Going where DNA has never gone before

If a modern Indiana Jones were looking for a new quest, he would be hard-pressed to find a more exhilarating one than the saga that follows.

Imagine a journey of discovery that begins with archaeologists trying to determine the family relationships of bodies they unearthed from an ancient Coptic cemetery in an Egyptian oasis. The route leads to a laboratory in Canada trying to determine if a tomb in Israel contains Jesus, Mary and Joseph's bones. And it ends with gene-based tests informing people worldwide about the extent to which the sun has damaged their skin - and how that damage might put them on the scary road to cancer.

The trail from cemetery to cancer tests begins with the research conducted in the 1980s by anthropologist El Molto on the skeletal remains buried at the Dakhleh Oasis in the western desert of Egypt - an oasis about 800 kilometres south-southeast of Cairo. Professor Molto, then at Lakehead University in Thunder Bay and now at the University of Western Ontario, wanted to use modern DNA analyses to do what visual examinations of bones couldn't do - unveil disease, kinship and other relationships between the skeletons.

To accomplish this, he enticed Ryan Parr, a PhD student at the University of Utah, to come to Lakehead and help establish a laboratory to analyze ancient DNA. Parr, who had worked in cancer-related molecular genetics for more than a decade, had recently experienced a major career rethink.

"One day I saw this article where they said, 'Wow, we can get DNA out of mummies,'" he reflects 15 years later. "And I thought, 'Oh, that's for me.'" The work was for him, but he wasn't sure exactly where he was going.

"Molto said 'Would you consider coming to Thunder Bay?' And I said, 'Where is that?' And he said, 'Well, it's up here in Canada, just North of Duluth.' And I said, 'Duluth? I only hear of Duluth when there's real bad weather there.'"

But the lure of doing what is known as paleo-DNA research transcended weather considerations, especially when it became apparent that the new laboratory, known as the Paleo-DNA Laboratory (PDL), was going to do DNA analysis over a wide range of old and sometimes ancient DNA.

The Thunder Bay facility has examined bones from a tomb in Israel that bore the names of Mary, Joseph and Jesus. Some believed it was the true grave of the Biblical Jesus, but the Lakehead analysis showed that bones from a box with the name Jesus on it were not maternally related to bones from the woman identified as Mary.

The facility has helped look for the parentage of a previously unidentified 13-month-old child whose body was found without a life jacket after the Titanic sunk in 1912. After bones from the child's skeleton were sent to PDL, a DNA analysis performed in conjunction with other laboratories' findings positively identified the boy as a member of a Finnish family who all perished in the disaster.

And PDL has traced the development of the interaction between leprosy and tuberculosis over millennia. They have used this information to explain why there is a historical decline in the incidence of leprosy.

At the same time, the laboratory has established a unique ancient DNA summer program that every year brings in students from around the world and trains them in the techniques of interpreting old or degraded DNA.

That's all good, but perhaps the seminal truth of modern science is that research takes researchers in directions they never expected. Parr's arrival attracted the attention of Bob Thayer, who at the time was a professor of both physiology and applied biomolecular science at Lakehead. He was interested in the involvement of mitochondrial DNA (mtDNA) - the DNA found outside the cell's nucleus - in aging and cell death.

Because there is so much mitochondrial DNA in a cell - roughly 10,000 copies of mtDNA for every strand of nuclear DNA - and because mitochondrial DNA is inherited only from the mother, mtDNA had become the bedrock of paleo-DNA analysis.

Most famously, this analysis has been used to argue that all existing humans are descended from a woman who lived in Africa more than 200,000 years ago.

Thayer walked over and started chatting with Parr about a possible collaboration. Parr was interested, but as he and Thayer and other Lakehead scientists began discussing the idea at what were quite literally Sunday afternoon coffee klatches, their thoughts quickly moved to an emerging area of scientific inquiry. "Papers started appearing in the late 90s in which people were using mitochondria as a kind of biosensor," explains Parr.

The reasoning here, was that because the mitochondria genomes have a much higher rate of mutation than nuclear DNA, changes in mtDNA might track the road toward cancer more accurately than traditional biopsies. While true in theory, at that point nobody had demonstrated the worth of an mtDNA cancer test.

The group then did what Parr characterizes as a little back-of- the-envelope calculation and determined that it could take upwards of 10 years and cost close to $80 million to bring such a cancer biomarker concept to market. So it was decided that the most practical and cost-efficient thing would be to create a company to develop a mitochondrial DNA test for cancer.

In 2002, with help from the university's Technology Transfer Office, the Sunday coffee klatches scientists founded Genesis Genomics - the genesis referring to the genesis of cancer in the body. The little Northern Ontario biotechnology company - armed with an as yet unproven good idea - attracted considerable venture funding.

FedNor, the federal agency set up to "increase the overall competitive position of the North and to accelerate its movement to a knowledge-based economy," and the Northern Ontario Heritage Fund Corporation contributed nearly $850,000 to get the company off the ground. "That's not available to companies in Toronto, so from a financing perspective I actually think it has been easier for us to be in Thunder Bay," remarks Robert Poulter, who is now president and CEO of Genesis Genomics.

As well, upwards of 50 angel investors, most of whom come from the Thunder Bay area, also signed on. The university itself took a stake in the company in lieu of any patent rights.

The founders were originally interested in identifying prostate cancers, which, because of their slow development, are notoriously difficult to definitively classify even after biopsies. However, along the way they discovered that the University of Newcastle's School of Medicine scientist Mark Birch-Machin was independently looking at the mitochondrial DNA's predictive value when it comes to changes in skin leading to cancer. "The cancer markers that Parr and Thayer were researching were essentially the same as what Birch-Machin was studying except in different diseases," says Poulter.

So Birch-Machin was invited to become one of the partners in Genesis Genomics.

Over the past six years, research has continued in both streams. The prostate diagnosis work early on showed something quite surprising - a cancer shadow effect. Put quite simply, cells near a cancer often looked quite normal but nonetheless exhibited mutations associated with true cancer when subjected to an mtDNA analysis. "They are not fully cancerous, but they are being recruited to become a cancer," says Parr, who is now Genesis's chief scientific officer and vice-president of research and development.

The tests also have been able to diagnose cancer from prostate tissues with an accuracy that may soon revolutionize the field. Today, upwards of 40 per cent of men are given a false negative result after a biopsy. A recent paper published by Genesis Genomics' scientists, in conjunction with researchers at the U.S. National Institute of Science and Technology, shows the mtDNA test is able to predict both true positive and true negative cases in 85 per cent of all cases.

But it is skin tests that have advanced the furthest. In 2008, Genesis, in collaboration with the Toronto-based VitalScience Corporation, began selling a genetic skin test using Genesis Genomics' technology in drug stores and dermatologists' offices across the country.

Its analysis of DNA from a skin swab - the nose is the usual swabbing area - tells concerned people two things. One, whether they carry a genetic deletion associated with a higher risk of skin cancer. And secondly, how much exposure to the sun has damaged their skin.

"If you have a genetic risk and if you have extensive skin damage, both of those are telling you that you need to cover up, stay out of the sun and put on the highest level of sun protection factor products," says Poulter about the simplest meaning of the tests.

Genesis Genomics' success is also telling Thunder Bay, a city whose wealth has been rooted in lumber mills, mines and grain shipping, something about its future potential. To begin with, there is a continuing interaction between Genesis and Lakehead, as PDL is currently trying to develop a better assay for mtDNA biomarkers for Genesis.

But far more important is the positive pull between people graduating from the university and Genesis Genomics' economic viability.

"We have an incredible university that the rest of the world honestly doesn't know about that generates top-notch people. And so we're able to hire the best of the best and, even better, because they really want to stay here, we don't have retention issues," says Poulter.

But in a community with three out of four lumber mills shut down and grain shipments shrunk by two-thirds, it is an advantage that comes with a price only an entrepreneurial Indiana Jones could likely relate to.

"I have a close personal friend of mine who is fairly well tapped into the community," says Poulter. "And he candidly told me a few months ago, 'Don't forget, Bob. This entire city is counting on you.'"