Targeted Genome Sequencing: The Future of Personalized Medicine

Targeted Genome Sequencing: The Future of Personalized Medicine


With targeted genome sequencing, doctors are able to determine the proper course of drug treatment for patients to prevent adverse drug reactions. Doctors hope to use such personalized medicine to change the landscape of treatments for children with special needs.

The Human Genome Project—the effort to completely identify the human genetic code—took 13 years and cost approximately $2.7 billion. Today, doctors can do the same thing within 50 hours for approximately $250, says Bruce C. Carleton, Pharm.D., director of the Pharmaceutical Outcomes Programme at BC Children’s Hospital in Vancouver, British Columbia.

“It will change how we perform medicine. Traditionally, you [learn the patient’s] history, you do the medical exam, and then you do the lab testing,” says Edward R. B. McCabe, M.D., Ph.D., medical director of March of Dimes. “What we’re talking about is having the lab testing, in the form of genome sequencing, being done upfront so that you know what to expect in terms of potential diseases and adverse drug reactions for those babies throughout their lives.”

The National Institutes of Health recently gave out four grants for studies on the value of DNA sequencing in newborns. “Newborn screenings are done on every baby born in the U.S. and nearly all developed countries. Right now we test for 31 disorders, but this series of grants is looking at if we can do DNA sequencing from dried blood spots,” Dr. McCabe says. “We know that DNA is stable in the dried blood spots used for newborn screening. We know it’s there, and we know it can be sequenced. The studies are also looking at the ethical, legal, and social implications of what it would mean if we sequenced all this DNA.”

We spoke to Dr. Carleton about targeted genome sequencing and how it will impact medical treatment for children in the future.

What is targeted genome sequencing?

The human genome is all of the information in your DNA—the human genetic alphabet. The human genome provides a massive amount of information. I often tell students that the amount of information in one human cell is the equivalent of writing the human genetic alphabet (GATC) on 300,000 pieces of 8½-by-11-inch paper in four-point font. Targeted genome sequencing looks at certain sequences of the DNA. We’re taking a specific region of the DNA to find relevant data to better understand whatever we’re looking for—disease prevalence, or in my case, adverse drug reactions.

There are a number of ways to do this. I can look for a particular gene—that’s called candidate gene sequencing. Then there’s the idea of looking at the entire genome and pulling out the relevant bits of information. But looking at everything and trying to find the little bit of information is one of the great debates because the cost of genetic sequencing is getting lower, and so more people want to do everything—but then the interpretation costs are higher because you have to sort out the wheat from the chaff.

How can targeted genome sequencing help prevent adverse reactions to drugs?

Prescription drugs are so amazing in that they have allowed our population to live longer with higher quality of life, but there are tragic consequences of drug therapy—by some estimates it’s the fifth leading cause of death in North America. It’s not just death that we care about, but the morbidity, or things that happen to change someone’s life. We need to come up with some sense of what happens if you or I were to give one of our children medication and they have an adverse reaction. What might that adverse reaction be? Is my child likely or unlikely to have that reaction? What percent of patients who take this medication have that reaction? Are the adverse reactions the fault of the drug, or is it the wrong drug for the patient?

All of those questions are largely unknown, and that’s what this sequencing, or pharmacogenomics, study is about: trying to understand the genetic factors that underlay these adverse drug reactions.

Is such personalized medicine currently being used anywhere specifically for children?

It is being used in a number of areas. There’s a lot of personalized or precision medicine being done in oncology, where we look at tumors and tumor responsiveness to understand the genetics of a tumor and how responsive it is to the cancer drugs being used to treat it.

But what I’m talking about is predicting when a serious reaction might occur. The answer is yes, we are using it. Codeine is a good example. We had a mother whose infant died at 12 days old, and the coroner found morphine in the infant’s blood. It turned out the mother was prescribed Tylenol with codeine—which was compatible with breast-feeding—to help with labor pains, and when we looked at her DNA, we found she had a duplication in the gene that converts codeine to morphine, so the mother breast-fed her infant to death. Not even remotely her fault. The idea of targeted genome sequencing is: Before you are prescribed codeine, let’s test to see whether you have this duplication and whether the drug is safe for you to use.

Another example is the number of anti-cancer drugs used for kids. If your child has a solid tumor and is taking Cisplatin, he has a risk of hearing loss. We can predict that risk by looking at your child’s genetic factors. If your child with leukemia is taking anthracyclines, she may develop heart problems. We’re using pharmacogenomic tests to predict who is at high risk of developing heart problems.

How can targeted genome sequencing change the landscape of treatments for children with special needs?

Children with special needs—let’s define them, for the moment, as neurodevelopmentally disabled—are incredibly complex children because their ability to express their response to medication, or anything really, is often impaired. So we end up treating them empirically and managing their symptoms.

Let’s say you have a child who is so neurodevelopmentally disabled that he can’t speak and he is experiencing pain, so you give him Tylenol with codeine. What if he doesn’t have the gene that converts codeine into morphine? That means that you’re essentially giving him plain Tylenol. For surgical pain or other types of acute and severe pain, plain Tylenol just isn’t good enough. And since your child can’t speak, you don’t know that the Tylenol with codeine isn’t reducing his pain. This type of information about the prediction of drug response can be helpful for us not only in uncovering adverse drug reaction risks, but also uncovering what pathways are preserved and what drugs would be the best choices for those patients.

I think we are going to move from an empiric sense of “Let’s try this [medication] because it works for the majority,” into one that looks at the individual’s likelihood of responding to a medication, and instead choosing accordingly. That’s why the term “personalized medicine” started to be bandied about—we can personalize drug therapy for patients based upon the pathways that are active and inactive in the individual.

Inherent Challenges

Since 2006, children with special needs have been included as subjects in the genetic research that Dr. Carleton and others are undertaking, but the efforts are not without challenges. “Children with special needs are often on multiple medications...and so I’d like to spend more time with them to understand their issues,” Dr. Carleton says. “You can’t sleep at night, okay take this drug. He’s irritable during the day, so take this drug. They’re always on drugs that treat symptoms. I’d like to go into these families and work with them for as long as it takes—because it takes time and energy—to find the best solution.

“In pharmacology, when studying a drug’s biologic effect and its safety in a population, you’re not looking for the complex patient with multiple disease entities and lots of genetic complications. You’re looking for the patients with a relatively clean disease because it’s easier to characterize the response of the medication. But these kids are different: They’re very complex, and you need to spend a lot of time figuring out what issues they have. The complicated patients are the ones that really need our help.”