Jenkins JL, Lavan P, Weber E, Doak AK, Côté S, Shoichet BK, Urban L

Chapter 4.

Designing Multi-Target Drugs

Elisabet Gregori-Puigjané, Michael J. Keiser

Chemical informatics and target identification in a zebrafish phenotypic screen.

Nature chemical biology

Laggner C, Kokel D, Setola V, Tolia A, Lin H, Irwin JJ, Keiser MJ, Cheung CY, Minor DL, Roth BL, Peterson RT, Shoichet BK

The chemical basis of pharmacology.

Biochemistry

Keiser MJ, Irwin JJ, Shoichet BK

The presynaptic component of the serotonergic system is required for clozapine's efficacy.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

Yadav PN, Abbas AI, Farrell MS, Setola V, Sciaky N, Huang XP, Kroeze WK, Crawford LK, Piel DA, Keiser MJ, Irwin JJ, Shoichet BK, Deneris ES, Gingrich J, Beck SG, Roth BL

Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors.

Journal of medicinal chemistry

Ferreira RS, Simeonov A, Jadhav A, Eidam O, Mott BT, Keiser MJ, McKerrow JH, Maloney DJ, Irwin JJ, Shoichet BK

Prediction and evaluation of protein farnesyltransferase inhibition by commercial drugs.

Journal of medicinal chemistry

DeGraw AJ, Keiser MJ, Ochocki JD, Shoichet BK, Distefano MD

Predicting new molecular targets for known drugs.

Nature

Keiser MJ, Setola V, Irwin JJ, Laggner C, Abbas AI, Hufeisen SJ, Jensen NH, Kuijer MB, Matos RC, Tran TB, Whaley R, Glennon RA, Hert J, Thomas KL, Edwards DD, Shoichet BK, Roth BL

A mapping of drug space from the viewpoint of small molecule metabolism.

PLoS computational biology

Adams JC, Keiser MJ, Basuino L, Chambers HF, Lee DS, Wiest OG, Babbitt PC

Quantifying biogenic bias in screening libraries.

Nature chemical biology

Hert J, Irwin JJ, Laggner C, Keiser MJ, Shoichet BK

Off-target networks derived from ligand set similarity.

Methods in molecular biology (Clifton, N.J.)

Keiser MJ, Hert J

ChemInform Abstract: Quantifying the Relationships among Drug Classes.

ChemInform

Jerome Hert, Michael J. Keiser, John J. Irwin, Tudor I. Oprea, Brian K. Shoichet

Quantifying the relationships among drug classes.

Journal of chemical information and modeling

Hert J, Keiser MJ, Irwin JJ, Oprea TI, Shoichet BK

Relating protein pharmacology by ligand chemistry.

Nature biotechnology

Keiser MJ, Roth BL, Armbruster BN, Ernsberger P, Irwin JJ, Shoichet BK