We use DNA to create a new world of structural engineering and biological computation
News
March 1, 2024
Pallav Kosuri named Hearst Foundation Developmental Chair!
February 12, 2024
Ryan Fantasia and Lauren Takiguchi present their work to a curious audience at Biophysical Society Annual Meeting in Philadelphia!
January 17, 2024
Kosuri Lab & Gage Lab win $1.3M award from W.M. Keck Foundation!
January 11, 2024
News article in The Scientist describing our work with Mark Rober.
December 24, 2023
Happy holidays from all of us at the Kosuri Lab!
December 19, 2023
Congratulations Ph.D. student Ryan Fantasia on winning an SRF Career Advancement Award!
November 1, 2023
News article on Freethink.com discussing our work with Mark Rober.
September 30, 2023
Collaboration with @MarkRober: We used DNA to make the world’s smallest NERF blaster!
[Watch YouTube video] (Update: 35M+ views as of Jan 2024!)
Using DNA origami, we made a molecular-scale replica of a NERF blaster, 3 million times smaller than the original.
For the full story, watch the NanoNERF video on Mark Rober’s YouTube channel.
For a technical description, read the NanoNERF manuscript on bioRxiv by Takiguchi et al.
September 26, 2023
Lauren Takiguchi starts her PhD in Biophysics at Stanford University – you’ve done amazing work in the lab and we wish you all the best on your next adventure!
September 14, 2023
Amanda Wacker is on a streak! Congratulations on being awarded the Salk Women & Science Professional Development Award!
July 28, 2023
Congratulations Amanda Wacker on winning the Dan and Martina Lewis Biophotonics Fellowship!
May 22, 2023
Congratulations Yuening Liu on winning the Edwards-Yeckel Postdoc Professional Development Award!
March 31, 2023
Congratulations to Jocelyn Olvera on being awarded an NSF Graduate Research Fellowship (GRFP)!
Congratulations also to Jerry Wu on winning a Goldwater Scholarship!
February 22, 2023
Kosuri Lab goes to Biophysical Society Annual Meeting (BPS 2023)!
February 12, 2023
Welcome to the lab Julia Rune!
Research
The Kosuri Lab studies how movement gives rise to biological function across scales, from molecular motors to muscles.
Molecular scale
What are the physical movements during the genetic processes of transcription, chromatin remodeling, and gene editing?
Ensemble scale
How do contributions from single molecules add up in an ensemble to produce collective mechanical behavior?
Organ scale
How does the mechanical and cellular architecture of the heart contribute to the pathophysiology of heart disease?
We are addressing these questions in three tracks, taking a cross-disciplinary approach that makes use of molecular design, computational methods, and functional imaging. When needed, we invent new technology.
Track 1: Using self-assembled DNA devices to study molecular movements
Genetic processes such as transcription, replication, DNA repair and editing are composed of a series of mechanical movements. Most of these movements have remained challenging or impossible to measure.
To see these movements, we make use of the rapidly advancing field of DNA self-assembly, and in particular the DNA origami method, which enables design and assembly of custom 3D structures. Using DNA origami, we are developing a suite of new devices that enable direct measurement of molecular movements.
Our first such technology, Origami Rotor Based Imaging and Tracking (ORBIT), uses self-assembled DNA origami rotors to amplify and visualize molecular rotation.
ORBIT uses DNA rotors to visualize transcription by RNA polymerase
We record the movements of thousands of molecules in each experiment, revealing a rich diversity of activities.
Our DNA origami approach makes it possible to launch a new kind of investigations into the mechanisms of DNA interacting proteins. We are excited to see how our concept of using DNA origami devices can be further put to use to address some of the most fundamental questions in molecular biology and genetics.
Future projects in Track 1 include:
Using ORBIT to investigate transcriptional stochasticity and regulation.
Using ORBIT to investigate how chromatin remodeling enzymes move nucleosomes on DNA.
Creating a DNA origami based single-molecule assay to study gene editing enzymes.
Developing a high-throughput DNA origami based assay to detect small molecule-DNA binding.
Multiplexing DNA origami based assays for applications in drug screening.
Track 2: Synthetic muscle as a model system for contractile tissues
How do the individual contributions of molecular components add up to produce the mechanical behavior of a muscle?
Answering this question will require a quantitative theory wherein the tissue’s mechanics can be described in terms of its molecular components. With a bottom-up description of muscle, we would be able to better predict pathological outcomes resulting from mutations, stress or damage, as well as the effect of therapeutic interventions.
To address this challenge, we are designing a model system that reproduces the basic features of muscle and that affords exquisite control of the geometry and stoichiometry of its components. This synthetic muscle experimental system will allow us to measure scaling phenomena and test theoretical and computational models, laying the groundwork for a bottom-up quantitative description of muscle.
Track 3: Creating a mechanical atlas of the heart
How does mechanical function and dysfunction of the heart arise from the tissue's cellular and molecular organization?
We are using novel imaging methods including spatially resolved transcriptomics to create functional 3D maps of the heart. These maps will help us study how the molecular and cellular structure of the heart leads to its mechanical function or dysfunction. In particular, we are focusing on tissue remodeling and fibrosis, two hallmarks of heart failure, to build quantitative models of disease progression and to identify new therapeutic strategies.
People
Alumni
We are always looking for highly motivated postdoctoral fellows, graduate students and research assistants!
Philosophy
Our mission is to seek knowledge for the benefit of humanity, to help solve our world’s most pressing problems, and to inspire people to think in new ways about what is possible to achieve.
As scientists, we must strive to be the best version of ourselves, and set our internal standards for ethics and integrity higher than what is expected from us. We must seek to build an inclusive community where we welcome diversity of background and encourage diversity of thought. The responsibility also rests on us to promote these values in society at large.
We need to be confident in our abilities yet critical of our practice. In our research, we must seek to disprove our own assumptions and hypotheses. And as mentors, we must continuously refine our approach so as to best support our mentees, and always stay open to feedback.
Expectations of postdocs
We expect that you will seek to realize your potential as an independent scientist. You should be goal-driven, critical and inquisitive, unafraid of problem solving, and supportive of your team. As a member of our lab, you will have opportunities to train in all the aspects that will make you impactful in science – academic or otherwise – including project design, writing, giving talks, and mentoring. You should communicate clearly what you need to be successful, and we will check in on a regular basis to make sure that we stay aligned with your goals.
Expectations of graduate students
We expect you to be curious, dedicated, excited to create new science, and open to change your mind when your experiments prove you wrong. You will have your own project, for which you will be involved in every aspect, from research design to writing a paper, and you are expected to be the lead author on the resulting publications. You will have the same access to career-building opportunities as the postdocs, and we will expect you to broaden your expertise through conference presentations, collaborations, grant writing, and potentially technology transfer and patenting. We expect you to ask lots of questions, communicate your concerns, and ask for help or guidance when you need it. We are all here to support you in your academic journey, and we will do our best to ensure that it is an exceptional one.
Expectations of PI
You can expect me to support you at every stage in your career, from the moment you join the lab to the time when you are preparing for your next job, and beyond. I will listen to you, take your feedback seriously, and strive to be available whenever you need advice or guidance. Most importantly, I will care about your physical and mental wellbeing, your personal development, and your success as a scientist.
Publications
Selected publications
DNA origami rotors
Rotation tracking of genome-processing enzymes using DNA origami rotors
Kosuri P*, Altheimer BD*, Dai M, Yin P, Zhuang X (*co-first authors)
Nature (2019)
Protein folding
Protein folding drives disulfide formation
Kosuri P, Alegre-Cebollada J, Feng J, Kaplan A, Ingles-Prieto A, Badilla C, Stockwell BR, Sanchez-Ruiz JM, Holmgren A, Fernandez JM
Cell (2012)
Muscle elasticity
S-glutathionylation of cryptic cysteines enhances titin elasticity by blocking protein folding
Alegre-Cebollada J*, Kosuri P*, Giganti D, Eckels E, Rivas-Pardo JA, Hamdani N, Warren CM, Solaro RJ, Linke WA, Fernandez JM (*co-first authors)
Cell (2014) cover story
Muscle contraction
Work done by titin protein folding assists muscle contraction
Rivas-Pardo JA, Eckels EC, Popa I, Kosuri P, Linke WA, Fernandez JM
Cell Reports (2016)
Full list of publications
Tetra-gel enables superior accuracy in combined super-resolution imaging and expansion microscopy
Lee H, Yu CC, Boyden ES, Zhuang X, Kosuri P
Scientific Reports (2021)
Rotation tracking of genome-processing enzymes using DNA origami rotors
Kosuri P*, Altheimer BD*, Dai M, Yin P, Zhuang X (*co-first authors)
Nature (2019)
Work done by titin protein folding assists muscle contraction
Rivas-Pardo JA, Eckels EC, Popa I, Kosuri P, Linke WA, Fernandez JM
Cell Reports (2016)
Predicting readmission of heart failure patients using automated follow-up calls
Inouye S, Bouras V, Shouldis E, Johnstone A, Silverzweig Z, Kosuri P* (corresponding author)
BMC Medical Informatics and Decision Making (2015)
S-glutathionylation of cryptic cysteines enhances titin elasticity by blocking protein folding
Alegre-Cebollada J*, Kosuri P*, Giganti D, Eckels E, Rivas-Pardo JA, Hamdani N, Warren CM, Solaro RJ, Linke WA, Fernandez JM (*co-first authors)
Cell (2014) cover story
Picomolar amyloid-β peptides enhance spontaneous astrocyte calcium transients
Lee L, Kosuri P, Arancio O
Journal of Alzheimer's Disease (2014)
Force dependency of biochemical reactions measured by single-molecule force-clamp spectroscopy
Popa I*, Kosuri P*, Alegre-Cebollada J, Garcia-Manyes S, Fernandez JM (*co-first authors)
Nature Protocols (2013)
Protein folding drives disulfide formation
Kosuri P, Alegre-Cebollada J, Feng J, Kaplan A, Ingles-Prieto A, Badilla C, Stockwell BR, Sanchez-Ruiz JM, Holmgren A, Fernandez JM
Cell (2012)
Direct observation of disulfide isomerization in a single protein
Alegre-Cebollada J, Kosuri P, Rivas-Pardo JA, Fernandez JM
Nature Chemistry (2011)
Protease power strokes force proteins to unfold
Alegre-Cebollada J, Kosuri P, Fernandez JM
Cell (2011) preview
Single-molecule paleoenzymology probes the chemistry of resurrected enzymes
Perez-Jimenez R, Ingles-Prieto A, Zhao Z, Sanchez-Romero I, Alegre-Cebollada J, Kosuri P, Garcia-Manyes S, Kappock TJ, Tanokura M, Holmgren A, Sanchez-Ruiz JM, Gaucher EA, Fernandez JM
Nature Structural & Molecular Biology (2011)
Single-molecule force spectroscopy approach to enzymatic catalysis
Alegre-Cebollada J, Perez-Jimenez R, Kosuri P, Fernandez JM
Journal of Biological Chemistry (2010)
Kalman filter estimates of the contour length of an unfolding protein in single-molecule force spectroscopy experiments
Fernandez VI, Kosuri P, Parot P, Fernandez JM
Review of Scientific Instruments (2009)
Partially folded equilibrium intermediate of the villin headpiece HP67 defined by 13C relaxation dispersion
O’Connell NE, Grey MJ, Tang Y, Kosuri P, Miloushev VZ, Raleigh DP, Palmer AG
Journal of Biomolecular NMR (2009)
Diversity of chemical mechanisms in thioredoxin catalysis revealed by single-molecule force spectroscopy
Perez-Jimenez R, Li J, Kosuri P, Berne BJ, Fernandez JM
Nature Structural & Molecular Biology (2009)
Force-clamp spectroscopy detects residue co-evolution in enzyme catalysis
Perez-Jimenez R, Wiita AP, Rodriguez-Larrea D, Kosuri P, Gavira JA, Sanchez-Ruiz JM, Fernandez JM
Journal of Biological Chemistry (2008)
Coupling of ribosomal L1 stalk and tRNA dynamics during translation elongation
Fei J, Kosuri P, MacDougall DD, Gonzalez RL
Molecular Cell (2008)
Development of a RILIS ionisation scheme for gold at ISOLDE, CERN
Marsh BA, Fedosseev VN, Kosuri P
Hyperfine Interactions (2006)
Contact information
Kosuri Lab
Salk Institute for Biological Studies
10010 N Torrey Pines Rd
La Jolla, CA 92037
pkosuri [at] salk.edu
Join the team!
We are always interested in applications from passionate people from all backgrounds who are willing to work hard to create the next generation of science and technology!
We currently recruiting postdoctoral fellows, graduate students, and computational scientists.
For UCSD graduate students, we consider rotation students from across all programs and backgrounds.
If you are interested in joining our team, send us an email at pkosuri[at]salk.edu!