By Brian E. Clark
WisBusiness.com
Craig January, who comfortably wears the hats of both scientist and heart doctor at UW-Madison, has had numerous chances to go into business.
But January, who developed a novel method to test drugs for heart toxicity in the late 1990s, resisted them – until recently.
“I’ve had offers from drug companies over the years, and I’d toyed with creating a company on my own,” said the 54-year-old January in a recent interview. His specialty is cardiac electrophysiology, the study of the heart’s electrical activity and pathways.
“But frankly, commercializing what we were doing was not high on my list of priorities,” said January, whose technology is licensed by the Wisconsin Alumni Research Foundation and is widely used around the globe.
His ambivalence about the business world began to change last year during talks with fellow scientist Tim Kamp, a noted cardiologist with whom January shares lab space at the university. The pair worked together at the University of Chicago and it was January who convinced Kamp to move to Madison.
The third faculty member in the discussions and their nascent enterprise is Jamie Thomson, who first isolated and reproduced human embryonic stem cells and is perhaps UW-Madison’s most famous scientist.
Though perhaps many years off, scientists believe stem cells — undifferentiated master cells — could eventually lead to cures of diabetes and Parkinson’s disease, as well as other medical breakthroughs.
Working with venture capitalists Bob and Tom Palay, founders of Madison-based companies NimbleGen and Genetics Assemblies, the trio of researchers launched Cellular Dynamics International (CDI) earlier this year to screen drugs for the pharmaceutical and biotechnology industries.
January is CDI’s medical officer. Kamp is the chief technical officer. And Thomson has the title of chief science officer. With their heavy schedules at the university, it is unclear how much time they will spend at the company as it ramps up. The fledgling firm is the first Wisconsin-based business with plans to use groundbreaking stem cell research from UW-Madison.
Initially, CDI will test altered or "transfected" kidney cells that are not derived from stem cells, but have been modified to have some of the electrical conductivity properties of human heart cells.
Within a few years, though, the company hopes to test human heart muscle cells – cardiomyocytes – created from stem cells. This technique, if broadened to include other organ tissues, could revolutionize drug screening, the scientists said.
CDI did not come to be overnight, said Nick Seay, the company’s chief operating officer.
“It was actually in the works for a long time,” added Seay, a veteran patent attorney with the Quarles & Brady law firm.
“There was a certain synergy to this,” he said. “Jamie had worked with Tim and Tim had worked with Craig. And the Palays had been talking to Jamie about stem cell opportunities for a while.”
Palay’s track record with NimbleGen and Genetic Assemblies – both biotechnology firms – helped convince the scientists to make the leap, he said. Also, over months of discussions, all the parties became comfortable about starting the enterprise.
“It wasn’t one thing made it happen,” said Seay, who signed on in June. “Let’s say there was a long get-acquainted period.
“But it is absolutely a coup,” he said. “This is not just a one shot deal. It’s a hybrid and there is a great amount of potential here for a lot of business in the future. The combined package is better than any one of these scientists alone.”
CDI is based at University Research Park on Madison’s west side – home to many other cutting-edge biotech firms. Gov. Jim Doyle recently awarded CDI $2 million in state grants and loans to help get its first products on the market. Doyle said the money would help leverage $4 million in other investments in CDI.
Though other companies offer the same service that CDI will unveil next year — and large pharmaceutical companies do similar testing internally — the Palays hope the drawing power of the names of Drs. January, Craig and Kamp will lure clients.
“This company will have Craig January’s imprimatur on it,” Seay said. “If you were a drug company, wouldn’t you want to hire the originator of this test?”
Kamp said initial tests on the human heart cells derived from embryonic stem cells he developed with Thomson in 2003 have been positive. But they are not ready for commercialization. Thomson’s initial stem cell discovery was published in 1998.
“When Jamie first started this, he saw cardiomyocytes early on because they spontaneously beat in culture,” Kamp said.
“We have proof of principal, but we are still in the development stage – which I hope won’t take more than a couple of years,” he said.
At this point, not a single product derived from human embryonic stem cells has been tested on people.
Kamp said the promise of using human heart cells and other cells derived from human embryonic stem cells is great.
“The idea is that if you want to understand how drugs work on the human heart, it’s best to test them on human hearts,” he said.
But adult heart cells don’t survive well or reproduce outside the body, so it isn’t practical to use them for screening drugs before testing on live animals or humans.
“Likewise, (living) people don’t want to part with their hearts and surgical specimens aren’t dependable,” he said.
And while using modified kidney cells is currently a state-of-the-art method, using human heart cells that are derived from stem cells in a tissue culture dish could create a new “gold standard,” Kamp said.
January concurred:
“A lot of testing – at least in principle – could be done on tissues derived from human embryonic stem cells,” he said.
Kamp chuckled at the idea of the stars being aligned for him, January and Thomson to start a company.
“I’m not good at astrology,” he said. “But I’ve worked with those guys a lot. And I can say we are fortunate to have good colleagues here at the university.”
Blake Anson, a scientist who works in January’s lab and at CDI, said he has been fortunate to have January as a mentor.
“Craig is one of the best I’ve ever worked with and he does what he can to help those beneath him,” Anson said, noting that UW-Madison is lucky that January, Thomson and Kamp have not left to work in private industry or another university.
January, for his part, said the academic world and patient care have suited him and his interests well. He spends about 60 percent of his time in his lab, with some days running well over 12 hours.
“But there is a certain beauty to CDI, what with two very similar technologies going on at one university in lab space that Tim and I share,” he mused.
“It was pretty simple to say they are both technologies that can be brought into a start-up company and that since my work is more mature, the company could have a product within a year of its inception to get off the ground,” he said.
January earned both his medical and doctoral degrees at the University of Iowa. But a brother had attended UW-Madison, a place he considered “pretty nice” from his first visits more than 30 years ago.
In 1976, January went to the University of Chicago to work with that school’s “world-renowned” electrophysiologists, including Harry Fozzard. January stayed for nearly two decades, starting as an intern and rising to cardiology fellow and ultimately an associate professor on the faculty.
“At one point, I figured I would stay there forever,” said January. He moved to UW-Madison to be the university’s chief of cardiology in 1995, a post he held for three-and-one-half years.
January called the heart a remarkable machine that in most people ticks correctly more than 3 billion times over the course of a lifetime.
But in some cases, the electrical signal that causes the heart to beat does not work properly. These irregularities in the heartbeat, called arrhythmias, have symptoms ranging in severity from mildly bothersome to deadly, he said.
To counter this in the late 1980s, anti-arrhythmic drugs were developed that prolonged the “QT interval,” the time between activation time and repolarization in each heart cycle. But if the QT interval was prolonged too much, he said, that could also cause sometimes-lethal problems.
“That was what I studied, the cellular mechanisms underlying these arrhythmias,” he said.
Then, in the 1990s, January’s work led to the removal from the market of several antihistamine drugs that had the catastrophic side effect of sudden death. He said thousands of lives have been saved because of this and other research.
“These were drugs that were developed to treat the sniffles,” said January, who began studying their compounds soon after arriving in Madison.
“We saw this happen in patients,” he said.
They included a woman admitted to the UW Hospital who’d taken an antihistamine and then collapsed from an arrhythmia in one of the lower chambers of her heart.
“Fortunately, paramedics were close by and resuscitated her,” he said. “We had the ability, which many places don’t have, to go straight from the bedside to the basic science lab because of our electrophysiology group here.”
January and other researchers’ work showed that the drug’s metabolites, or breakdown products, caused this potentially lethal arrhythmia.
At the same time in another UW-Madison lab, other scientists who were studying twitchy fruit flies identified a gene with a channel that is a key to passing electrical signals to heart muscles.
Back then, researchers trying to express, or make, these genes usually put them in frog eggs, January said. Because he worked with human patients, he didn’t want to use frog eggs. Besides, they often gave unreliable results.
So January and colleagues put the gene – called HERG – in a stable human-origin cell line that was easier to study and gave drug sensitivity similar to human heart cells.
Ultimately, they created a cell line that is used widely to screen drugs to see if they disturb the electrical conductivity of specific channels in heart muscles.
Many regulators – both here and in other countries – now require the screening before drugs can go on the market.
Ironically, January said WARF was not interested in licensing the cell line when he first approached them in the late 1990s.
“I think they didn’t understand it,” January said wryly.
Because pharmaceutical companies can spend hundreds of millions of dollars to develop a drug, January said they are keenly interested in learning early on about potential side effects – especially ones that could be fatal.
“To have a drug fail shortly after it gets to market or even shortly before is hugely expensive undertaking,” he said.
“Companies want to start screening earlier, when they are in basic development,” he said. “They will screen one, 10 or more than 100 compounds to weed out those that have high potential to cause problems.”
And while the financial interests of CDI and drug companies concern January, he said he and his colleagues hope their work will greatly reduce the need to for drug companies to kills tens of thousands of animals annually as part of their tests.
“Going to a drug company is in some ways a humbling experience,” he said. “What you see is a lot of animal research on mice, rats, rabbits, dogs, chimps…”
In some cases, animal organs – including hearts – are taken and used in toxicity tests. In others, the entire animal is given a drug.
“By creating human cell lines, we have the potential to reduce, perhaps dramatically, the use of animals by the pharmacy world,” he said. “Instead of using animals, you could use the cells.”
The difficulty with the heart, he said, is that cells from an adult animal cannot live in culture for more than a day or two, he said.
“So it is not so simple as to say I am going to take animal cells or even human cells and put them in the culture," he said. "It won’t work.”
January called drug development a “complicated process.” And while the use of animals is a “necessary component,” he said it is something drug companies do not want publicized.
“You will never completely replace the need for animals to be tested,” he said. “But a lot of screening, we think, could be done on tissues derived from human embryonic stem cells.
January said he surprised by the extensive facilities these companies have for housing these animals for drug development.
“I was never aware of the extent of animal research until my work took me to pharmaceutical companies,” he said soberly.
“At CDI, one of our goals is to use non-animal biotechnology, including tissues derived from stem cells, for testing.
“We are creating technologies the have the potential to greatly diminish animal use in drug development. I feel good about that, though you will never get rid of it.”
