Academic Appointments

Honors & Awards

  • Chan-Zuckerberg Biohub Investigator, Chan-Zuckerberg Biohub- San Francisco (2022)
  • Reid and Polly Anderson Faculty Fellow, Stanford University (2022)
  • V Scholar, V Foundation (2022)
  • Career Award at the Scientific Interface, Burroughs Wellcome Fund (2021)
  • Merck Postdoctoral Fellowship, Cancer Research Institute (2017-2021)
  • Postdoctoral Fellowship, UC MEXUS (2016-2017)
  • Christensen Prize for Outstanding Research Achievement, Harvard University (2012)

Boards, Advisory Committees, Professional Organizations

  • Co-founder and board member, Science Clubs International (2016 - Present)
  • Co-founder and board member, Clubes de Ciencia Mexico (2014 - Present)

Professional Education

  • Postdoctoral Fellow, University of California San Francisco, Synthetic Biology, Immune engineering (2022)
  • Ph.D., Harvard University, Chemical Physics (2015)
  • B.S., National Autonomous University of Mexico, Chemistry (2008)

Current Research and Scholarly Interests

Cell engineering has become an exciting field that leverages the power of synthetic and natural biological systems to carry out complex behaviors with important applications in human health, energy, and the environment. For example, T cells can be redirected to kill cancer cells using synthetic receptors and this approach has shown remarkable success against hematologic cancers. Nonetheless, many challenges still remain unsolved to apply this therapy to a broader range of cancers. Our research integrates mechanistic cell biology and synthetic biology to understand and engineer fundamental cellular behaviors such as recognition and communication. We are currently interested in developing novel receptors and therapeutic T cells targeted to solid tumors. We are also launching new research programs to expand our approach to other molecules, cells and tissues for a variety of applications.

1) Programming enhanced cellular recognition in T cells
A fundamental behavior in biology is cellular recognition. In cancer immunotherapy, highly discriminatory cell recognition would expand the applications of engineered T cells to treat solid cancers. Current CAR T cells, while effective at killing cells expressing the target antigen, fail to discriminate between high and low antigen-expressing cells. Therefore, common antigens (e.g. HER2, EGFR, and GD2) that are overexpressed in solid tumor cells cannot currently be used as good targets, as this has led in some cases to the lethal off-target killing of bystander tissues expressing lower levels of antigen.

We are using principles of molecular recognition to understand and compare the limits among different strategies for engineering cellular discrimination. We recently built a two-step circuit that links a low-affinity recognition event with a subsequent high-affinity activation event. In this circuit, transcription activation, via a synthetic Notch (synNotch) receptor induces expression of a high-affinity CAR. This low-to-high synNotch to CAR circuit leads to an ultrasensitive antigen density response that allows robust discrimination of high and low HER2 expressing target cells in vitro and in vivo.

2) Uncovering the principles of cell-cell communication in the tumor microenvironment
How a tissue structure affects its function and the progression of disease are outstanding questions in cell and developmental biology with fundamental applications in cancer treatment. Tumor heterogeneity and the immunosuppressive tumor microenvironment, which affects T cell migration and infiltration, remain some of the major barriers to effective solid tumor immunotherapy. Addressing these problems is challenging because tumors are complex multicellular systems. We know that T cells can recognize tumors with high specificity, and we also know that tumors modulate T cell activity via the so-called tumor microenvironment. However, we understand little about the tumor microenvironment, in particular, we do not know how tumor composition and organization mechanistically affect the response of engineered cell therapies. Our group is interested in understanding how the organization of a solid tumor affects immune cell response.

We are combining cellular and tissue engineering to systematically interrogate the activity of immune cells targeted to solid tumors. We are interested in deconstructing features of tumors such as composition, structure and organization and aim for designing and building synthetic circuits that can program biomedical useful cellular behaviors to treat solid tumors.

2023-24 Courses

Stanford Advisees

All Publications

  • A synthetic biology approach to engineering circuits in immune cells. Immunological reviews Hoces, D., Miguens Blanco, J., Hernandez-Lopez, R. A. 2023


    A synthetic circuit in a biological system involves the designed assembly of genetic elements, biomolecules, or cells to create a defined function. These circuits are central in synthetic biology, enabling the reprogramming of cellular behavior and the engineering of cells with customized responses. In cancer therapeutics, engineering T cells with circuits have the potential to overcome the challenges of current approaches, for example, by allowing specific recognition and killing of cancer cells. Recent advances also facilitate engineering integrated circuits for the controlled release of therapeutic molecules at specified locations, for example, in a solid tumor. In this review, we discuss recent strategies and applications of synthetic receptor circuits aimed at enhancing immune cell functions for cancer immunotherapy. We begin by introducing the concept of circuits in networks at the molecular and cellular scales and provide an analysis of the development and implementation of several synthetic circuits in T cells that have the goal to overcome current challenges in cancer immunotherapy. These include specific targeting of cancer cells, increased T-cell proliferation, and persistence in the tumor microenvironment. By harnessing the power of synthetic biology, and the characteristics of certain circuit architectures, it is now possible to engineer a new generation of immune cells that recognize cancer cells, while minimizing off-target toxicities. We specifically discuss T-cell circuits for antigen density sensing. These circuits allow targeting of solid tumors that share antigens with normal tissues. Additionally, we explore designs for synthetic circuits that could control T-cell differentiation or T-cell fate as well as the concept of synthetic multicellular circuits that leverage cellular communication and division of labor to achieve improved therapeutic efficacy. As our understanding of cell biology expands and novel tools for genome, protein, and cell engineering are developed, we anticipate further innovative approaches to emerge in the design and engineering of circuits in immune cells.

    View details for DOI 10.1111/imr.13244

    View details for PubMedID 37464881

  • T cell circuits that sense antigen density with an ultrasensitive threshold SCIENCE Hernandez-Lopez, R. A., Yu, W., Cabral, K. A., Creasey, O. A., Lopez Pazmino, M., Tonai, Y., De Guzman, A., Makela, A., Saksela, K., Gartner, Z. J., Lim, W. A. 2021; 371 (6534): 1166-+


    Overexpressed tumor-associated antigens [for example, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2)] are attractive targets for therapeutic T cells, but toxic "off-tumor" cross-reaction with normal tissues that express low levels of target antigen can occur with chimeric antigen receptor (CAR)-T cells. Inspired by natural ultrasensitive response circuits, we engineered a two-step positive-feedback circuit that allows human cytotoxic T cells to discriminate targets on the basis of a sigmoidal antigen-density threshold. In this circuit, a low-affinity synthetic Notch receptor for HER2 controls the expression of a high-affinity CAR for HER2. Increasing HER2 density thus has cooperative effects on T cells-it increases both CAR expression and activation-leading to a sigmoidal response. T cells with this circuit show sharp discrimination between target cells expressing normal amounts of HER2 and cancer cells expressing 100 times as much HER2, both in vitro and in vivo.

    View details for DOI 10.1126/science.abc1855

    View details for Web of Science ID 000630096400037

    View details for PubMedID 33632893

    View details for PubMedCentralID PMC8025675

  • DNA scaffolds enable efficient and tunable functionalization of biomaterials for immune cell modulation. Nature nanotechnology Huang, X., Williams, J. Z., Chang, R., Li, Z., Burnett, C. E., Hernandez-Lopez, R., Setiady, I., Gai, E., Patterson, D. M., Yu, W., Roybal, K. T., Lim, W. A., Desai, T. A. 2021; 16 (2): 214-223


    Biomaterials can improve the safety and presentation of therapeutic agents for effective immunotherapy, and a high level of control over surface functionalization is essential for immune cell modulation. Here, we developed biocompatible immune cell-engaging particles (ICEp) that use synthetic short DNA as scaffolds for efficient and tunable protein loading. To improve the safety of chimeric antigen receptor (CAR) T cell therapies, micrometre-sized ICEp were injected intratumorally to present a priming signal for systemically administered AND-gate CAR-T cells. Locally retained ICEp presenting a high density of priming antigens activated CAR T cells, driving local tumour clearance while sparing uninjected tumours in immunodeficient mice. The ratiometric control of costimulatory ligands (anti-CD3 and anti-CD28 antibodies) and the surface presentation of a cytokine (IL-2) on ICEp were shown to substantially impact human primary T cell activation phenotypes. This modular and versatile biomaterial functionalization platform can provide new opportunities for immunotherapies.

    View details for DOI 10.1038/s41565-020-00813-z

    View details for PubMedID 33318641

    View details for PubMedCentralID PMC7878327