Joseph Nadeau is trying to find the missing link between heritability and genetics. What? You thought Gregor Mendel had it all figured out in the 19th Century? Well he did. But then DNA sequencing came along and upset the apple cart.
What we know about the fundamental laws of inheritance began to take shape in a monastery garden in Moravia in the middle of the 19th century, when Gregor Mendel patiently cross-bred pea plants over the course of several years, separated the progeny according to their distinct traits, and figured out the mathematical foundations of modern genetics. Since the rediscovery of Mendel's work a century ago, the vocabulary of Mendelian inheritance—dominant genes, recessive genes, and ultimately our own era's notion of disease genes—has colored every biological conversation about genetics. The message boils down to a single premise: your unique mix of physiological traits and disease risks (collectively known as your phenotype) can be read in the precise sequence of chemical bases, or letters, in your DNA (your genotype).The news for the "genes are destiny" folks are grim. Reality is more complicated than previously imagined. This will probably put the kibosh on full blown genetic engineering - at least for a time.
But what if—except in the cases of some rare single-gene disorders like Tay-Sachs disease—the premise ignores a significant portion of inheritance? What if the DNA sequence of an individual explains only part of the story of his or her inherited diseases and traits, and we need to know the DNA sequences of parents and perhaps even grandparents to understand what is truly going on?
Large-scale genomic studies over the past five years or so have mainly failed to turn up common genes that play a major role in complex human maladies. More than three dozen specific genetic variants have been associated with type 2 diabetes, for example, but together, they have been found to explain about 10 percent of the disease's heritability—the proportion of variation in any given trait that can be explained by genetics rather than by environmental influences. Results have been similar for heart disease, schizophrenia, high blood pressure, and other common maladies: the mystery has become known as the "missing heritability" problem. Francis Collins, director of the National Institutes of Health, has sometimes made grudging reference to the "dark matter of the genome"—an analogy to the vast quantities of invisible mass in the universe that astrophysicists have inferred but have struggled for decades to find.There are studies confirming this. One of them has to do with the heritability of PTSD.
Joseph H. Nadeau has been on a quest to uncover mechanisms that might account for the missing components of heritability. And he is finding previously unsuspected modes of inheritance almost everywhere he looks.
Nadeau, who until recently was chair of genetics at Case Western Reserve University in Cleveland and is now director of research and academic affairs at the Institute for Systems Biology in Seattle, has done studies showing that certain traits in mice are influenced by specific stretches of variant DNA that appeared on their parents' or grandparents' chromosomes but do not appear on their own. "Transgenerational" genetics, as he calls these unusual patterns of inheritance, fit partly under the umbrella of traditional epigenetics—the idea that chemical changes wrought by environmental exposures and experiences can modify DNA in ways that either muffle a normally vocal gene or restore the voice of a gene that had been silenced. Researchers have begun to find that these changes are heritable even though they alter only the pattern of gene expression, not the actual genetic code. Yet it's both more disconcerting and more profound to suggest, as he does, that genes an ancestor carried but didn't pass down can influence traits and diseases in subsequent generations.
It is often said of a particularly dramatic event – such as the September 11 attacks or the July 7 bombings – that its consequences will "reverberate for generations". It can seem like hyperbole, yet new evidence suggests that traumatic events can affect the genes, and lives, of children as yet unborn. Take the July 7 London bombings. As the harrowing evidence continues to emerge, the psychological impact on the survivors has been all too clear."The sins of the fathers are visited on the sons..." is more than a social construct evidently.
As many as 30 per cent of those directly caught up in the atrocities have gone on to develop full post-traumatic stress disorder (PTSD). This is in line with similar incidents: after the Oklahoma City bombing in 1995, 41 per cent of survivors were diagnosed with PTSD after six months, and 26 per cent were still suffering after seven years. Among soldiers returning from Iraq and Afghanistan, the British Armed Forces reckon that 10 per cent develop PTSD. However, an American study gave a figure as high as 30 per cent.
Yet new evidence suggests that the trauma is not just psychological, but biological and even heritable. By altering the chemical mechanisms regulating gene expression, these modifications may become embedded in the male germ line, and can be passed down to the victim's children.
Embedded within the DNA sequence are epigenetic regulators, chemical marks that control which genes are expressed and which are not. This is a crucial function, given that every cell in our bodies contains our entire lexicon of DNA. It is the regulators that selectively silence some genes so that particular cells become, say, skin or brain cells, and stay like that when they divide.Hmmmm schizophrenia. A lot in the news these days.
The heretical proposition here is that these epigenetic marks can be transmitted along with the DNA. It is the result of intensive research into how these mechanisms work. The best understood is DNA methylation, in which methyl molecules latch on to some areas of the DNA strand and act as switches that render a gene active or inactive.
Too much or too little methylation, and a host of problems occur, from fragile X syndrome to a variety of cancers. The latest findings, however, indicate that psychological conditions, such as trauma and stress, also leave an epigenetic mark. Professor David Sweatt and his colleagues at the University of Alabama have found that maltreating rat pups for just one week is enough to trigger epigenetic changes that deactivate the gene for a protein important in memory formation and emotional balance. This same agent – brain-derived neurotrophic factor – is often abnormally low in schizophrenics and those with bipolar disorder.
In a similar experiment, Professor Eric Richards at Washington University, St Louis, showed that the way rats are nurtured affects the methylation of a crucial receptor in the hippocampus. After a positive nurturing experience, the appropriate gene gets turned on at a vital early stage; after a bad one, the gene remains unused. The same is found in humans. A study of women in Holland who were pregnant during a prolonged famine after the Second World War found that their daughters had twice the normal risk of developing schizophrenia.
The bad news is the dramatic lag between these advances in science and their appreciation by the general public or their application in either practice or public policy settings. There is a wide gap between scientific facts and public perceptions about drug abuse and addiction. For example, many, perhaps most, people see drug abuse and addiction as social problems, to be handled only with social solutions, particularly through the criminal justice system. On the other hand, science has taught that drug abuse and addiction are as much health problems as they are social problems. The consequence of the gap is a significant delay in gaining control over drug abuse problems.From twin studies about alcohol we find that the heritability of addiction propensities runs about 50% to 60%. What accounts for the other 40% to 50%? My article, Heroin, provides a clue. And the clue points to trauma. There are more clues in my article PTSD and the Endocannabinoid System.
Surprisingly the NIDA says “addiction” is a genetic disease triggered by environmental factors. They had to be dragged kicking and screaming to this conclusion. It was pretty much established science by the time they allowed as how it might be true.
Here is what they have to say:
Evidence from adoption and twin studies and from animal models suggests that vulnerability to addiction has a moderate to high heritable component. The gene variants underlying increased vulnerability to addiction are unknown, but new advances in science and technology will facilitate the identification and characterization of these gene variants. Like many other psychiatric illnesses, drug abuse and dependence comprise a complex set of genetic disorders lacking a simple pattern of Mendelian inheritance. Multiple genes with relatively small effects are likely to influence vulnerability to addiction, gene x environment x development interactions appear to play significant roles in mediating outcomes, and there may be no simple correspondence between current phenotypes and the genotype(s). Therefore, a broad range of scientific approaches will be needed to elucidate the role and identity of genetic factors in drug abuse vulnerability.So I wrote a letter to the NIDA asking what I think is the critical question:
It is pretty well established (at least anecdotally) that besides a genetic base, addiction requires an environmental trigger. It appears that that trigger is trauma that generates an intense emotional reaction.In any case we know that the genetic factor is an important component. Why doesn’t the NIDA trumpet this? Well it hardly helps the drug war to think of it as a scheme for genetic discrimination and persecuting the tormented.
Here is one anecdote that I received today at my blog:I was a heavy user of hard drugs for a long time, and know many people in the situation. Having some sort of unpleasant past or fractured personality was an almost universal factor- long before most of these people ever started using drugs- physical detox fails because leaves underlying psychological factors intact (in many cases I don't think people can ever really be "cured" anyway). The war on drugs has made criminals people who are mostly either looking for relaxation/stress relief, or escaping some form of psychic torment. oh- Literally every female junkie I've met had either been raped or molested.This fits in well with the work of Dr. Lonnie Shavelson who wrote a book on his findings.
Is Addiction Real?
Social studies of actual users could put definitive numbers to these anecdotes.
Are any such studies being done in conjunction with the genetic studies?
Bill Quick at The Daily Pundit has posted my latest article on the subject of addiction. Bill also has a link to this related article at LGF. I will post the full article that Bill has put up later today or early tomorrow.
And thanks Bill for the exposure.
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Is addiction real? A very interesting question.I think there is an answer to that question. Obviously I think the answer is not in the affirmative. Why? Well there in lies a tale.
For me it started with Dr. Lonnie Shavelson. In July of 2001 I read a review of his book "Hooked" and learned some things. One of the things I learned was that in his sample of female heroin users 70% were sexually molested before they started heroin use. He also found that male heroin users were 25 to 50 times more likely to have been sexually abused than the general population. I wrote an article on the subject. Heroin. What I suggested in that article was that a large number of heroin users were taking the drug for relief from severe PTSD.
The next piece of the puzzle came to me in November of 2002 when I read this report done on the CB1 receptor in mice. A cannabinoid receptor also found in human brains. The report showed that fear memories which seem to be mediated by the CB1 receptors decay at different rates depending on genetics. I wrote this review of that report: Addiction or Self Medication? What I figured out from the report is that the reason drugs are addictive (long term use) for some and not others was based on genetics. A very big key to the puzzle of addiction. In the past the fact that some get addicted and others do not was ascribed to the "addictive personality". Now no one could tell you what an addictive personality was. It couldn't be defined. So in fact it was mumbo jumbo. I now had another piece of the puzzle. However twin studies showed that genetics only accounted for 50% of the cause for addiction. What was the other 50%? Pretty obvious from Dr. Shavelson's report. Trauma.
Well that lead me to look deeper into the genetics aspect. I wrote an article Genetic Discrimination which goes into some of the genes involved in tobacco addiction and marijuana addiction. It turns out that the genes involved in tobacco addiction vary by race. It also turns out that some people do not produce enough cannabinoids to feel normal. Again the idea that genetics only accounts for 50% of addiction (in this case to pot) comes up.
Looking further into the opiate question I looked into endorphins, the body's natural heroin, and how the body produces them. Sex, food, and exercise. And of course we know about sex junkis, food junkies, and even exercise junkies.I wrote about that in an article called Big Mac Heroin Attack.
What about stimulants? Stimulants seem to work well for people with ADD/ADHD problems. Of course this has got the pharma folks in full hue and cry mode against street drugs.
The War On Unpatented Drugs
To sum up:
1. We now kow that severe PTSD may be the cause of 70% or more of heroin use.
2. We know that there is a genetic connection.
3. We know there is a trauma connection.
4. We know that stimulants treat a different class of problems than opiates
What I have done is come up with a hypothesis that fits the facts. Why some people and not others are susceptable to addiction (as opposed to habituation which we know how to treat: Detox). Surprisingly this is a Well Known Secret in some segments of the medical community.
What we do not know is the true extent of the problem. Exactly how much of what we call addiction is due trauma/genetics? We don't know the answer because the problem is not being studied in any systematic way. We have the most information on pot/PTSD and stimulants/ADD-ADHD. A very few studies on opiates. Most studies so far have been anecdotal rather than statistical. The reason in my opinion is that there is no research money out there to make a statistical study of the self medication hypothesis. Such studies would be very expensive if they included DNA work ups and extensive interviews.
Self medication appears to be a very lage part of our "addiction" problem. In fact we may not even have an addiction problem. What we may have is seriously undertreated population with various mental problems caused by imbalances in the brain.
What is needed is more research. The only way we will get that any time soon is to pressure the government.Obviously the drug companies have no interest in finding out what addiction is because it will impact their bottom line if people take drugs for Problem Solving. In fact there are a lot of actors in this farce who would stand to lose big if such a study showed what I expect it might. The only folks to be benefitted would be "addicts". And they don't have much of a lobby in Washington.
I have also written about soldiers/police and PTSD here:
The Soldiers Disease
Aftermath
A test for PTSD
Police and PTSD
And if you go to my sidebar I have lots of other links to articles on the subject.
I just ran across a fascinating article on cousin marriage in the Middle east and why it might hamper development of a national democracy in Iraq.
LGF also covered this a while back with refrence to Saudi Arabia.
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. I can use the money - well actually I will use the proceeds to buy something from Amazon. I get a better deal that way.
