Celebrating 175 Years: 1846-2021
The isolation of mouse embryonic stem cells (mESCs) by Martin Evans in 1981 ushered in a new era of biomedical research. It enabled investigators to study the function of any gene in a mouse. Almost 40 years of mouse research has cured many mouse diseases that are used to model the human versions, from cancer to Alzheimer’s disease. Numerous failed clinical trials demonstrate that humans are very different from mice. The derivation of human embryonic stem cells (hESCs) in 1998 by James Thomson ignited the hope in doing for humans what was done for mice. Ethical concerns on the use of human embryos stimulated the search for alternatives, which culminated in the revolutionary discovery of induced pluripotent stem cells (iPSCs) by Shinya Yamanaka, for mouse in 2006 and for human in 2007. This disruptive technology enables investigators to study any inborn condition of an individual by converting easily accessible cells (e.g., those flushed out in urine) to iPSCs, which are virtually the same as hESCs and can thus be differentiated into any types of cells. Explosive growth in this area is rapidly changing biomedical research, drug discovery, and therapeutic development. It is now possible to generate virtually any types of human cells, not only in a flat layer, but in 3-D organoids that bear structural and functional resemblance to various human organs. We have converted human iPSCs to the naïve state, which is very similar to the state of mESCs. When naïve human iPSCs are injected into mouse blastocysts, human cells develop with the mouse embryos and generate chimeric embryos with up to 4 percent of mature human cells of various types, e.g., enucleated red blood cells, lens fiber cells, and liver cells. Several disruptive technologies on the horizon will fundamentally change our understanding of human biology and medicine in the next 25 years.
By injecting naïve human iPSCs into mouse blastocysts lacking a critical gene (e.g., Pdx1) for making a certain organ, it may be possible to make human organs, such as a pancreas, in a mouse. This technology, called blastocyst complementation, has been used to make a rat pancreas in a mouse and vice versa, by Hiromitsu Nakauchi. The goal is to make human organs in large animals with physiology similar to human (e.g., pigs). On a parallel track, pigs have been made compatible for human organs by CRISPR-mediated deletion of all porcine proviruses that are innocuous to pigs but harmful to humans. On the other hand, it is now possible to study the development of human cells, tissues and organs in mice through blastocyst complementation. These mouse-human chimeras will have the same appearance as mice, but with human components that would enable more accurate disease-modeling and therapeutic development. Because the development of human cells is dramatically accelerated to match the developmental pace of the mouse, it is also possible to study how human cells define age epigenetically. These studies may lead to such dramatic applications as attenuation or even reversal of aging.
From a fertilized egg to an adult, any organism is a DNA-based information processing system that deploys a prescribed sequence of epigenetic changes in cell states.
The next 25 years will witness the revelation of this operating system for humans. UB is well-positioned to ride the wave to the forefront of making disruptive medical breakthroughs. The most important task is to acquire talents who can shape the trajectory of the wave. There will be plenty of resources ready to support such exciting explorations. The time to act is now.