13-year-old, $38 million facility was British leader
HINXTON, U.K. —The Sanger Institute, a global leader since 2006 in producing genetically modified mice for biomedical research use, on May 16, 2019 announced to staff that it will close by 2022, if not sooner.
The impending closure is among the first hints that the biomedical research industry is at last responding to more than a decade of increasing mainstream scientific recognition that genetically modified mouse studies, begun more than 30 years ago, have produced little of value in either treating or preventing human disease.
Money not the issue
Money is not the issue for the Sanger Institute, a project of the London-based Wellcome Trust. Boasting an endowment of £25.9 billion, or $32.8 billion in U.S. dollars, the Wellcome Trust is the fourth wealthiest private foundation in the world.
The £30 million ($38 million USD) Sanger Institute animal research facility, located in Hinxton, South Cambridgeshire, England, “hosts mice, zebrafish, rats and frogs used in research, and employs about 70 people,” reported Holly Else for Nature.
But the site, still nearly new in comparison to others doing similar work, is doomed, “driven by the Institute’s scientific strategy,” according to a media statement posted to the Sanger Institute web site.
The statement was signed by Wellcome Sanger Institute director Mike Stratton.
“Transferring the mouse work”
“The Sanger Institute is increasingly using alternative technologies to deliver its scientific strategy and this has led to fewer mice being needed,” the Stratton statement explained. “Because of this decrease in animal numbers, transferring the mouse work to another facility is the best way for the Institute to deliver all of its scientific goals.”
Already under criticism from pro-animal research organizations for allegedly retreating from animal use, Stratton made clear that the Sanger Institute is not entirely abandoning mouse studies, and is “working with other institutions to find a solution to accommodate its future mouse research requirements.”
“The staff that operate the animal facility will be fully supported throughout the process,” Stratton pledged.
“Scientific research involving mice will remain an important part of Sanger Institute science,” Stratton finished, “and will continue at reduced levels in the future. This has been a difficult decision, but we believe it is the best way to continue to deliver the science and make the discoveries that impact on human health and the natural world.”
Tree of Life
Wrote Else for Nature, “The institute says that the closure, announced to staff on 16 May, is a consequence of a move towards using alternative technologies such as cell lines and organoids — 3D biological structures that can be grown in a dish — in genetics research, instead of animals.
“But Sanger scientists studying complex diseases such as cancer, which require an understanding of how genes interact in whole organisms, will still use mice in individual labs on site until the facility closes. They may also be able to use animal facilities at nearby institutions, such as the University of Cambridge.”
Wellcome Trust science director Mike Turner told Else that the Sanger Institute is now focusing on projects such as one called the Tree of Life, “which will sequence the genetic codes of 66,000 species of U.K. plants and animals,” Else wrote.
“Sanger is also a partner in the international Human Cell Atlas project, which will create reference maps of all human cells,” Else mentioned.
GMO mice were dead end
The Sanger Institute “is most famous for its role in the Human Genome Project” Else recalled, “decoding one third of the sequence of human DNA. The institute is also well known for the part it played in a project in which researchers ‘knocked out’ every gene from the mouse genome one by one. It also created a reference library of the genomes of mouse strains commonly used in research, which enables researchers worldwide to work out whether mutations they find in experiments are new or established.”
The technologies of genomic mapping and of gene transfer, used to create mice who have been genetically modified to develop human diseases, were developed more-or-less parallel to each other in the 1980s. But the initial hope that genetically modified mice would decode medical mysteries has been largely unrealized, while progress achieved through genomic mapping has surged ahead.
Animal welfare issues
Else noted that the Sanger Institute closure announcement “comes six months after Sanger scientists voiced ‘grave concerns’ about animal welfare at the facility in a letter to Sanger’s chief operating officer, Martin Dougherty.
“In the November 2018 letter, an unsigned version of which Nature has seen,” Else recounted, “the scientists said that staff shortages were risking the facility’s high welfare standards and that the lack of trained staff meant animals were being culled because they could not be used. This violates ethical standards, as well as requirements laid out by the Home Office, the U.K. government department responsible for animal research, said the letter.
“A Sanger spokesperson told Nature that it responded to those concerns, implemented a program to address them, and notified the Home Office,” Else said. “The closure of the facility is not linked to welfare issues, said the spokesperson, and animal welfare is of the utmost importance at the institute.”
Stratton in his statement said that “Discussions [of the details of the Sanger Institute closure] will continue over coming months, to establish how to deliver this change in line with the Animals (Scientific Procedures) Act, to safeguard the welfare of the animals.”
Has mouse use peaked?
The most recent available Home Office data shows that 3.79 million animals were used in U.K. laboratories in 2017. Of those, 1.89 million were actually used in experiments; 1.9 million, just over half, were used to produce genetically modified experimental subjects, chiefly mice.
The Home Office said that the number of procedures performed using animals fell by 4% in 2017, after a 4% rise over the preceding 10 years.
About 1.09 experimental procedures (87%) used mice. Also used were 308,000 fish, 230,000 rats, 2,496 dogs, 2,215 monkeys, 228 horses, 71 cats, and a variety of guinea pigs, hamsters, rabbits, birds, goats, sheep, and pigs.
Comparable data is not available for the U.S. because mice, rats, and birds are exempted from the tracking requirements of the U.S. Animal Welfare Act.
“Mice are lousy models”
Among the first influential voices from within the biomedical research establishment to question the use of genetically modified mice to mimic human disease was Stanford Institute for Immunity, Transplantation & Infection director Mark M. Davis, Ph.D.
“We seem to be in a state of denial, where there is so much invested in the mouse model that it seems almost unthinkable to look elsewhere,” wrote Davis in the December 19, 2008 edition of the peer-reviewed scientific journal Immunity.
“Mice are lousy models for clinical studies,” Davis bluntly concluded. “We can’t depend on the mouse for all the answers, because in some cases it’s not giving us the right answers.”
“We all drank the Kool-Aid”
Elias Zerhouni, who headed the U.S. National Institutes of Health from 2002 to 2008, warned in a 2013 address to his former NIH colleagues that because of the relative ease of doing studies using genetically modified mice, disease researchers had become excessively reliant on animal data.
“We have moved away from studying human disease in humans, Zerhouni said. “We all drank the Kool-Aid on that one, me included. The problem is that it hasn’t worked. It’s time we stopped dancing around the problem. We need to refocus and adapt new methodologies for use in humans to understand disease biology in humans.”
Explained Francis Collins, director of the National Institutes of Health since 2009, in a 2013 blog posting describing the findings from a 10-year NIH study of sepsis treatments, “If it works in mice, so we thought, it should work in humans. But 150 drugs that successfully treated sepsis in mice later failed in human clinical trials.
“Very little overlap”
“Mice apparently use distinct sets of genes to tackle trauma, burns, and bacterial toxins,” Collins continued. “When the authors compared the activity of the human sepsis-trauma-burn genes with that of the equivalent mouse genes, there was very little overlap. No wonder drugs designed for the mice failed in humans: they were, in fact, treating different conditions!
“But this study’s implications may well go beyond mice and sepsis,” Collins suggested. “It provides more reason to develop better and more sophisticated models of human disease. More than 30% of all drugs successfully tested in animals fail in human trials.”
But mouse use in U.S. soared
Despite the skepticism voiced most prominently by Davis, Zerhouni, and Collins, People for the Ethical Treatment of Animals investigators Justin Goodman, Alka Chandna, and Katherine Roe reported in the February 25, 2015 online edition of the Journal of Medical Ethics, based on an analysis of “use of all vertebrate animals by the top institutional recipients of National Institutes of Health research funds over a 15-year period,” that there had been a 72.7% increase in animals used in experiments during the study time frame.
The increase was “driven primarily by increases in the use of mice,” Goodman, Chandna, and Roe wrote, in a peer-reviewed article entitled “Trends in animal use at U.S. research facilities.”