Dr. Liu makes the case for genomics and personalized medicine

Hopes for the future of “personalized medicine” lie at the heart of the state’s investment in a new research institute for The Jackson Laboratory on the UConn Health Center’s Farmington campus. Proponents often talk of developing the ability to tailor treatments for cancer and other complex ailments to each person’s unique genetic code.

But as Dr. Edison Liu, Jackson’s new president and CEO, told an audience at the Connecticut Science Center in Hartford Friday, the real root of the concept is as simple as the medical treatment we now take for granted.

Edison Liu

Edison Liu with a representation of the genome

“We know you can’t treat a virus with penicillin, so we don’t,” Liu told an audience that included members of the business group, MetroHartford Alliance. “But in the old days when you didn’t have this, you were given arsenic for everything,” he said. “And that is a classic example of personalized medicine.”

These days, researchers are looking to significantly more complex ways to determine the exact nature of a particular illness and the best way to treat it. There are drugs targeted to specific types of leukemia and lung cancer, and research aimed at developing therapies with similar specificity for a host of other conditions.

Jackson Laboratory, an 83-year-old Bar Harbor, Maine-based research institute that specializes in mouse genetics, is aiming to become a key player in the field with its Connecticut institute, JAX Genomic Medicine, which is slated to begin work later this year.

The motivation to find more personalized treatments stems from the limitations of existing therapies. Chemotherapy, for example, is far more effective than giving all patients arsenic, but many cancer patients who get it don’t improve, while others face severe side-effects. Figuring out which patients would respond to it, and which wouldn’t, could mean more of the patients who get a chemotherapy agent would benefit, while many other patients would avoid going through expensive treatments that are unlikely to help them.

The field of genomics represents a key tool in achieving that. While genetics is the study of individual genes and their functions, genomics looks at all genes in an organism and how they function together, allowing for insights into complex systems based on the interactions of multiple genes. In their experiments, scientists now frequently ask to find out all the possible genes involved in a biological process, like the development of a heart or a disease like diabetes or cancer, Liu said.

Technological advances are making genomic research faster and less expensive. It now costs about $3,000 to sequence the entire set of DNA bases that form a person’s genetic code, a dramatic drop from less than a decade ago, when the first sequencing of the human genome cost $2.7 billion. Within the next year, Liu said, the cost will drop to $1,000 — “the price of a CT scan.”

A pipeline in Farmington

At Jackson’s Connecticut institute, Liu said, researchers will sequence genomes from cancer and other diseases and analyze them to make sense of the data. If they turn up mutations, they’ll need to test whether the mutations are important. And they’ll develop “surrogates” for the diseases, to test whether a certain drug would work on the particular mutation or condition a person has.

Liu said the technology for doing so already exists. “It’s a matter of putting all of this together into a pipeline,” he said.

JAX Genomic Medicine is being created with $291 million in state funds — $192 million for construction and a $99 million 10-year operating subsidy. Jackson must create at least 300 jobs within 10 years, including 90 senior scientists; the lab announced the first hire Thursday. The state will share in royalties from intellectual property developed at the new facility.

Critics, including some Republican lawmakers, have questioned the size of the state’s financial commitment, but supporters, including Gov. Dannel P. Malloy, say it’s a worthwhile investment that can create high-paying jobs and spawn a larger bioscience industry in a state that has struggled to grow jobs in the past two decades.

On Friday, Liu said he’s “absolutely confident” about creating 300 jobs. “My goal is to increase it to 500, because that’s about the capacity of what this facility will do,” he said.

Liu also spoke of the “soft aspects” of Jackson’s presence in Connecticut, saying the organization wants to help recruit new biotechnology businesses to the state. “We will not sit on our hands,” he said. “We will go out and offer our hands to people that [Economic Development Commissioner] Catherine Smith brings to us and say, ‘Connecticut is a great place to work. And by the way, our trainees need jobs and they’re well-trained.'”

As for the $291 million, he said, “if the operations are successful, quite frankly, it sounds like a lot of money but it really isn’t. We will need at least $750 million of other funds in the next 10 years to make this a competitive space.” He noted that that will come from federal, state and international grants, as well as from philanthropy and royalties.

Tailoring treatments

Before coming to Jackson, Liu led the Genome Institute of Singapore, where researchers made a key discovery about a type of leukemia known as chronic myelogenous leukemia, or CML. The drug Gleevec has helped make the disease a chronic condition for many patients by targeting the results of a mutation in patients with the disease. But some patients with that mutation don’t respond to the drug.

Liu and his team in Singapore sequenced the genomes of five people, three of whom were resistant to the drug. They found that those three had a mutation in another gene that caused the leukemia cells not to die when exposed to Gleevec. And, it turned out, that mutation exists in the genetic makeup of 12 percent to 15 percent of north Asians, but not at all in Caucasians or Africans.

“It turns out that our hematologists in Singapore said, ‘My gosh, this is the reason why we have never been able to achieve the same therapeutic efficacy in our population as what we read all the time in the white population,'” Liu said.

As a result, he added, patients with CML in Singapore now receive tests for that mutation, so their doctors know they will need to be ready to move on to the next generation of drugs relatively soon if Gleevec doesn’t work.

Liu also cited a 2007 case in which researchers in Japan did a genomic analysis on the lung cancer found in a 62-year-old smoker. They noticed something unusual, and because they knew a lot about the genome, they determined to drill down.

Ultimately, they found that a glitch in one of the patient’s chromosomes had led to the activation of something known as ALK, which causes about 6 percent of lung cancers. That’s such a small percentage that extensive work on it might not seem justified, Liu said. But companies had already developed compounds that counteracted ALK — they had thought it would work in another type of cancer — and it produced responses in about 60 percent of patients with that type of lung cancer, Liu said.

If you gave that compound to all patients with lung cancer, between 94 and 97 percent would not respond, “And statistically, you wouldn’t know the difference,” Liu said.

“But by zeroing in on those 6 percent [with cancers caused by ALK], you now have a treatment which is standard now for that disease,” he said.

That sort of path to discovery, using a small number of cases, could represent an alternate approach to clinical trials, which typically involve large numbers of subjects. In places without access to a large volume of patients with a certain condition — like Singapore or Bar Harbor — researchers can take another strategy, Liu said: “Use smaller numbers of cases, but smarter questions to address.”

“If we can identify 10 or 14 individuals with a particular type of cancer, if we can actually do this very deep analysis, and if we can test that with these surrogates of our own disease, the possibilities, you can imagine that one can mine a tremendous amount of information with a small number of cases,” he said.

The challenge, he added, is that researchers must be able to identify when unusual cases occur, so they can be recruited for trials. And there needs to be a “vertical infrastructure” that would identify the individual, collect tissues, do the genomic analysis, analyze it and then work with the patient’s doctor to find the right personalized therapy for that patient.

Liu said he’s been talking to people at Connecticut hospitals about redirecting some of their focus to identify opportunities for that type of personalized medical experimentation.