by Alan Trounson
Leading light in animal cloning
Jerry Yang, who died on 5 February in Boston, Massachusetts, made exceptional contributions to research on animal biotechnology and cloning, and he was a prominent figure in the scientific dialogue between the United States and China. He was only 49 when he died, finally succumbing to cancer of the salivary gland. Losing battles, however, was not Yang's way of life.
He was born in 1959, in China, and barely survived the famine of 1959–1960. His parents were poor pig farmers in the tiny village of Dongcun, about 500 kilometres south of Beijing, but in the late 1970s the award of a place at Beijing Agricultural College set Yang on the road to a wider world. A scholarship to Cornell University in New York followed, where he took a master's degree and completed his PhD in reproductive physiology.
Success in his subsequent research at Cornell led to his being hired by the University of Connecticut in 1996, where he held various positions, including director of the Center for Regenerative Biology. It was no mean achievement to have risen from such humble beginnings to conquer the Chinese education system, and then to have won major grants and promotions in the demanding US tertiary research system.
In another respect, Yang was fortunate in having a well-prepared mind at a momentous juncture in the history of research on animal embryology. The birth of the cloned sheep Dolly was announced in 1997, and had an influence far beyond the scientific community concerned. Her birth was achieved through the procedure of somatic cell nuclear transfer (SCNT), in which the nucleus — and so the genetic complement — of a mammary gland cell from a mature ewe was transferred into an unfertilized sheep oocyte or egg cell, which was then allowed to develop before being implanted in a recipient ewe and coming to term. Cloning from an adult cell rarely works; it requires hundreds of nuclear transfers to produce a viable animal. Nor is it successful in humans. But it promised to revolutionize animal breeding through the cloning of prize livestock. And it had the potential to create a new branch of regenerative medicine, one using the patient's own immune-compatible cells that could be reprogrammed by cloning to produce pluripotent stem cells for the repair of damaged and diseased tissues.
Yang was in the thick of the ensuing period of intensive research. In papers that appeared between 2000 and 2006, his work confirmed that — in cattle, rabbits, pigs, mice and swamp buffalo — fully differentiated adult somatic cells can be reprogrammed into developmentally normal embryonic cells capable of forming fully viable offspring. (See Figure 1.) Moreover, he showed that first- and second-generation clones have normal fertility, which was particularly informative for sustained breeding of genetically valuable cloned bulls.
Also in early work, Yang settled the debate on telomere shortening — the serial reduction in length of the ends of chromosomes as cells divide — which had been proposed as a limiting factor in the viability of cloned animals. Telomere length was unaffected by nuclear transfer procedures, and no shortening was found in offspring cloned from even aged adults. Yang's work on cattle and many other species catapulted the United States into the forefront of animal cloning, with many biotechnology companies examining the commercial opportunities for investment in animal breeding and for protein production in transgenic and cloned animals.
In his basic research, Yang explored the cell biology of nuclear reprogramming. Notably — and contrary to expectations at the time — in 2006 he controversially reported that cloning efficiency increased with increasing differentiation within the hierarchy of progenitor cells in the haematopoietic system; put technically, terminally differentiated post-mitotic granulocytes yielded cloned pups with greater efficiency than did the earlier adult stem cell or progenitor types. Furthermore, he used molecular microarray analyses to demonstrate that adult stem cells could be reprogrammed by SCNT to acquire an embryonic-like profile of expressed genes, and he showed that the gene profile was closer to that observed in embryos fertilized in vivo than to that in embryos fertilized in vitro. But the SCNT embryos had markedly reduced developmental capacity. The apparent disconnect between embryonic gene expression and embryo viability was a particular preoccupation towards the end of his life.
In 2006, Yang's life's work, and indeed a whole field of research, was put in jeopardy by the exposure of fraud committed by the South Korean cloning team led by Woo Suk Hwang. Hwang falsely claimed to have achieved the highly efficient production of numerous human SCNT embryonic stem cell lines. Yang was a strong advocate for human SCNT, given its promise in therapeutic cloning by providing immune-compatible tissues for cell replacement, and he was deeply concerned that this episode would seriously damage the field of regenerative medicine. In high-profile articles, he argued the case both for continued research in cloning by SCNT and for increased vigilance of scientific fraud.
International collaboration was the other main strand of Yang's professional life, and he was a prominent proponent of global partnerships in science and medicine. He achieved the feat of being respected in both the academic and political sectors in China, and was a persuasive advocate for US–China cooperation. He pursued his goals with typical tenacity, an example being his advocacy for an Asian–Pacific network of stem-cell scientists. His case was simple: Asia is a region where political and religious ideologies are not antagonistic towards human stem cell science. He proposed the creation of a network of regenerative-medicine institutes in China, with an international oversight committee to guarantee transparency, trust and compliance with established ethical standards, and he worked hard to establish funding and to create a suitable organization for this network. He hoped this model would be a beacon to guide the formation of other international scientific networks.
Jerry Yang had a passion and determination that marks the very best in the traditions we admire and respect. He was an inspiration to the young Chinese and US scientists who studied with him and who have since populated many different laboratories. He was a terrific person to spend time with: I, like many others, regret that I cannot now shoot the breeze with him on animals, embryos and biotechnology.
A version of this article appeared in Nature458, 161; 2009
Source: Nature