Interview conducted by April Cashin-Garbutt, BA Hons (Cantab) on 29th June 2012
Please can you tell us a little bit about nicotine addiction?
Cigarette smoking and nicotine addiction are widespread problems throughout the world.
Many people continue to smoke despite high taxes and the available public information on the dangers of smoking.
In the US, 19-20% of adults continue to smoke and in some other parts of the world the frequency is much higher than that.
The reason for this is that nicotine, one of the molecules in cigarettes, is addictive. When people smoke they feel calmer.
The problem with smoking is not the addictive molecule, nicotine, but the other compounds contained in cigarettes.
These compounds can cause problems such as chronic obstructive pulmonary disease (COPD), which includes bronchitis and emphysema. COPD is the third biggest killer in the United States.
Also, cigarettes can cause lung cancer, which is the most lethal cancer for men and women.
Cigarettes also have a major impact on cardiovascular disease.
Overall, cigarette smoking and nicotine addiction are major worldwide problems and there is currently an unmet need to solve them.
You have recently developed and successfully tested a vaccine to treat nicotine addiction. How did this work originate?
The work started about four years ago when I was walking by a news store and I saw a news magazine. On the front cover it had the title, ‘Addiction: we need a vaccine’.
This sparked an idea that genetically we could produce antibodies against nicotine.
How does the vaccine work?
There are basically two types of vaccine: active and passive vaccines.
Active vaccines, like those for mumps, measles and tetanus, work by taking a piece of the pathogen, that is foreign to the individual, and administering it to the individual.
The individual’s immune system then actively produces antibodies.
It is very hard to create an active vaccine for nicotine, as nicotine is a small molecule.
In passive vaccines, such as what you would be given if you were bitten by a snake, antibodies are administered.
Many of the cancer vaccines now being used are antibody vaccines.
The problem for creating a passive vaccine for nicotine is that antibodies have a short lifespan.
Once they have been administered (by injection), they work for around 3-4 weeks at most.
This would not be very good for nicotine addiction: first of all, because it would be expensive.
And secondly, it would mean that the patients would have to go to the doctors every month to receive the injection, which most patients would not enjoy.
The strategy we’ve chosen is to take an antibody against nicotine, and instead of injecting the antibody itself, we have used the genetic sequence for that antibody.
We have placed the genetic sequence for the antibody into a gene transfer virus, which is a virus that will transport the genetic sequence to the appropriate cells.
We decided to use a virus that would carry the genetic sequence to the liver cells.
This meant that the liver cells, once they received the genetic sequence, produced antibodies for nicotine.
The antibodies act like little Pac-Men travelling around the blood. Essentially, they act as a shield to protect the brain from the effects of nicotine.
The antibodies bind to nicotine and prevent it from reaching the brain.
Consequently, the animal does not feel any physiological effects of nicotine.
For example, if you give nicotine to a normal mouse, you see physiological effects: the mice stop walking around as much, their blood pressure and heart rate drops a little bit and so forth.
We found that if you vaccinate the mice before giving them nicotine. Then they react as if you were only giving them water.
They show no physiological effects when given nicotine.
The vaccine was tested in mice. Could you explain why mice were chosen as the research subjects? Are there any plans to test the vaccine in other animals?
We usually start studies on mice because they are easy to work with; they are inexpensive and so forth.
We are now going to move up in terms of animals. We will probably test the vaccine in rats and then non-human primates.
The biggest challenge is whether we can scale it up to humans.
Is it likely that the vaccine will work in humans? And, if so, when do you expect that it will be available?
The data in the mice looked terrific. The caveat is that mice are not just little humans.
Consequently, we will have to wait until we have done the studies to see whether the vaccine will work in humans. But so far, everything looks good.
It will probably take us around 2 years before we will be able to trial the vaccine in humans. In this time we would be doing studies in other animals.
The human studies themselves will take approximately 3 or 4 years.
Overall then, it will take around 5 to 7 years before the vaccine will be available for humans.
When would the vaccine be given? I.e. would it be given to treat those who are already addicted, or to prevent people from becoming addicted?
The initial studies would be in people that want to stop smoking, i.e. those that are already addicted.
If it was successful in that group, then we would consider using the vaccine in a preventative way.
In order to be used in a preventative way, however, the vaccine would have to be very safe.
Were there any recorded side effects of taking the vaccine?
There have been no recorded side effects so far.
The virus that we are using to transfer the genetic information has already been used in humans in a different study for totally different genes.
In the other study, the virus is being administered directly to the brain of children. So the safety of the virus is not going to be a problem.
How many times would the vaccine need to be administered to treat nicotine addiction?
The beauty of the type of vaccine that we have created is that it would only need to be administered once, as it would last forever.
This is because the vaccine genetically modifies the liver cells to produce the antibodies.
Would the dosage need to be altered for different people, or would there be a standard dosage?
We currently don’t know the answer to this.
There is genetic variability in most humans so they may respond differently to the vaccine.
However, this is a different kind of vaccine, as we are not trying to actively invoke immunity, but to get the liver cells to make the antibodies.
So I don’t think the dosage is going to be a big problem, but until we test it in humans we do not know for sure.
Do you think the vaccine would stop people smoking altogether, or do you think there are other social reasons why people would still continue to smoke?
Smoking is complex, so it is very hard to say.
The smokers who had been vaccinated would not get the physiological effects of smoking; however, there may still be other reasons why they may continue to smoke.
Essentially, until we do the studies it is impossible to say.
Are there any plans to create vaccines to tackle other addictions, such as alcohol and so forth?
We have done similar kinds of things for cocaine addiction.
It is a platform strategy. This means that as long as we have an antibody against the addictive molecule, we should be able to create a vaccine for it.
It should be able to work for heroin and methamphetamines and so on.
The difficulty with treating alcohol addiction would be whether you could create an antibody against alcohol. That would not be easy to do.
About Dr. Crystal
Ronald G. Crystal, MD, is Professor and Chairman of the Department of Genetic Medicine at NewYork-Presbyterian Hospital/Weill Cornell Medical College.
After earning a BA in physics from Tufts University, an MS in physics from the University of Pennsylvania, and an MD from the University of Pennsylvania, Dr. Crystal served as Chief of the Pulmonary Branch of the National Heart, Lung and Blood Institute.
After first focusing his research on the pathogenesis and therapy of inflammatory diseases of the lung, Dr. Crystal became a pioneer in the field of gene therapy.
He has received numerous professional honors, published over 790 scientific articles, and has served on a number of advisory boards to government and industry. Major focus areas of his current research include developing vaccines against addictive drugs and investigating how genetic variability modulates the risk for chronic obstructive pulmonary disease and lung cancer.
Unraveling the mysteries of gastro-esophageal junction development