About

Harvey F. Lodish is a Professor of Biology and Biological Engineering at MIT and a Founding Member of the Whitehead Institute. Before closing his lab in 2020, his research focused on the development of red blood cells and the use of modified red cells for introducing novel therapeutics into the human body, as well as the development of brown and white fat cells. He has been a leader in molecular cell biology and biotechnology entrepreneurship for over five decades. His early research concentrated on the regulation of messenger RNA translation and the biogenesis of plasma membrane glycoproteins. Beginning in the 1980s, his work involved cloning and characterizing many proteins, microRNAs, and long noncoding RNAs important for red cell development and function. His laboratory was the first to clone and sequence mRNAs encoding hormone receptors, mammalian glucose transport proteins, and proteins involved in adipose cell formation and function. He identified and characterized several genes and proteins involved in insulin resistance and stress responses in adipose cells. Throughout his career, he has mentored hundreds of students and postdoctoral fellows and continues to teach classes on biotechnology. He has received numerous awards, including the Wallace H. Coulter Award for Lifetime Achievement in Hematology and the Donald Metcalf Award, and is a member of the National Academy of Sciences and the American Academy of Arts and Sciences.

Research topics

• Biology
• Cell biology
• Molecular biology
• Chemistry
• Biochemistry

Selected publications

• Reconstruction of Megaloblastic Anemia in a Novel Erythroblastic Island Humanized Mouse Model with Mature Circulating Human Red Blood Cells

  Blood · 2024-11-05

  articleOpen access

  Human immune system (HIS) mice are powerful tools for human hematopoietic system research but lack efficient reconstitution of human red blood cells (hRBCs) as a result of peripheral clearance by murine macrophages. Administration of clodronate liposome (Clod) abrogates murine macrophages and rescues circulating peripheral blood (PB) hRBCs in HIS mice, but only transiently and with significant toxicity. In 2021, liver and cytokine double humanized huHepMISTRG-Fah model destructs murine liver macrophages and rescues circulating hRBCs. However, the maturation status of hRBCs in PB of this model is not comparable with that of human counterparts, as indicated by the abnormal expression of human CD71. Consequently, the development and evaluation of therapeutics for maturation-associated erythropoietic diseases in HIS mice, such as hereditary megaloblastic anemia (MgA), is severely hindered by the maturation abnormality of hRBCs. Previous studies focused on the erythro-phagocytotic function of murine macrophages, thereby overlooking their supporting role in the erythropoiesis. The differentiation of erythroblasts is accompanied by the formation of erythroblastic islands (EBIs), which are described as a macrophage surrounded by erythroblasts of different maturation stages. The macrophage within the EBI is involved in nucleus digestion, iron transportation and organelles clearance of erythroblasts. Clod depletes macrophages in several organs including bone marrow (BM), which destroys murine EBI structure and contributes to significant toxicity due to impaired erythropoiesis. Our preliminary results indicated the maturation sufficiency of human erythroblasts in HIS mice, as indicated by the hemoglobin switch and potential to differentiate into mature RBCs in vivo. Interestingly. we also observed hybrid EBIs with human erythroblasts and murine macrophage NCG HIS mouse BM, and hypothesized that human EBI reconstitution in HIS mice would improve human erythroblasts development and increase circulating mature hRBCs in vivo. We used a combination of anti-mouse CSF1R and F4/80 antibodies with dexamethasone for repopulating human EBIs in HIS mice (EBI-HIS). Human EBI structure in BM was captured by imaging flow cytometry, which was characterized by human CD14+CD163+ macrophages surrounded by human CD235a+ erythroblasts of varying sizes. Our finding demonstrated that human EBIs reconstitution allowed higher percentages of circulating hRBCs compared to Clod injection, representing up to 14.4% of total RBCs in PB. Notably, hRBCs in PB of EBI-HIS mice closely resemble those in human blood, which show similar hCD71 and hCD235a expression, as well as comparable enucleation rates. Hereditary MgA is an inherited blood disorder caused by genetic mutations affecting Vitamin B12 and folate absorption. Megaloblasts are prone to destruction in blood vessels, resulting in anemic syndromes of patients. Few mouse models have successfully recapitulated MgA due to its genetic complexity. To determine whether circulating mature hRBCs in EBI-HIS mice would be sufficient to replicate human anemic diseases in vivo, we purified human HSCs from BM samples of hereditary MgA patients and engrafted them into newborn pups. Human erythroblasts in BM showed larger cell size. Abnormal nucleated hRBCs were observed in PB of patients HSCs-engrafted mice but not in normal HSCs-engrafted mice. Tissues analysis of MgA HSC-engrafted mice revealed significant abnormalities, identified by human hemoglobin alpha antibody. Lungs showed increased thrombosis and alveolar hemorrhage, microvascular thromboses and presence of hRBCs in sinusoids was observed in liver samples. Peritubular capillaries and glomeruli engorged were identified in kidneys, vascular occlusion and thrombosis were obvious in spleens of MgA HSCs-engrafted mice but not of normal HSCs-engrafted mice. Thus, EBI-HIS model allows successful establishment of human erythropoiesis and recapitulates pathologic changes of MgA diseases in vivo. In summary, we herein present our EBI-HIS mice with enhanced human erythropoiesis and circulating fully mature hRBCs. This improved human RBC model recapitulated clinical features of life-threatening erythropoietic disorders like hereditary MgA, and could serve as a valuable preclinical animal model for development and evaluation of therapeutics.

  PublisherOA PDFDOI

• Supplementary Figure Legends 1-2 from Enrichment of a Population of Mammary Gland Cells that Form Mammospheres and Have <i>In vivo</i> Repopulating Activity

  2023-03-30

  preprintOpen access

  Supplementary Figure Legends 1-2 from Enrichment of a Population of Mammary Gland Cells that Form Mammospheres and Have <i>In vivo</i> Repopulating Activity

  PublisherOA PDFDOI

• Data from Enrichment of a Population of Mammary Gland Cells that Form Mammospheres and Have <i>In vivo</i> Repopulating Activity

  2023-03-30

  preprintOpen access

  <div>Abstract<p>The identification of mammary gland stem cells (MGSC) or progenitors is important for the study of normal breast development and tumorigenesis. Based on their immunophenotype, we have isolated a population of mouse mammary gland cells that are capable of forming “mammospheres” <i>in vitro</i>. Importantly, mammospheres are enriched for cells that regenerate an entire mammary gland on implantation into a mammary fat pad. We also undertook cytogenetic analyses of mammosphere-forming cells after prolonged culture, which provided preliminary insight into the genomic stability of these cells. Our identification of new cell surface markers for enriching mammosphere-initiating cells, including endoglin and prion protein, will facilitate the elucidation of the cell biology of MGSC. [Cancer Res 2007;67(17):8131–8]</p></div>

  PublisherDOI

• Supplementary Figures 1-2 from Enrichment of a Population of Mammary Gland Cells that Form Mammospheres and Have <i>In vivo</i> Repopulating Activity

  2023-03-30

  preprintOpen access

  Supplementary Figures 1-2 from Enrichment of a Population of Mammary Gland Cells that Form Mammospheres and Have <i>In vivo</i> Repopulating Activity

  PublisherDOI

• Supplementary Figure Legends 1-2 from Enrichment of a Population of Mammary Gland Cells that Form Mammospheres and Have <i>In vivo</i> Repopulating Activity

  2023-03-30

  preprintOpen access

  Supplementary Figure Legends 1-2 from Enrichment of a Population of Mammary Gland Cells that Form Mammospheres and Have <i>In vivo</i> Repopulating Activity

  PublisherDOI

• Supplementary Figures 1-2 from Enrichment of a Population of Mammary Gland Cells that Form Mammospheres and Have <i>In vivo</i> Repopulating Activity

  2023-03-30

  preprintOpen access

  Supplementary Figures 1-2 from Enrichment of a Population of Mammary Gland Cells that Form Mammospheres and Have <i>In vivo</i> Repopulating Activity

  PublisherOA PDFDOI

• Data from Enrichment of a Population of Mammary Gland Cells that Form Mammospheres and Have <i>In vivo</i> Repopulating Activity

  2023-03-30

  preprintOpen access

  <div>Abstract<p>The identification of mammary gland stem cells (MGSC) or progenitors is important for the study of normal breast development and tumorigenesis. Based on their immunophenotype, we have isolated a population of mouse mammary gland cells that are capable of forming “mammospheres” <i>in vitro</i>. Importantly, mammospheres are enriched for cells that regenerate an entire mammary gland on implantation into a mammary fat pad. We also undertook cytogenetic analyses of mammosphere-forming cells after prolonged culture, which provided preliminary insight into the genomic stability of these cells. Our identification of new cell surface markers for enriching mammosphere-initiating cells, including endoglin and prion protein, will facilitate the elucidation of the cell biology of MGSC. [Cancer Res 2007;67(17):8131–8]</p></div>

  PublisherDOI

• An adipose lncRAP2-Igf2bp2 complex enhances adipogenesis and energy expenditure by stabilizing target mRNAs

  iScience · 2021-12-24 · 19 citations

  articleOpen accessCorresponding

  interactome analyses, we show that lncRAP2 forms complexes with proteins that stabilize mRNAs and modulate translation, among them Igf2bp2. Surveying transcriptome-wide Igf2bp2 client mRNAs in white adipocytes reveals selective binding to mRNAs encoding adipogenic regulators and energy expenditure effectors, including adiponectin. These same target proteins are downregulated when either Igf2bp2 or lncRAP2 is downregulated, hindering adipocyte lipolysis. Proteomics and ribosome profiling show this occurs predominantly through mRNA accumulation, as lncRAP2-Igf2bp2 complex binding does not impact translation efficiency. Phenome-wide association studies reveal specific associations of genetic variants within both lncRAP2 and Igf2bp2 with body mass and type 2 diabetes, and both lncRAP2 and Igf2bp2 are suppressed in adipose depots of obese and diabetic individuals. Thus, the lncRAP2-Igf2bp2 complex potentiates adipose development and energy expenditure and is associated with susceptibility to obesity-linked diabetes.

  PublisherOA PDFDOI

• Engineered red blood cells carrying PCSK9 inhibitors persistently lower LDL and prevent obesity

  PLoS ONE · 2021-11-03 · 4 citations

  articleOpen access

  Low plasma levels of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) are associated with decreased low-density lipoprotein (LDL) cholesterol and a reduced risk of cardiovascular disease. PCSK9 binds to the epidermal growth factor-like repeat A (EGFA) domain of LDL receptors (LDLR), very low-density lipoprotein receptors (VLDLR), apolipoprotein E receptor 2 (ApoER2), and lipoprotein receptor-related protein 1 (LRP1) and accelerates their degradation, thus acting as a key regulator of lipid metabolism. Antibody and RNAi-based PCSK9 inhibitor treatments lower cholesterol and prevent cardiovascular incidents in patients, but their high-cost hampers market penetration. We sought to develop a safe, long-term and one-time solution to treat hyperlipidemia. We created a cDNA encoding a chimeric protein in which the extracellular N- terminus of red blood cells (RBCs) specific glycophorin A was fused to the LDLR EGFA domain and introduced this gene into mouse bone marrow hematopoietic stem and progenitor cells (HSPCs). Following transplantation into irradiated mice, the animals produced RBCs with the EGFA domain (EGFA-GPA RBCs) displayed on their surface. These animals showed significantly reduced plasma PCSK9 (66.5% decrease) and reduced LDL levels (40% decrease) for as long as 12 months post-transplantation. Furthermore, the EGFA- GPA mice remained lean for life and maintained normal body weight under a high-fat diet. Hematopoietic stem cell gene therapy can generate red blood cells expressing an EGFA-glycophorin A chimeric protein as a practical and long-term strategy for treating chronic hyperlipidemia and obesity.

  PublisherOA PDFDOI

• An adipocyte-specific lncRAP2 – Igf2bp2 complex enhances adipogenesis and energy expenditure by stabilizing target mRNAs

  bioRxiv (Cold Spring Harbor Laboratory) · 2020-09-29

  preprintOpen accessCorresponding

  Abstract lncRAP2 is a conserved cytoplasmic adipocyte-specific lncRNA required for adipogenesis. Using hybridization-based purification combined with in vivo interactome analyses, we show that lncRAP2 forms ribonucleoprotein complexes with several mRNA stability and translation modulators, among them Igf2bp2. Transcriptome-wide identification of Igf2bp2 client mRNAs in white adipocytes reveals selective binding to mRNAs encoding adipogenic effectors and regulators. Depleting either lncRAP2 or Igf2bp coordinately downregulates these same target proteins. Ribosome profiling and quantitative proteomics show that this occurs predominantly at the level of mRNA, as binding of the lncRAP2-Igf2bp complex does not affect mRNA translation. Suppressing lncRAP2 or Igf2bp2 selectively destabilizes many mRNAs encoding proteins essential for energy expenditure, including Adiponectin, reducing adipocyte lipolytic capacity. Genome-wide association studies reveal specific association of genetic variants within both lncRAP2 and Igf2bp2 with body mass and type 2 diabetes, and we find that adipose lncRAP2 and Igf2bp2 are suppressed during obesity and diabetes progression. Thus, the lncRAP2-Igf2bp complex potentiates adipose development and energy expenditure and is associated with susceptibility to obesity-linked diabetes.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01DK037571

  NIH · $1.2M · 1991

• NIH Grant R01AI022347

  NIH · $269k · 1986

• NIH Grant R01GM035012

  NIH · $1.8M · 1994

• NIH Grant R01DK067356

  NIH · $2.4M · 2012

• Project 1 BCL11A Protein in Hemoglobin Regulation, Stuart H. Orkin

  NIH · $79.9M · 1997–2022

Frequent coauthors

• Mike Hennessy

  Target (United States)

  320 shared

• Nora A. Janjan

  STATinMED (United States)

  320 shared

• Sonali M. Smith

  320 shared

• Angela J. Fought

  Mayo Clinic

  320 shared

• Tara Ghalambor

  University of Arizona

  320 shared

• Nikia R. McFadden

  University of California Davis Medical Center

  320 shared

• Kirk E. Cahill

  Loyola University Chicago

  320 shared

• Whitney Ly

  University of North Carolina Health Care

  320 shared

Awards & honors

• Wallace H. Coulter Award for Lifetime Achievement in Hematol…
• Donald Metcalf Award, International Society for Experimental…
• American Society for Cell Biology WICB Sandra K. Masur Senio…
• Pioneer Award, Diamond Blackfan Anemia Foundation, 2016
• Mentor Award in Basic Science, American Society of Hematolog…