Skip to main content
SpringerLink
Log in
Book cover

Chimera Research pp 221–231Cite as

Human-Monkey Chimeras for Modeling Human Disease: Opportunities and Challenges

Part of the Methods in Molecular Biology book series (MIMB,volume 2005)

Abstract

The search for a better animal model to simulate human disease has been a “holy grail” of biomedical research for decades. Recent identification of different types of pluripotent stem cells (PS cells) and advances in chimera research might soon permit the generation of interspecies chimeras from closely related species, such as those between humans and other primates. Here, we suggest that the creation of human-primate chimeras—specifically, the transfer of human stem cells into (non-ape) primate hosts—could surpass the limitations of current monkey models of neurological and psychiatric disease, but would also raise important ethical considerations concerning the use of monkeys in invasive research. Questions regarding the scientific value and ethical concerns raised by the prospect of human-monkey chimeras are more urgent in light of recent advances in PS cell research and attempts to generate interspecies chimeras between humans and animals. While some jurisdictions prohibit the introduction of human PS cells into monkey preimplantation embryos, other jurisdictions may permit and even encourage such experiments. Therefore, it is useful to consider blastocyst complementation experiments more closely in light of advances that could make these chimeras possible and to consider the ethical and political issues that are raised.

Key words

  • Interspecies chimeras
  • Pluripotency
  • Chimeras
  • Reprogramming
  • Naïve pluripotency
  • Naïve pluripotent stem cells
  • Primed pluripotent stem cells
  • Nonhuman primates
  • Human-monkey chimeras
  • Disease modeling
  • Stem cells

This is a preview of subscription content, access via your institution.

Protocol
USD   49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. World Health Organization (2006) Neurological disorders: public health challenges. WHO Press, Switzerland

    Google Scholar 

  2. Miller G (2010) Is pharma running out of brainy ideas? Science 329:502–504

    CrossRef  CAS  PubMed  Google Scholar 

  3. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676

    CrossRef  CAS  PubMed  Google Scholar 

  4. Takahashi K, Tanabe S, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872

    CrossRef  CAS  PubMed  Google Scholar 

  5. Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H, Chung W, Croft GF, Saphier G, Leibel R, Goland R, Wichterle H, Hendersen CE, Eggan K (2008) Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321:1218–1221

    CrossRef  CAS  PubMed  Google Scholar 

  6. Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, Lensch MW, Cowan C, Hochedlinger K, Daley GQ (2008) Disease-specific induced pluripotent stem cells. Cell 134:877–886

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  7. Brennand KJ, Marchetto MC, Benvenisty N, Brustle O, Ebert A, Izpisua Belmonte JC, Kaykas A, Lancaster MA, Livesey FJ, McConnell MJ, McKay RD, Morrow EM, Muotri AR, Panchision DM, Rubin LL, Sawa A, Soldner F, Song H, Studer L, Temple S, Vaccarino FM, Wu J, Vanderhaeghen P, Gage FH, Jaenisch R (2015) Creating patient-specific neural cells for the in vitro study of brain disorders. Stem Cell Rep 5:933–945

    CrossRef  Google Scholar 

  8. Soldner F, Stelzer Y, Shivalila CS, Abraham BJ, Latourelle JC, Barrasa MI, Goldmann J, Myers RH, Young RA, Jaenisch R (2016) Parkinson-associated risk variant in distal enhancer of alpha-synuclein modulates target gene expression. Nature 533:95–99

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  9. Goldman SA, Nedergaard M, Windrem MS (2015) Modeling cognition and disease using human glial chimeric mice. Glia 63:1483–1493

    CrossRef  PubMed  PubMed Central  Google Scholar 

  10. Windrem MS, Osipovitch M, Liu Z, Bates J, Chandler-Militello D, Zou L, Munir J, Schanz S, McCoy K, Miller RH, Wang S, Nedergaard M, Findling RL, Tesar PJ, Goldman S (2017) Human iPSC glial mouse chimeras reveal glial contributions to schizophrenia. Cell Stem Cell 21:195–208

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  11. Benraiss A, Wang S, Herrlinger S, Li X, Chandler-Militello D, Mauceri J, Burm HB, Toner M, Osipovitch M, Jim Xu Q, Ding F, Wang F, Kang N, Kang J, Curtin PC, Brunner D, Windrem MS, Munoz-Sanjuan I, Nedergaard M, Goldman SA (2016) Human glia can both induce and rescue aspects of disease phenotype in Huntington disease. Nat Commun 7:11758

    CrossRef  PubMed  PubMed Central  Google Scholar 

  12. Langston JW, Forno LS, Rebert CS, Irwin I (1984) Selective nigral toxicity after systemic administration of 1-methyl-4phenyl 1-1,2,3,6, tetrahydropyridine (MPTP) in the squirrel monkey. Brain Res 292:390–394

    CrossRef  CAS  PubMed  Google Scholar 

  13. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F (2013) Multiplex genome engineering using CRISPR/Cas systems. Science 339:819–823

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, Norville JE, Church GM (2013) RNA-guided human genome engineering via Cas9. Science 339:823–826

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  15. Niu Y, Shen B, Cui Y, Chen Y, Wang J, Wang L, Kang Y, Zhao X, Si W, Li W, Xiang AP, Zhou J, Guo X, Bi Y, Si C, Hu B, Dong G, Wang H, Zhou Z, Li T, Tan T, Pu X, Wang F, Ji S, Zhou Q, Huang X, Ji W, Sha J (2014) Generation of gene-modified cynomolgus monkeys via Cas9/RNA-mediated gene targeting in one-cell embryos. Cell 156:836–845

    CrossRef  CAS  PubMed  Google Scholar 

  16. Liu Z, Cai Y, Wang Y, Nie Y, Zhang C, Xu Y, Zhang X, Lu Y, Wang Z, Poo M, Sun Q (2018) Cloning of macaque monkeys by somatic cell nuclear transfer. Cell 172:881–887

    CrossRef  CAS  PubMed  Google Scholar 

  17. De Los Angeles A, Ferrari F, Xi R, Fujiwara Y, Benvenisty N, Deng H, Hochedlinger K, Jaenisch R, Lee S, Leitch HG, Lensch MW, Lujan E, Pei D, Rossant J, Wernig M, Park PJ, Daley GQ (2015) Hallmarks of pluripotency. Nature 525:469–478

    CrossRef  PubMed  Google Scholar 

  18. Nichols J, Smith A (2009) Naïve and primed pluripotent states. Cell Stem Cell 4:487–492

    CrossRef  CAS  PubMed  Google Scholar 

  19. Tesar PJ, Chenoweth JG, Brook FA, Davies TJ, Evans EP, Mack DL, Gardner RL, McKay RD (2007) New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448:196–199

    CrossRef  CAS  PubMed  Google Scholar 

  20. Tachibana M, Sparman M, Ramsey C, Ma H, Lee HS, Penedo MC, Mitalipov S (2012) Generation of chimeric rhesus monkeys. Cell 148:285–295

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wu J, Platero-Luengo A, Sakurai M, Sugawara A, Gil MA, Yamauchi T, Suzuki K, Bogliotti YS, Cuello C, Morales Valencia M, Okumura D, Luo J, Vilarino M, Parrilla I, Soto DA, Martinez CA, Hishida T, Sanchez-Bautista S, Martinez-Martinez ML, Wang H, Nohalez A, Aizawa E, Martinez-Redondo P, Ocampo A, Reddy P, Roca J, Maga EA, Esteban CR, Berggren WT, Nunez Delicado E, Lajara J, Guillen I, Guillen P, Campistol JM, Martinez EA, Ross PJ, Izpisua Belmonte JC (2017) Interspecies chimerism with mammalian pluripotent stem cells. Cell 168:473–486

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kobayashi T, Yamaguchi T, Hamanaka S, Kato-Itoh M, Yamazaki Y, Ibata M, Sato H, Lee YS, Usui J, Knisely AS, Hirabayashi M, Nakauchi H (2010) Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. Cell 142:787–799

    CrossRef  CAS  PubMed  Google Scholar 

  23. Theunissen TW, Friedli M, He Y, Planet E, O’Neil RC, Markoulaki S, Pontis J, Wang H, Iouranova A, Imbeault M, Duc J, Cohen MA, Wert KJ, Castanon R, Zhang Z, Huang Y, Nery JR, Drotar J, Lungjangwa T, Trono D, Ecker JR, Jaenisch R (2016) Molecular criteria for defining the naïve human pluripotent state. Cell Stem Cell 19:502–515

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cohen MA, Markoulaki S, Jaenisch R (2018) Matched developmental timing of donor cells with the host is crucial for chimera formation. Stem Cell Rep 10:1–8

    CrossRef  Google Scholar 

  25. Wu J et al (2015) An alternative pluripotent state confers interspecies chimeric competency. Nature 521:316–321

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mascetti VL, Pedersen RA (2016) Human-mouse chimerism validates human stem cell pluripotency. Cell Stem Cell 18:67–72

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  27. Boroviak T, Nichols J (2017) Primate embryogenesis predicts the hallmarks of human naïve pluripotency. Development 144:175–186

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ramos-Ibeas P, Sang F, Zhu Q, Tang WWC, Withey S, Klisch D, Loose M, Surani MA, Alberio R. Lineage segregation, pluripotency and X-chromosome inactivation in the pig pre-gastrulation embryo. bioRxiv. Accessed 30 Jun 2018

    Google Scholar 

  29. Tsukiyama T, Ohinata Y (2014) A modified EpiSC culture condition containing a GSK3 inhibitor can support germline-competent pluripotency in mice. PLoS One 9:e95329

    CrossRef  PubMed  PubMed Central  Google Scholar 

  30. De Los Angeles A, Pho N, Redmond DE Jr (2018) Generating human organs via interspecies chimera formation: advances and barriers. Yale J Biol Med 91:333–342

    PubMed  PubMed Central  Google Scholar 

  31. Walker LC, Jucker M (2017) The exceptional vulnerability of humans to Alzheimer’s disease. Trends Mol Med 23:534–545

    CrossRef  PubMed  PubMed Central  Google Scholar 

  32. Gomez-Isla T, West HL, Rebeck GW, Harr SD, Growdon JH, Locascio JJ, Perls TT, Lipsitz LA, Hyman BT (1996) Clinical and pathological correlates of apolipoprotein E epsilon 4 in Alzheimer’s disease. Ann Neurol 39:62–70

    CrossRef  CAS  PubMed  Google Scholar 

  33. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijin CM (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer disease meta-analysis consortium. JAMA 278:1349–1356

    CrossRef  CAS  PubMed  Google Scholar 

  34. Tang MX, Stern Y, Marder K, Bell K, Gurland B, Lantigua R, Andrews H, Feng L, Tycko B, Mayeux R (1998) The APOE-epsilon4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics. JAMA 279:751–755

    CrossRef  CAS  PubMed  Google Scholar 

  35. Chang AN, Liang Z, Dai H-Q, Chapdelaine-Williams AM, Andrews N, Bronson RT, Schwer B, Alt FW (2018) Neural blastocyst complementation enables mouse forebrain organogenesis. Nature 563:126–130

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  36. Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobwitz DM, Kopin IJ (1983) A primate model of Parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine. PNAS 80:4546–4550

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  37. Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979–980

    CrossRef  CAS  PubMed  Google Scholar 

  38. Hyman SE (2018) The daunting polygenicity of mental illness: making a new map. Philos Trans R Soc Lond Ser B Biol Sci 19:373

    Google Scholar 

  39. Jentsch JD, Redmond DE Jr, Elsworth JD, Taylor JR, Youngren KD, Roth RH (1997) Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine. Science 277:953–955

    CrossRef  CAS  PubMed  Google Scholar 

  40. Farahany NA, Greely HT, Hyman S, Koch C, Grady C, Pasca SP, Sestan N, Arlotta P, Bernat JL, Ting J, Lunshof JE, Iyer EPR, Hyun I, Capestany BH, Church GM, Huang H, Song H (2018) The ethics of experimenting with human brain tissue. Nature 556:429–432

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hyun I (2016) Illusory fears must not stifle chimaera research. Nature 537:281

    CrossRef  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Reprinted from Stem Cells and Development with permission from Mary Ann Liebert, Inc., New Rochelle, NY.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Alejandro De Los Angeles & John D. Elsworth

  2. Department of Bioethics, Case Western Reserve University, School of Medicine, Cleveland, OH, USA

    Insoo Hyun

  3. Yale Interdisciplinary Center for Bioethics, Yale University, New Haven, CT, USA

    Stephen R. Latham

  4. Axion Research Foundation, Hamden, CT, USA

    D. Eugene Redmond Jr.

Authors
  1. Alejandro De Los Angeles
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Insoo Hyun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen R. Latham
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John D. Elsworth
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D. Eugene Redmond Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D. Eugene Redmond Jr. .

Editor information

Editors and Affiliations

  1. Department of Bioethics, Case Western Reserve University, School of Medicine, Cleveland, OH, USA

    Insoo Hyun

  2. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Alejandro De Los Angeles

Rights and permissions

Reprints and Permissions

Copyright information

© 2019 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

De Los Angeles, A., Hyun, I., Latham, S.R., Elsworth, J.D., Redmond, D.E. (2019). Human-Monkey Chimeras for Modeling Human Disease: Opportunities and Challenges. In: Hyun, I., De Los Angeles, A. (eds) Chimera Research . Methods in Molecular Biology, vol 2005. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9524-0_15

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-9524-0_15

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-4939-9523-3

  • Online ISBN: 978-1-4939-9524-0

  • eBook Packages: Springer Protocols

search

Navigation