BAR HARBOR, ME. — The best-laid plans of mice and men are being hatched in this pretty New England tourist town — with a heavy dose of genetic manipulation.
In the rapidly emerging world of genome-based, personalized medicine for human diseases such as cancers and diabetes, the mice that produce basic scientific breakthroughs will require vast DNA diversity and much more genetic manipulation.
Here at the Jackson Laboratory — a centre that can claim a Nobel prize of its own plus key inputs into 26 others — a good percentage of the research mice that will underpin future medical advances across the globe are being designed and bred.
Sheltered by twin Appalachian mountains, scientists at the lab complex are developing unique animals — models for the study of specific, genetically linked human ailments — at the pace of 50 a week.
More importantly, perhaps, they are increasingly creating disease models in mice that match the genetic diversity of humans far better than any used in the century during which the twitch-nosed rodents have been mainstays of medical science.
For decades, using a host of DNA-altering techniques, scientists have been implanting versions of human genes into embryonic mice, genes that have known or suspected links to the development of Parkinson’s disease and a host of other ailments.
Unlike the humans who might host those disease-linked genes, however, the “base” mice they were implanted in were virtual clones of one another, says Jackson scientist Gary Churchill. So inbred were these animals that a mouse strain used at the University of Tokyo would be genetically indistinguishable from one being used at the University of Toronto.
And just one of these inbred mice strains — known as the C57 Black 6 and created by the Jackson lab’s founder, C.C. Little — was used in upwards of 60 per cent of all mouse research worldwide. That genetic uniformity helped ensure that research conducted anywhere in the world could be more certainly reproduced anywhere else.
It also ensured, however, that many therapy “breakthroughs” that worked in the mice would translate poorly into human applications, and that many other therapies that might have worked in people would be missed.
That’s because it’s now known that genes do not act on their own. They are directed by other genes and by segments of the vast swaths of DNA that those genes sit between.
In humans, those genetic regulators can dictate which therapies might work to counter a genetically linked disease on an individual basis.
That, in a nutshell, is the concept of personalized medicine: to discover and diagnose through individual genomic profiles which course of treatments will work best for each of us.
But because research mice strains such as the C57 Black 6 share the same genome, therapies that may work on those mice might have little or no effect on animals with a different DNA makeup. So to test novel medicines, a more genetically diverse mouse would be needed. And that’s what Churchill and his team have produced in the Jackson lab’s humanized NSG mice.
These “outbred mouse” strains combine the genomes of eight strains of inbred mice from around the world — building a mouse as close to humans in genetic diversity as possible.
The progeny of these genetically varied, outbred mice can be fat, skinny, black, white, big or small — much like the human population. And much the same way your siblings will be genetically different from you.
Drugs or other therapies tested on this humanized strain may work on some but be ineffectual or even toxic for their genetically different, outbred sisters or brothers.
These studies “should be done in animals that have as much diversity as possible,” Churchill says, “so we can understand what the range of possibilities is for humans.”
A technique known as CRISPR is allowing scientists at the Jackson lab to greatly speed up the production of the new mouse models, and do it cheaply.
The lab was previously able to genetically alter only a few mice per week on average. It is now producing 50 a week, using CRISPR (which stands for clustered regularly interspaced short palindromic repeats).
CRISPR, which is derived from bacterial DNA, allows scientists to cut the DNA of any organism at any specific location and insert new genetic material into the resulting gap.
New mice strains raise hope for Toronto researchers
1. Drugs for sarcoma
Mice are a mainstay in Dr. Rebecca Gladdy’s research into sarcoma cancers. And Gladdy, a cancer surgeon and scientist at Toronto’s Mount Sinai Hospital, has helped create unique mouse models of a childhood form of the disease using CRISPR technology. Her team will be using these mice, in part, to test different drug therapies to see which work best in response to the genetic signatures of the human sarcomas they implant.
Gladdy, who implants CRISPR-altered stem cells to produce cancer in her animals, is working with mice bred without immune systems. Gladdy likes the idea, advanced by Jackson scientist Carol Bult, of using the results from mouse research to help build a global cancer database that would match the genetic signatures of an individual’s tumour with the best therapy options.
She says such an electronic repository would need to be open-access and would take a co-ordinated effort by major research labs around the world — something Jackson might be in a position to lead. “You want to have collaborative teams where people say, ‘I’m going to model … sarcoma this way, you’re going to do it slightly differently (and) we’re going to compare,’” Gladdy says.
2. Tumour research
Jeff Wrana’s groundbreaking work centres on the interplay between cancer cells and the surrounding, healthy tissues in which they sit. The Mount Sinai Hospital scientist has shown that normal cells in a tumour’s environment play a key role in the way those cancers grow and metastasize. But this research means he has to look at not only the genetic makeup of his tumours but also at DNA anomalies in the healthy cells.
So for Wrana, the Jackson lab’s CRISPR technologies — which can easily and cheaply edit any mouse genome to place new genetic materials into his research animals at any desired location — are a godsend.
“The impact is enormous,” says Wrana. “Previously, doing these kind of experiments where you were looking at the interaction between different cells … would be a long, tedious process.”
Instead of laborious breeding processes that he had to use to get desired gene mutations into his animals, CRISPR can give him a mouse with four or five genetic changes in a matter of months and at a fraction of the cost. This also allows him the freedom to test more hunches.
3. Stem cell advances
Mount Sinai’s Andras Nagy says the world of research mice is undergoing a kind of leap only rarely seen in science. “You feel like this was a revolution,” says the top Toronto stem cell scientist, who has been working with mice for 30 years.
“It’s a huge step forward … as far as the mouse model is concerned.”
Nagy, who recently visited the Jackson lab, is referring mostly to the CRISPR technology it uses. He says it will accelerate his stem cell research, which will be fuelled by the rapid availability of mice, produced with a host of human genetic traits, such as human-like immune systems.
Having a human immune system in a mouse can allow him to see how such things as cancer stem cells and potential treatments for the tumours they cause would work in people, says Nagy.
In the end, he says, the new advances in mouse science have reinforced his view that the animal has been one of medicine’s best friends.