Timely Challenge

Siegfried Hekimi, PhD embraced an opportune set of circumstances to establish Chronogen

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By Deborah Komlos

It had never really occurred to Siegfried Hekimi, PhD that he ought to found a biotech firm. Essentially, the idea found him.

In the late ’90s, Hekimi was a professor in McGill University’s (Montreal, QC) department of biology, working to understanding the mechanisms of aging on model organisms. His group had already published their findings that particular genetic mutations in “clock” (clk) genes in the nematode worm, Caenorhabditis elegans, cause the organism to live five times longer than its normal lifespan.

Hekimi says he received quite a bit of media coverage regarding his work, and was subsequently approached by venture capitalists, wondering if he was interested in starting up a firm.

“I didn’t have any personal rationale,” Hekimi says of the founding. “There was clearly a scientific rationale, but I didn’t have any plan, ever. At the time I hadn’t thought about the notion that it would allow me to do things at a different scale . . . scientifically not just commercially.”

He says he was contacted “left and right,” by firms in the U.S. and by big pharma. “So, in a way, I was aware that the commercial world would get some interest in our work,” he continues. “But then, still, it was a surprise that they would come and actually want to start a company.”

In 1998, Hekimi ventured down the business path and founded Chronogen Inc. (Montreal, QC). With a backing of $4.5 million in series A funding — which, along with R&D tax credits, amounted to nearly $6 million — the firm initially conducted its research at McGill until November 2003, Hekimi says. After that, extramural laboratory space was secured, which also remains in use today, he adds.

Chronogen now employs more than 30 researchers, and Hekimi is still the chief scientific officer, as well as a full-time professor at McGill.

Concepts of Aging

Privately owned, Chronogen is a drug-discovery firm looking to develop therapeutics to treat oxidative stress and lipid disorders in age-related diseases. The company has identified several clock genes and currently has five research platforms underway, including one in relation to clk-1, for which the firm hopes to file an IND within 18 months. This main program focuses on the control of oxidative stress by regulating the production of reactive oxygen species (ROS), molecules that are known to be toxic to cells.

“We found a number of targets that, when inhibited, actually will decrease the production (of ROS),” Hekimi says. “And that’s a bit of a novel approach; people intended more to go for scavengers.”

Hekimi explains that there are two main viewpoints regarding lifespan. The first is that lifespan is programmed, that “the organism wants to live longer,” he says, adding that this perspective is incorrect.

Another viewpoint holds that lifespan is a secondary effect, having to deal with the physiology of the organism. “Your body is made to live the life it lives and then it’s left to its own devices, and depending on how well you made it and how well you repaired it, it’s going to live more or less long,” Hekimi says.

A further perspective, he adds, is that aging exists per se, and that it is made worse by age-dependent diseases.

“And my point of view,” he continues, “(is) I’m not sure there is a true difference between aging and age-dependent diseases. Maybe aging is but the sum of all age-dependent diseases, where we can speak separately about (it). But mechanistically, what happens to the organism, there is no difference; there is no shadowy process called aging.”

While it is a significant finding that introducing genetic mutations could result in a several-fold increase in the lifespan of nematodes — which live to an average of 20 days — Hekimi points out that the results don’t directly translate to higher organisms. For instance, the mouse lives an average of three years, and a fivefold increase would result in an additional 15 years of life. But there are cellular effects, basic observations at the gene level that have similarities to what’s found higher up, Hekimi says.

In the long run, elucidating the mechanisms of aging will have application in finding drugs that affect age-related diseases, Hekimi says, such as atherosclerosis, cancer and neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

Science Goals, Business Realities

Reflecting on the journey that has taken him down the business road, Hekimi says that while he didn’t intend to start up a firm, having done so alone made it much easier to make business decisions. Though, this also meant a lack of support, he adds.

Later in the firm’s life cycle, a well-timed large financing was particularly advantageous.
The closing of a $17-million series B financing came at the end of 2003, at a time when it was very difficult to secure any funding, which was probably why the firm received less than what it had ideally wanted, Hekimi says.

“However,” he says, “we are in a rather good position now, (more so) than many other firms who secured money when it was easier but earlier. And they’re having a harder time now.”

Hekimi attributes the financial success to a combination of luck, the amenable R&D tax credit situation in Quebec, and a favourable grouping of investors — both old and new.

“I had also some very good management at the time, one person in particular,” he adds. “We worked hard, and we got a bit lucky and there was quite a bit of pain involved.”

Hekimi says that all his “free” time is “monopolized” by Chronogen, but he does not feel conflicted by maintaining both his scientist and business roles. And, despite taking on the position of CSO, Hekimi says he had not set out to make a formal career change.

“I never had any impression that I was to be assimilated into the business world,” he says.

“The world of business functions along very different rules from academia . . . different qualities, different concerns to go along with it,” he continues.

A particular obstacle, he says, is that there is a lot of uncommon ground between science and business.

“If you want to do something together, everybody just has to realize that there is only partial common ground — then you can live together,” Hekimi says. “But, sometimes there is a misunderstanding almost of what is common ground and what is not common ground.”

As an example, scientists are used to thinking extremely long-term, Hekimi says.

“You work to have this great achievement and understanding in 10 years, and this is not the sort of timeline with money spending in industry,” he explains.

For this reason, Hekimi says it’s important to be mindful of the differences between the two fields when making decisions.

In business, “You always have to consider a shorter timeline because you have to have a constant flow of money,” he says.

The initial goal for companies, Hekimi says, is to survive, and then ideally, to see fundamental insights translated into practical results.

“My vision is to get it to work,” he elaborates. “Imagine there’s this box of pills which says clk-1 inhibitors . . . it’s almost impossible, might probably never happen under that form. But, it’s for the fun.”

The idea to found Chronogen may not have been his own, but Hekimi was compelled to see the notion crystallize.

“One thing which attracted me in starting the company, in doing this, it’s still the challenge for pure challenge sake,” Hekimi explains. “I used to be a professional cyclist — I did the Tour de France, I went to the world championships numerous times — and the pure challenge per se is a lot of fun.

“And that’s actually something which is almost not a common ground,” he continues.

“It’s true that in business you want it to be for a reason, not for fun. But I think to just get it done is sort of fun — because it’s hard, because it’s different.”