Of mice and men: recent developments in the field of transgenic research

The mouse is the workhorse of experimental biomedical research. The mouse genetic code is 75% similar to ours, so researchers often use mice to study human illnesses and how they develop.¹ Amazingly, researchers have now sequenced the entire mouse genome. An international team of researchers recently published the news in the open-access journal PLoS Biology.² The mouse (Mus musculus) is the first mammal after humans to have its genetic sequence published. Notably, 20% of mouse genes are new copies that emerged in the last 90 million years of mouse evolution.³ Now that scientists have filled in the gaps in our collective knowledge of the mouse genome, we can definitively identify important similarities and differences.

However, this remarkable achievement may be outshone by another exciting development in the field of transgenics. Japanese researchers recently reported the passage of a transgene from parent to offspring - in primates!⁴ Dr. Erika Sasaki successfully engineered transgenic marmosets to express the gene for green fluorescent protein (GFP) in several organs. More importantly, the researchers successfully expressed the transgene in the sex cells of these marmosets. After the GFP gene passed successfully from parent to offspring, the transgenic offspring developed normally - except for one that died after being bitten by its mother.

How did they do it? Sasaki et al. found that naturally produced embryos, taken from the reproductive tract of mated females, were better transgene carriers than embryos generated by in vitro fertilization.⁵ To improve the efficiency of transgene delivery, scientists placed the embryo in a sugar solution to create a space between the embryo and its outer coating.⁶ This additional wiggle-room allowed the researchers to inject more transgene-containing particles.

This new transgenic primate model has several advantages over the traditional mouse model because mice cannot be engineered to serve as a model for all human disorders, especially disorders of higher brain function that affect social relationships. Interestingly, marmoset researchers have long noted that the species engages in monagamy. Since marmosets maintain familial relationships and share certain social characteristics with humans, these New World monkeys could represent a way to study diseases that affect aspects of human brain function and sociality. Furthermore, germ-line transmission of the transgene represents a huge technological leap forward. The creation of a transgenic animal from square one is time-intensive. In a self-perpetuating colony, the vast amount of labor that goes into the creation of founder animals will only need to be invested once. So Dr. Sasaki's discovery might accelerate the translation of scientific findings from mice to patients. Finally, there are the logistics. Marmosets are small and relatively easy to handle. They reach sexual maturity in little over a year. Females can have up to 80 offspring, compared to 10 in the more commonly used rhesus macaque.

But the selection of marmosets as a model species also presents certain disadvantages. Marmosets are New World primates, more distant to us than Old World primates, such as rhesus macaques and baboons. Due to certain biological differences, diseases such as HIV/AIDS, macular degeneration and tuberculosis can only be studied in Old World primates. What's more, normal marmosets fail tests used to gauge Parkinson's disease.⁵ Their brains are too small for positron emission tomography scans. Also, most primate biomedical research to date has been performed in rhesus macaques. In contrast, there is little accumulated knowledge with regard to these same biological phenomena in marmosets.
    
The technique that the Sasaki group developed has also caused concern among some scientists. Dr. Sasaki used a lentivirus vector to carry the transgene into the genome of the embryo. After injection, the GFP transgene inserted randomly into the DNA. In contrast, transgenic mice are routinely generated using embryonic stem cells. In the latter technique, the transgene is directly targeted to a specific site in the genome by a method that harnesses the power of homologous recombination. The random insertion site used in the case of the marmosets could lead to the activation of sequences in the primate genome that are poorly understood.

This new frontier will require explicit regulations and a clear dialogue between scientists and animal rights activists. Dr. Sasaki's first target is finding a cure for Huntington's disease. The road will be challenging.

¹Rincon, Paul. Mouse genome laid bare to science. BBC News. 27 May 2009.
²Church, DM, et al. Lineage-Specific Biology Revealed by a Finished Genome Assembly of the Mouse. PLoS Biol, 7(5): e1000112 DOI: 10.1371/journal.pbio.1000112
³More genetic differences between mice and humans than previously thought. ScienceDaily 27 May 2009.
⁴Cyranoski, David. Marmoset model takes center stage. Naturenews. 27 May 2009.
⁵Schatten, G. and Mitalipov, S. Developmental Biology: Transgenic primate offspring. Nature 459, 515-516 (28 May 2009).
⁶Sasaki, et al. Generation of non-human primates with germline transmission. Nature 459, 523-527 (28 May 2009).