Heini M Natri, PhD

I am a computational biologist and a functional genomicist widely interested in genetic variation and its functional consequences in the context of health and disease. As a Research Assistant Professor within the Division of Bioinnovation and Genome Sciences at the Translational Genomics Research Institute (TGen), an affiliate of City of Hope, I pursue both highly collaborative fundamental and translational research studies on cancer and other conditions, as well as more theoretical and conceptual projects focused on human diversity, disability, identity, and the Ethical, Legal and Social Implications (ELSI) of genetic research.

Response to CAR T cell therapies in patients with brain tumors

Glioblastoma Multiforme (GBM) is an aggressive, lethal type of cancer that can occur in the brain or the spinal cord. The average survival time is 12-18 months after diagnosis, with only 5% of GBM patients surviving more than five years. GBM is resistant to traditional cancer therapies, calling for the urgent development of novel treatment approaches. Chimeric Antigen Receptor (CAR) T cell therapy shows promise in treating GBM and other brain tumors. We work on a number of correlative studies to better understand the patient response to CAR T therapy.

With our collaborators as City of Hope, we are investigating the factors impacting patient response to CAR T cell therapy in a number of pre-clinical and clinical trials across different CAR targets and cancer types, including adult and pediatric brain tumors. In trials spanning multiple CAR product types and CAR T therapy combined with other molecules, we are uncovering new mechanisms underlying treatment response and developing novel, more effective therapies to target these hard-to-treat tumors.

As a significant component of these studies, we characterize CAR T product and cells from patient cerebrospinal fluid, peripheral blood, and tumors by integrating multimodal data types (gene and surface protein expression, T cell receptor sequencing, spatial transcriptomics) on a single-cell level to gain a comprehensive understanding of the cellular and molecular drivers of response to CAR T therapy.

Read our paper on IL-13Rα2-targeting CAR T cells in the treatment of recurrent high-grade glioma, published in Nature Medicine.

Immune landscape in the tumor microenvironment

Cancer progression and response to therapies is determined by many factors, including intrinsic pathways, metabolic profiles, and the compositional and functional landscape of the tumor microenvironment. Different cell populations, including cytotoxic T cells, suppressive macrophages, and cancer associated fibroblasts (CAFs), all play an important role in shaping the TME. These processes are determined by both intrinsic pathways and extrinsic signaling.

Across a number of projects, organ systems, and tumor models, I use single-cell and spatial multiomics to unravel the immune dynamics in the TME of highly lethal tumors, such as brain tumors and peritoneal metastasis of gastric cancers.

Read our preprint "Overcoming myeloid-driven resistance to CAR T therapy by targeting SPP1".

Peritoneal metastasis and response to regional therapy

Colorectal cancer (CRC) with peritoneal metastasis (PM) occurs when cancer cells spread to the abdominal lining. PM is common and an advanced stage of disease: as many as 25% of patients with CRC develop PM, and the median survival time after diagnosis is only 5 to 7 months, with a 5-year survival rate of 6%. Current treatment strategies, such as systemic chemotherapy, are inadequate due to therapeutic resistance. CRC PM tumors are highly heterogeneous, and the mechanisms of therapeutic resistance are not adequately understood.

In collaboration with Dr. Mustafa Raoof (City of Hope), our recent clinical trials of pressurized intraperitoneal aerosolized chemotherapy (PIPAC) have demonstrated encouraging safety, feasibility, and efficacy signals in patients with refractory CRC PM. Importantly, these cohorts include both patients showing clinical benefit and those who do not respond to therapy, creating a uniquely rich dataset to define the cellular and molecular determinants of treatment response and resistance.

Using single-cell and spatial transcriptomics, we characterize the architecture, cellular composition, and cell-cell interactions of peritoneal tumors at baseline and following PIPAC. Our studies on the mechanisms of therapeutic resistance in CRC PM will identify biomarkers and generate novel hypotheses to guide future translational research. The molecular and cellular features identified in our studies will have an immediate translational impact, catalyzing the rational design of next-generation therapeutic trials for CRC PM.

Genetic underpinnings of gene expression and complex traits

Much of my work has focused on the genetic regulation of gene expression with the goal of connecting trait-associated variants to their regulatory targets and biological processes across tissues, cell types, and contexts.

Idiopathic Pulmonary Fibrosis (IPF) is a severe form of Interstitial Lung Disease (ILD) that typically leads to respiratory failure and death or a lung transplant within five years of diagnosis. In collaboration with Dr. Jonathan Kropski (Vanderbilt) and as a part of the Human Cell Atlas, The Banovich Lab has characterized heterogeneous cells types and gene regulatory networks in ILD and healthy lungs on a single-cell level.

In collaboration with Dr. Davis McCarthy and postdoctoral researcher Dr. Christina Azodi (Univ. Melbourne), integrating whole-genome genotype data and gene expression measurements from more than 450,000 single cells, we have explored genetic effects on gene regulation in disease-relevant cell types. By integrating these cell-type expression quantitative trait loci (eQTL) with IPF GWAS (genome-wide association study) statistics, we reveal the regulatory mechanisms connecting IPF GWAS loci to disease risk and progression.

Read our paper on cell type-specific and disease-associated eQTL, published in Nature Genetics.

I have also studied the genetic regulation of gene expression across human populations. Integrating genotype, DNA methylation, and gene expression data across the Indonesian archipelago, we mapped regulatory variation shaped by local ancestry and archaic introgression.

Read our paper on the genetic architecture of gene regulation in Indonesian populations, published in the American Journal of Human Genetics.

Ethical, Legal, and Social Implications (ELSI) of genomics research

My contributions to examining the ethical, legal, and social implications of genetics and genomics research are largely focused on studies of behavioral, psychiatric, neurodevelopmental, and other sensitive traits. This work asks how genomic research can be conducted responsibly and equitably, and how the communities most affected by it can be meaningfully engaged in its design, conduct, and governance.

Much of my ELSI work examines questions at the intersection of genetics, bioethics, and disability, including the risks that genomic research and data can pose to groups rather than only individuals, and the frameworks needed to protect and empower those groups.

Read our paper "Towards justice and community empowerment in genomics studies on sensitive traits," published in the Hastings Center Report.

I advocate for more socially responsible research, and for diversity, equity, and inclusion in genomics research and the workforce.

I believe that members of marginalized groups affected by genetics and genomics research must be adequately represented at all levels of research and decision-making. I believe that improving the recruitment, support, and retention of underrepresented minorities in the genetics and genomics workforce will benefit individuals, institutions, science, and society as a whole.

I'm particularly interested in the questions at the intersection of genetics, bioethics, and disability, and the societal and ethical implications of the implementation of genetic data and testing in research and clinical practice.

I have served in numerous workgroups to facilitate discussion and debate around genomics research on neurodevelopmental, psychiatric, and other sensitive traits. I serve in the Spectrum 10K advisory board redesigning the study following a community consultation. I'm a member of the HEARD (Healthy Engagement in Autism Research Dialogue) leadership committee. HEARD is an initiative coordinated by The NeuroDevelopmental Variability Initiative of the Broad Institute, together with the Autism Science Foundation, to promote dialogue between and among stakeholder groups, including researchers, clinicians, autistic individuals, and their family members.

I have led, facilitated, and participated in numerous collaborative efforts to advocate for more sustainable research practices in psychiatric and neurodevelopmental research, particularly autism-related genomics studies. Supported by The Autism Intervention Research Network on Physical Health (AIR-P), I led and supervised an effort to develop a framework and guidelines for ethical genetic and genomic autism research. The Ethics in Genetics and Autism Research (EGAR) Workgroup is formed by autistic and non-autistic geneticists, bioethicists, genetic counselors, autism researchers, and advocates. Our paper Ethical challenges in autism genomics: Recommendations for researchers was published in the European Journal of Medical Genetics.

I am part of the American Society of Human Genetics (ASHG) professional guidance writing group on the participation of people with disabilities in genomics and precision medicine research. The guidance will be published in the coming months.

I have previously served in The Translational Genomics Research Institute's (TGen) Diversity, Equity, and Inclusion council.

View my CV with a complete list of publications and activities.