Publications

Two major hurdles in chimeric antigen receptor (CAR) T cell therapy for solid tumors are ensuring specificity to tumor cells without affecting healthy cells and avoiding tumor escape due to antigen loss. To address these challenges, Hyrenius-Wittsten et al. and Choe et al. developed synthetic notch (synNotch)–CAR T cells targeting solid tumor antigens and used them to treat mouse models of mesothelioma, ovarian cancer, and glioblastoma. In both studies, the authors demonstrated that synNotch-CAR T cells were better at controlling tumors than traditional CAR T cells and did not result in toxicity or damage to healthy tissue. These results suggest that synNotch-CAR T cells may be an effective treatment strategy for solid tumors.

As non-“self” macromolecules, biotherapeutics can trigger an immune response that can reduce drug efficacy, require patients to be taken off therapy, or even cause life-threatening reactions. To enable the flexible and facile design of protein biotherapeutics while reducing the prevalence of T-cell epitopes that drive immune recognition, we have integrated into the Rosetta protein design suite a new scoring term that allows design protocols to account for predicted or experimentally identified epitopes in the optimized objective function. This flexible scoring term can be used in any Rosetta design trajectory, can be targeted to specific regions of a protein, and can be readily extended to work with a variety of epitope predictors. By performing extensive design runs with varied design parameter choices for three case study proteins as well as a larger diverse benchmark, we show that the incorporation of this scoring term enables the effective exploration of an alternative, deimmunized sequence space to discover diverse proteins that are potentially highly deimmunized while retaining physical and chemical qualities similar to those yielded by equivalent nondeimmunizing sequence design protocols.

The NANOGrav Collaboration reported strong Bayesian evidence for a common-spectrum stochastic process in its 12.5-yr pulsar timing array dataset, with median characteristic strain amplitude at periods of a year of Ayr=1.92+0.75−0.55×10−15. However, evidence for the quadrupolar Hellings \& Downs interpulsar correlations, which are characteristic of gravitational wave signals, was not yet significant. We emulate and extend the NANOGrav dataset, injecting a wide range of stochastic gravitational wave background (GWB) signals that encompass a variety of amplitudes and spectral shapes, and quantify three key milestones: (I) Given the amplitude measured in the 12.5 yr analysis and assuming this signal is a GWB, we expect to accumulate robust evidence of an interpulsar-correlated GWB signal with 15--17 yrs of data, i.e., an additional 2--5 yrs from the 12.5 yr dataset; (II) At the initial detection, we expect a fractional uncertainty of 40% on the power-law strain spectrum slope, which is sufficient to distinguish a GWB of supermassive black-hole binary origin from some models predicting more exotic origins;(III) Similarly, the measured GWB amplitude will have an uncertainty of 44% upon initial detection, allowing us to arbitrate between some population models of supermassive black-hole binaries. In addition, power-law models are distinguishable from those having low-frequency spectral turnovers once 20~yrs of data are reached. Even though our study is based on the NANOGrav data, we also derive relations that allow for a generalization to other pulsar-timing array datasets. Most notably, by combining the data of individual arrays into the International Pulsar Timing Array, all of these milestones can be reached significantly earlier.

This Science White Paper, prepared in response to the ESA Voyage 2050 call for long-term mission planning, aims to describe the various science possibilities that can be realized with an L-class space observatory that is dedicated to the study of the interactions of cosmic microwave background (CMB) photons with the cosmic web. Our aim is specifically to use the CMB as a backlight -- and survey the gas, total mass, and stellar content of the entire observable Universe by means of analyzing the spatial and spectral distortions imprinted on it. These distortions result from two major processes that impact on CMB photons: scattering by electrons (Sunyaev-Zeldovich effect in diverse forms, Rayleigh scattering, resonant scattering) and deflection by gravitational potential (lensing effect). Even though the list of topics collected in this White Paper is not exhaustive, it helps to illustrate the exceptional diversity of major scientific questions that can be addressed by a space mission that will reach an angular resolution of 1.5 arcmin (goal 1 arcmin), have an average sensitivity better than 1 uK-arcmin, and span the microwave frequency range from roughly 50 GHz to 1 THz. The current paper also highlights the synergy of our BACKLIGHT mission concept with several upcoming and proposed ground-based CMB experiments.

We propose a method to improve the computational and memory efficiency of numerical solvers for the nonequilibrium Dyson equation in the Keldysh formalism. It is based on the empirical observation that the nonequilibrium Green's functions and self energies arising in many problems of physical interest, discretized as matrices, have low rank off-diagonal blocks, and can therefore be compressed using a hierarchical low rank data structure. We describe an efficient algorithm to build this compressed representation on the fly during the course of time stepping, and use the representation to reduce the cost of computing history integrals, which is the main computational bottleneck. For systems with the hierarchical low rank property, our method reduces the computational complexity of solving the nonequilibrium Dyson equation from cubic to near quadratic, and the memory complexity from quadratic to near linear. We demonstrate the full solver for the Falicov-Kimball model exposed to a rapid ramp and Floquet driving of system parameters, and are able to increase feasible propagation times substantially. We present examples with 262144 time steps, which would require approximately five months of computing time and 2.2 TB of memory using the direct time stepping method, but can be completed in just over a day on a laptop with less than 4 GB of memory using our method. We also confirm the hierarchical low rank property for the driven Hubbard model in the weak coupling regime within the GW approximation, and in the strong coupling regime within dynamical mean-field theory.

Systematic study of tissue-specific function of enhancers and their disease associations is a major challenge. We present an integrative machine-learning framework, FENRIR, that integrates thousands of disparate epigenetic and functional genomics datasets to infer tissue-specific functional relationships between enhancers for 140 diverse human tissues and cell types, providing a regulatory-region-centric approach to systematically identify disease-associated enhancers. We demonstrated its power to accurately prioritize enhancers associated with 25 complex diseases. In a case study on autism, FENRIR-prioritized enhancers showed a significant proband-specific de novo mutation enrichment in a large, sibling-controlled cohort, indicating pathogenic signal. We experimentally validated transcriptional regulatory activities of eight enhancers, including enhancers not previously reported with autism, and demonstrated their differential regulatory potential between proband and sibling alleles. Thus, FENRIR is an accurate and effective framework for the study of tissue-specific enhancers and their role in disease. FENRIR can be accessed at fenrir.flatironinstitute.org/.

We numerically solve the Hubbard model on the Bethe lattice with finite coordination number z=3, and determine its zero-temperature phase diagram. For this purpose, we introduce and develop the `variational uniform tree state' (VUTS) algorithm, a tensor network algorithm which generalizes the variational uniform matrix product state algorithm to tree tensor networks. Our results reveal an antiferromagnetic insulating phase and a paramagnetic metallic phase, separated by a first-order doping-driven metal-insulator transition. We show that the metallic state is a Fermi liquid with coherent quasiparticle excitations for all values of the interaction strength U, and we obtain the finite quasiparticle weight Z from the single-particle occupation function of a generalized "momentum" variable. We find that Z decreases with increasing U, ultimately saturating to a non-zero, doping-dependent value. Our work demonstrates that tensor-network calculations on tree lattices, and the VUTS algorithm in particular, are a platform for obtaining controlled results for phenomena absent in one dimension, such as Fermi liquids, while avoiding computational difficulties associated with tensor networks in two dimensions. We envision that future studies could observe non-Fermi liquids, interaction-driven metal-insulator transitions, and doped spin liquids using this platform.

To enable large-scale analyses of regulatory logic in model species, we developed DeepArk, a set of deep learning models of the cis-regulatory codes of four widely-studied species: Caenorhabditis elegans, Danio rerio, Drosophila melanogaster, and Mus musculus DeepArk accurately predicts the presence of thousands of different context-specific regulatory features, including chromatin states, histone marks, and transcription factors. In vivo studies show that DeepArk can predict the regulatory impact of any genomic variant (including rare or not previously observed), and enables the regulatory annotation of understudied model species.

Terminal regions of Drosophila embryos are patterned by signaling through ERK, which is genetically deregulated in multiple human diseases. Quantitative studies of terminal patterning have been recently used to investigate gain-of-function variants of human MEK1, encoding the MEK kinase that directly activates ERK by dual phosphorylation. Unexpectedly, several mutations reduced ERK activation by extracellular signals, possibly through a negative feedback triggered by signal-independent activity of the mutant variants. Here we present experimental evidence supporting this model. Using a MEK variant that combines a mutation within the negative regulatory region with alanine substitutions in the activation loop, we prove that pathogenic variants indeed acquire signal-independent kinase activity. We also demonstrate that signal-dependent activation of these variants is independent of kinase suppressor of Ras, a conserved adaptor that is indispensable for activation of normal MEK. Finally, we show that attenuation of ERK activation by extracellular signals stems from transcriptional induction of Mkp3, a dual specificity phosphatase that deactivates ERK by dephosphorylation. These findings in the Drosophila embryo highlight its power for investigating diverse effects of human disease mutations.

Stellar streams record the accretion history of their host galaxy. We present a set of simulated streams from disrupted dwarf galaxies in 13 cosmological simulations of Milky Way (MW)-mass galaxies from the FIRE-2 suite at z=0, including 7 isolated Milky Way-mass systems and 6 hosts resembling the MW-M31 pair (full dataset at: this https URL). In total, we identify 106 simulated stellar streams, with no significant differences in the number of streams and masses of their progenitors between the isolated and paired environments. We resolve simulated streams with stellar masses ranging from ∼5×105 up to ∼109M⊙, similar to the mass range between the Orphan and Sagittarius streams in the MW. We confirm that present-day simulated satellite galaxies are good proxies for stellar stream progenitors, with similar properties including their stellar mass function, velocity dispersion, [Fe/H] and [α/H] evolution tracks, and orbital distribution with respect to the galactic disk plane. Each progenitor's lifetime is marked by several important timescales: its infall, star-formation quenching, and stream-formation times. We show that the ordering of these timescales is different between progenitors with stellar masses higher and lower than ∼2×106M⊙. Finally, we show that the main factor controlling the rate of phase-mixing, and therefore fading, of tidal streams from satellite galaxies in MW-mass hosts is non-adiabatic evolution of the host potential. Other factors commonly used to predict phase-mixing timescales, such as progenitor mass and orbital circularity, show virtually no correlation with the number of dynamical times required for a stream to become phase-mixed.