Research Summary

Research Interests: The mechanisms of globin production and exploring novel ways of inserting genes into mammalian cells; investigating newer approaches for fetal diagnosis of genetic disorders.

Research Summary: The research in our laboratory is focused on the study of two inherited blood diseases; sickle cell anemia and thalassemia. These two diseases constitute the most common genetic diseases in the world and they affect people of African, Mediterranean, Middle East, and Asian origins. At present, treatment mostly consists of treatment of symptoms and complications. Bone marrow or cord blood transfusion can be curative when compatible donors can be found. However, since most of these families have a small number of children, only a minority of patients can be treated by transplantation.

An effective way of preventing genetic diseases such as sickle cell anemia and thalassemia is by carrier screening, genetic counseling, and prenatal diagnosis. Our laboratory has been involved in prenatal diagnosis from the 1970s. Currently, amniocentesis and chorionic villus sampling is used to obtain DNA for diagnosis. We are investigating the isolation of fetal cells from the mother’s blood for testing so that an invasive procedure to the fetus can be avoided.
Out laboratory is also investigating gene and cell therapy for treating these conditions. In a thalassemia, the affected fetus usually dies in the third trimester or soon after birth. We have explored in utero gene therapy to treat this condition. Using a mouse model of alpha thalassemia that we have previously made, we introduced to the mouse embryo at the 14th day of gestation a lentiviral vector that contained the human alpha globin gene. Preliminary studies showed that human alpha globin was expressed at moderately levels. Our plan is to see if these vectors can rescue the fetal mouse affected by homozygous a thalassemia.

The mutations in sickle cell anemia and most clinically important ß thalassemia lie in the ß globin gene. Therefore, the approach to stem cell therapy for both is similar. We first tested embryonic stem cell therapy for a mouse model of sickle cell anemia. We made embryonic stem cells from a sickle cell anemia mouse, corrected the mutation by homologous recombination, differentiated the stem cells into hematopoietic cells and showed that the blood cells made hemoglobin A in additional to hemoglobin S.

To apply this treatment for the human diseases, it will be necessary to use nuclear transfer in stem cells in order to avoid immunological rejection. However, nuclear transfer to make embryonic stem cell has not been successful in humans. Also, the procedure is complicated, requires egg donors from normal individuals and raises ethical concern. With the description of induced pluripotent stem (iPS) cells, we have now changed to this approach for the treatment of these conditions. Our laboratory has successfully made iPS cells from mouse and human fibroblasts by retroviral delivery of transcription vectors.

Currently, we are working on correcting mutation in these iPS cells and differentiate them into hematopoietic cells. The future goal to treatment is to take skin cells from patients, differentiate them into iPS cells, correct the mutations by homologous recombination, and differentiate into the hematopoietic cells and re-infuse them into the patients. Since the cells originate from the patients, there would not be immuno-rejection. In order to achieve this goal, several conditions must first be met. First, to convert the skin cell into IPs cell it is necessary to use retrovirus induction. However, integration of retrovirus may disturb vital gene functions. Second, a reliable way of differentiating iPS cells into hematopoietic cells has to be established. We feel strongly that this approach will provide a means for curing these diseases.

Research Funding

  • September 30, 2011 - July 31, 2016 - Development of iPS Cells for Treatment of Hemoglobinopathies, Principal Investigator. Sponsor: NIH/NIDDK, Sponsor Award ID: P01DK088760
  • June 1, 1975 - April 30, 2015 - California National Primate Research Center, Co-Investigator. Sponsor: NIH, Sponsor Award ID: P51RR000169
  • February 1, 1999 - March 31, 2014 - Basic Research in Hematology and Oncology, Co-Principal Investigator. Sponsor: NIH/NIDDK, Sponsor Award ID: T32DK007636
  • July 1, 2003 - March 31, 2010 - Northern California Comprehensive Sickle Cell Centers, Co-Investigator. Sponsor: NIH, Sponsor Award ID: U54HL070583


University of Hong Kong, Hong Kong, M.B.B.S., 1958, Medicine
University of Hong Kong, Hong Kong, D.Sc., 1980, Medicine

Honors & Awards

  • 1979
    Dameshek Award, American Society of Hematology
  • 1980
    Stratton Award, International Society of Hematology
  • 1980
    George Thorn Award, Howard Hughes Medical Institute
  • 1984
    Gairdner Foundation International Award, Canada
  • 1984
    Allan Award, American Society of Human Genetics
  • 1984
    Lita Annenberg Hazen Award for Excellence in Clinical Research
  • 1985
    NIH Career Development Award
  • 1987
    Waterford Award
  • 1988
    American College of Physicians Award
  • 1989
    Sanremo International Award for Genetic Research, Italy
  • 1989
    Warren Alpert Foundation Prize
  • 1991
    Albert Lasker Clinical Medical Research Award
  • 1992
    Christopher Columbus Discovery Award in Biomedical Research
  • 1993
    City of Medicine Award
  • 1995
    Helmut Horten Research Award (Switzerland)
  • 2004
    Shaw Foundation Prize (Hong Kong)
  • M.D. Honoris Causa, University of Cagliari, Sardenia; DSC. Honoris Causa: University of Hong Kong, Chinese University of Hong Kong, Open University of Hong Kong. Honorary Professor: University of Hong Kong; Peking Union Medical College, Beijing; Zhejiang University, Hangzhou; Jia Tong University, Xi'an; First Military Medical University, Guanzhou; Fourth Medical Military University, Xi'an, China.

Selected Publications

  1. Morvan MG, Teque F, Ye L, Moreno ME, Wang J, VandenBerg S, Stoddart CA, Kan YW, Levy JA. Genetically edited CD34+ cells derived from human iPS cells in vivo but not in vitro engraft and differentiate into HIV-resistant cells. Proc Natl Acad Sci U S A. 2021 May 18; 118(20).  View on PubMed
  2. Mingoia M, Caria CA, Ye L, Asunis I, Marongiu MF, Manunza L, Sollaino MC, Wang J, Cabriolu A, Kurita R, Nakamura Y, Cucca F, Kan YW, Marini MG, Moi P. Induction of therapeutic levels of HbF in genome-edited primary ß0 39-thalassaemia haematopoietic stem and progenitor cells. Br J Haematol. 2021 01; 192(2):395-404.  View on PubMed
  3. Teque F, Ye L, Xie F, Wang J, Morvan MG, Kan YW, Levy JA. Genetically-edited induced pluripotent stem cells derived from HIV-1-infected patients on therapy can give rise to immune cells resistant to HIV-1 infection. AIDS. 2020 07 01; 34(8):1141-1149.  View on PubMed
  4. Zhao L, Xiao D, Liu Y, Xu H, Nan H, Li D, Kan Y, Cao X. Biochar as simultaneous shelter, adsorbent, pH buffer, and substrate of Pseudomonas citronellolis to promote biodegradation of high concentrations of phenol in wastewater. Water Res. 2020 Apr 01; 172:115494.  View on PubMed
  5. Tan YT, Ye L, Xie F, Wang J, Müschen M, Chen SJ, Kan YW, Liu H. CRISPR/Cas9-mediated gene deletion efficiently retards the progression of Philadelphia-positive acute lymphoblastic leukemia in a p210 BCR-ABL1T315I mutation mouse model. Haematologica. 2020 05; 105(5):e232-e236.  View on PubMed
  6. Zhao L, Nan H, Kan Y, Xu X, Qiu H, Cao X. Infiltration behavior of heavy metals in runoff through soil amended with biochar as bulking agent. Environ Pollut. 2019 Nov; 254(Pt B):113114.  View on PubMed
  7. Tan YT, Ye L, Xie F, Beyer AI, Muench MO, Wang J, Chen Z, Liu H, Chen SJ, Kan YW. Respecifying human iPSC-derived blood cells into highly engraftable hematopoietic stem and progenitor cells with a single factor. Proc Natl Acad Sci U S A. 2018 02 27; 115(9):2180-2185.  View on PubMed
  8. Wang JY, Fang M, Boye A, Wu C, Wu JJ, Ma Y, Hou S, Kan Y, Yang Y. Interaction of microRNA-21/145 and Smad3 domain-specific phosphorylation in hepatocellular carcinoma. Oncotarget. 2017 Oct 17; 8(49):84958-84973.  View on PubMed
  9. Xu X, Huang D, Zhao L, Kan Y, Cao X. Role of Inherent Inorganic Constituents in SO2 Sorption Ability of Biochars Derived from Three Biomass Wastes. Environ Sci Technol. 2016 Dec 06; 50(23):12957-12965.  View on PubMed
  10. Ye L, Wang J, Tan Y, Beyer AI, Xie F, Muench MO, Kan YW. Genome editing using CRISPR-Cas9 to create the HPFH genotype in HSPCs: An approach for treating sickle cell disease and ß-thalassemia. Proc Natl Acad Sci U S A. 2016 09 20; 113(38):10661-5.  View on PubMed
  11. Xie F, Gong K, Li K, Zhang M, Chang JC, Jiang S, Ye L, Wang J, Tan Y, Kan YW. Reversible Immortalization Enables Seamless Transdifferentiation of Primary Fibroblasts into Other Lineage Cells. Stem Cells Dev. 2016 08 15; 25(16):1243-8.  View on PubMed
  12. Xu X, Kan Y, Zhao L, Cao X. Chemical transformation of CO2 during its capture by waste biomass derived biochars. Environ Pollut. 2016 Jun; 213:533-540.  View on PubMed
  13. Suzuki S, Sargent RG, Illek B, Fischer H, Esmaeili-Shandiz A, Yezzi MJ, Lee A, Yang Y, Kim S, Renz P, Qi Z, Yu J, Muench MO, Beyer AI, Guimarães AO, Ye L, Chang J, Fine EJ, Cradick TJ, Bao G, Rahdar M, Porteus MH, Shuto T, Kai H, Kan YW, Gruenert DC. TALENs Facilitate Single-step Seamless SDF Correction of F508del CFTR in Airway Epithelial Submucosal Gland Cell-derived CF-iPSCs. Mol Ther Nucleic Acids. 2016 Jan 05; 5:e273.  View on PubMed
  14. Zhao L, Cao X, Zheng W, Kan Y. Phosphorus-assisted biomass thermal conversion: reducing carbon loss and improving biochar stability. PLoS One. 2014; 9(12):e115373.  View on PubMed
  15. Xie F, Ye L, Chang JC, Beyer AI, Wang J, Muench MO, Kan YW. Seamless gene correction of ß-thalassemia mutations in patient-specific iPSCs using CRISPR/Cas9 and piggyBac. Genome Res. 2014 Sep; 24(9):1526-33.  View on PubMed
  16. Ye L, Wang J, Beyer AI, Teque F, Cradick TJ, Qi Z, Chang JC, Bao G, Muench MO, Yu J, Levy JA, Kan YW. Seamless modification of wild-type induced pluripotent stem cells to the natural CCR5?32 mutation confers resistance to HIV infection. Proc Natl Acad Sci U S A. 2014 Jul 01; 111(26):9591-6.  View on PubMed
  17. Ye L, Muench MO, Fusaki N, Beyer AI, Wang J, Qi Z, Yu J, Kan YW. Blood cell-derived induced pluripotent stem cells free of reprogramming factors generated by Sendai viral vectors. Stem Cells Transl Med. 2013 Aug; 2(8):558-66.  View on PubMed
  18. Cao A, Kan YW. The prevention of thalassemia. Cold Spring Harb Perspect Med. 2013 Feb 01; 3(2):a011775.  View on PubMed
  19. Ye L, Chang JC, Lin C, Qi Z, Yu J, Kan YW. Generation of induced pluripotent stem cells using site-specific integration with phage integrase. Proc Natl Acad Sci U S A. 2010 Nov 09; 107(45):19467-72.  View on PubMed
  20. Kan YW, Chang JC. Molecular diagnosis of hemoglobinopathies and thalassemia. Prenat Diagn. 2010 Jul; 30(7):608-10.  View on PubMed

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