Daniel Hommer, M.D. (left), and Markus Heilig, M.D., Ph.D., discuss functional magnetic resonance imaging (fMRI) scan results
Markus Heilig, M.D., Ph.D., was working at the Karolinska Institute in Stockholm, Sweden, when, like many scientists looking to refresh or acquire new knowledge, he decided to take a six-week sabbatical—this time in the lab of Jacqueline Crawley, Ph.D., of the NIH’s National Institute of Mental Health (NIMH). Being part of the IRP, even for six weeks, was cathartic for Heilig.
“I couldn’t help being fascinated by the ethos of the place—the idea that everyone and everything was together on one campus was completely novel to me. I was struck by the immediacy of good ideas.”
Bethany Stangl (right), Ph.D., and Vijay Ramchandani (center), Ph.D., administer behavioral alcohol testing with a healthy volunteer
Because of that experience, Heilig did not hesitate when offered an opportunity to return to the NIH as Chief of the Laboratory of Clinical Studies (LCS) and Clinical Director at the National Institute on Alcohol Abuse and Alcoholism (NIAAA).. He accepted the position with a single aim in mind—to use translational approaches to discover new medications for alcoholism, a chronic relapsing disorder that affects more than 12% of the U.S. population. Heilig’s vision was grand—so grand, in fact, that an external advisor bluntly told him his ideas were not realistic, a statement that further fueled Heilig’s resolve to find a solution to this problem.
Vijay Ramchandani, Ph.D., measures a healthy volunteer’s blood alcohol level
“Clinicians had noticed for some time that some individuals with alcohol addiction responded very dramatically to the medication naltrexone, while others responded very poorly,” Heilig explains. “Based on this observation, we and others had wondered if some people might be genetically primed in some way to respond to the medication, and others not.”
Naltrexone is one of the few approved therapies for alcoholism, and works by blocking the actions of endogenous opioids, thereby disrupting the molecular cascade leading to release of dopamine, a feel-good chemical released when alcohol is consumed. But this cascade seems to be much more strongly activated by alcohol in some people than in others.
Merged image showing neurons (green) in a rat prefrontal cortex and MeCP2 (red), a protein that regulates gene expression and plays a role in addiction
Heilig hypothesized that variations in the gene encoding the target molecule of naltrexone, the μ-opioid receptor, or MOR, might be responsible for these differing responses to alcohol, and therefore also to the medication. Testing that hypothesis led Heilig and his colleagues to develop some of the most complex and elegant translational studies ever performed in the field of alcohol addiction.
“Our first observation was that both humans and rhesus monkeys displayed a similar functional variant in the OPRM1 gene, which encodes the MOR,” Heilig says. “It appeared that it was this single nucleotide polymorphism, or SNP, which altered the response to alcohol and the therapeutic efficacy of naltrexone.”
A rat self-administering alcohol as a model for human behavior
Heilig set out to validate the findings in another way. His team used positron emission tomography (PET) to compare dopamine release in two groups of people that had been given a dose of alcohol: one group carrying two normal copies of the gene for the MOR, and one group carrying at least one copy of the variant gene.
“We found that only people with the variant had a measurable dopamine response to alcohol—no such response occurred in subjects with two normal copies of the gene,” Heilig says.
Positron emission tomography (PET) scans of two male social drinkers after alcohol consumption. The brain on the left is from a subject with two copies of the normal OPRM1 gene allele and shows no measurable dopamine release. The subject on the right carries a variant copy of OPRM1 and exhibits a robust dopamine release
He was thrilled to have validated the correlation, but geneticists remained skeptical because the sample size of patients in the PET study was small. Undeterred, Heilig pressed on.
“We then inserted each of the human MOR genes into mice and directly measured the animals' dopamine response to a dose of alcohol,” Heilig explains. “Mice with the variant MOR showed a four-fold higher peak dopamine response to the alcohol challenge compared to mice with the normal gene. When given a chance, they also drank more alcohol —and the effect was completely mitigated with naltrexone.”
Predoctoral fellow Nathan Juergens prepares cells for study
Heilig’s team had taken a clinical observation, sought to understand its molecular terms in the lab, and then brought the conclusions back into the clinic. Based on these and other findings, a simple pharmacogenetic test might in the near future be able to differentiate between patients who will benefit from naltrexone treatment and those who will not, thus helping to target and expedite treatment.
Do other genetic variations behind alcoholism likely predict how individuals respond to a medication?
Dr. Heilig and predoctoral fellow Matthew Solomon working in the lab
“The answer,” says Heilig, “is most likely yes,” and so the treatment of alcohol addiction now enters into the realm of personalized medicine, where the underlying differences in each of our genomes can be used as the basis for the development of individualized treatments.
Heilig’s quiet demeanor disguises an extremely sharp mind that has not stopped pushing the boundaries of how scientists investigate alcoholism since the day he arrived at NIAAA. Although he claims that his immersion amongst the many talented IRP scientists keeps him motivated, one cannot help wondering if the best motivator for Heilig is simply to tell him that something cannot be done.
Markus Heilig, M.D., Ph.D., is Clinical Director and Chief of the Laboratory of Clinical and Translational Studies (LCTS) at the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and Clinical Director at the National Institute on Drug Abuse (NIDA).