Our brains, however, make a big deal about the passage of years. Right around mid-December, we start seeing just about every organization publishing their list of the the top 10 moments in whatever they happen to be interested in – the top 10 harpsichord riffs of 2009, the top 10 videos in big game fishing, the decade’s best basket-weaver.

Science is no exception, and it’s with a certain amount of pride that I say that my own supervisor, Dr. Michael Meaney, with Dr. Gustavo Turecki from here at the Douglas, are the recipients of Radio-Canada’s awards for Scientist of the Year for 2009. Working in collaboration with Dr. Meaney, Dr. Turecki, and Dr. Moshe Szyf at McGill University, post-doctoral fellow Patrick McGowan showed that DNA from suicide victims who were abused as children is qualitatively different from those who were not abused.

This finding got a great deal of media attention when it was published almost a year ago, and rightfully so. It is a tremendously important finding, even if certain laypeople think that the results are “obvious.” I agree to a certain extent – it is, in fact, obvious that child abuse is wrong and has detrimental effects on a person that can last their whole lives. Hence “abuse.”

What isn’t obvious is how the effects of abuse can persist through a person’s life. There is tremendous stigma regarding mental health issues and a certain attitude that sufferers should “get over it,” or that they can somehow think themselves into health. Without hard evidence that there are biological underpinnings for mental disorders, it is very difficult to defeat a misconception of this nature.

In many ways, this is what the study shows. I have written about epigenetics before, and how our environments can “talk” to our DNA, and program it to do certain things. This study is very much in the same vein. The sequence of our DNA doesn’t change through our lives, but the way it is organized within our cells can change as a result of our environments, and this affects the way our DNA functions. It’s a code for making proteins, the workhorses of our cells, and if it’s organized in such a way that a part of the code can’t be read, then that protein doesn’t get made and the work doesn’t get done.

A key mechanism for the way this happens is by DNA methylation. Specific sites within DNA can be chemically modified so that what we call a methyl group gets attached. This methyl group is a sign for the cell to organize the DNA such that the bit with the methyl groups doesn’t get read anymore.

Dr. McGowan’s research used tissue from the Douglas Institute Brain Bank to show that there were different patterns of DNA methylation in suicide victims who were abused as children compared to suicide victims that were not. A certain gene which is very important in controlling stress and anxiety was found to be more heavily methylated in the brains of abused suicide victims. This would result in reduced amounts of the protein, and a reduced ability to control anxiety and stress.

This is important for numerous reasons, but in my opinion the most important one is that legislators and health care professionals can use this as an example of the biological phenomena that underlie mental health issues. These are not things we can think our way out of, or will ourselves to change, but rather serious biological issues that, in many ways, are almost undefined by science.

Despite all the New Years’ celebrations since we started investigating mental disorders from a biological perspective, we have a lot of work to do. A great deal of that work is research, but it’s clear that we also have a lot to do in terms of convincing the public that biology, rather than “mind,” is what underlies mental disorders; and that the development of treatment programs that address the biology of mental health are of paramount importance. No one asks a patient to “just get over” multiple sclerosis, or think themselves free of epilepsy. Other disorders affecting the biology of our brains should be no different.

***

For more on epigenetics, I am shamelessly plugging a video of myself giving a talk on epigenetic programming by the environment at a recent McGill conference. It’s aimed at a scientific audience rather than the layperson, but I encourage you to have a look. You know where to find me if you have questions.

The Leatherman is a folding pocket tool with pliers, blades, screwdrivers and pretty much every basic tool you could need in a hurry. It’s like a Swiss Army Knife on steroids. I love that thing, and I carry it everywhere – even when I’m part of the honour party at a wedding. I get excited when I get to use it, just like when a new Canadian Tire flyer comes to my door.

I also love when new tools are invented in biology, and watching tools that I use develop into potentially lifesaving treatments. A couple months ago I talked about using lentiviral vectors in some of the more mad scientist-type experiments that I do. This tool is based on the HIV virus that gives rise to AIDS in humans, and allows us to put any gene we want into any cell.

For years now, scientists have been saying that this opens the door to what we call “gene therapy,” the treatment of diseases at the genetic level. There are serious obstacles in the way of this approach, however. It remains very difficult to deliver these genes to specific areas, and there are certain safety concerns about inserting pieces of foreign DNA into our own cells – some of our important bits of DNA might be changed and this could have some seriously averse consequences for the patient.

Recently, scientists have managed to use lentiviral vectors to help cure a serious genetic defect in two young boys. The boys have a disease called adrenoleukodystropy (ALD), in which a gene that produces a vital component of our neurons (ABCD1, necessary for myelin maintenance) is mutated and doesn’t do what it should. The disease is always fatal, and is currently treated with very limited success by giving bone marrow transplants from an appropriate donor if one can be found. Sadly, even with this treatment, most children diagnosed with ALD die within 3 years.

The scientists in this case took stem cells from the boys’ own bone marrow and infected them with a lentivirus containing a working version of the ABCD1 gene. They let the infected cells multiply and then put them back into the boys, eliminating a serious obstacle for transplants – the risk of rejection. After 3 years, about 15% of the boys’ bone marrow cells are producing the protein properly and the symptoms of ALD – degeneration of the myelin around neurons – have stopped progressing. The boys are in school and living normal lives.

This is a wild success story for gene therapy, and gives us all reason to be optimistic for future treatments. However, any excitement we have about gene therapies should be tempered. Similar approaches have been used in the past and had disastrous results. In 1999, 18-year-old Jesse Gelsinger died as a result of the injection of an adenoviral vector meant to treat another genetic disease. In 2003, gene therapy for a genetic immune disorder led to the development of leukemia in 2 young patients. However, we seem to be getting better. Gene therapy has been used in one recent clinical trial for treatment of AIDS, and another recent study “cured” colour blindness in monkeys using a similar approach.

Gene therapy is an amazing tool for specific genetic disorders like ALD or Huntingdon’s disease. However, for most neurological and psychiatric disorders, the causes are much more complex than a mutation to a single gene. Lentiviral vectors are not much like a Leatherman – they’re more like a hammer. There are specific jobs where these tools are the best thing going, and others where you might as well be using a saw to screw a shelf onto your wall.

Gene therapy has come a long way in the last 2 decades, but not far enough for my mother, whom I think would like me to start working on a lentiviral vector targeting parts of the Y chromosome to stop myself from engaging in some of the more distasteful of my “manly” behaviours…

Last time I talked about some of the more Frankenstein-ish things that I do in the lab. Maternal observations are not one of those things. Our lab is very concerned with maternal care in general. Some people study the mothers and look at the things in the brain that drive maternal care, whereas others like myself are interested in the effects of different early life environments on development.

For a lab rat, the early life environment is solely determined by the mother’s behaviour. They are all fed the same, they are in the same kind of cage, they all get the same bedding. However, maternal care varies quite a bit between rat mothers, just as it does for humans.

A rat mother’s behavioural repertoire is, however, much more limited than a human’s. What we score are simple things like whether the mother is in contact with her litter or not, what sort of position she holds while nursing, and most importantly, how much time she spends licking and grooming her pups. We do this 5 times a day for 75 minutes over the first six days of life, which as you imagine can be quite boring (hence the blog update). Also not particularly Frankenstein-ish, but you get a white coat and a clipboard so you feel very much like a not-so-mad scientist.

What we have found in the past is that pups that receive a small amount of licking and grooming grow up to be more anxious than their well-licked brethren. This is a fascinating effect, and it’s interesting trying to imagine what the equivalent would be in humans. One alumnus from our lab gave a seminar in New York and was approached by a group of women after the talk, who proudly announced that they’d been licking their children to reduce their anxiety, just like in our research papers.

I wish I was joking.

Again, clearly humans have a wider range of behaviours than rats, even crazy New York humans who have just enough knowledge to be dangerous. We have things like thumbs and vocal cords that allow us to talk to our children, hold them in our arms, make faces and noises and all manner of things. Rats get their mouths, more or less, which limits the sorts of things they can do with their babies.

For the record, we do not endorse licking your children. Personally, I think that the licking and grooming in the rat is a rodent equivalent to the attention we lavish upon our own children like in the examples above. If rats had thumbs, things would likely be much different in their lives, and not just where maternal behaviour is concerned.

t’s very much a taboo these days to judge mothers (or people in general) as “good” or “bad.” One important thing that we try to make clear in our research is that we classify the moms based on their behaviour, but we don’t try to label them as “good” or “bad” moms. A rat that received a high amount of licking is less anxious as an adult, and that may seem like a good thing. However, in the rodent world, a little anxiety and fearful behaviour go a long way to promote survival. A fearless rat in the wild quickly becomes fast food.

Unless we’re talking crazy New York sewer rat, in which case I guess they can afford to be fearless. Good thing they don’t have thumbs…

While I don’t cackle madly over experiments performed in thunderstorms on the roof of Lehmann Pavilion – and I sure don’t get an Igor to help me with my lab work – I do get to do some fairly wild and freakish stuff sometimes. The most wild and freakish of those things would be the experiments I perform using lentivirus.

The main reason people find these experiments so freaky is because the primary tool, the lentivirus itself, is derived from the HIV virus that causes AIDS. We use a strain that has been heavily engineered into a sort of genetic Lego set that can perform some pretty amazing tricks for us, while eliminating many of the health risks you would expect to be a problem when working with something like the HIV virus.

HIV is an amazing organism, which is probably part of why it causes such a devastating disease. I have mentioned before that, in the dogma of biology, we have genes in our DNA that go on to make mRNA “middlemen,” which then go on to make the proteins that perform the actual work inside a cell. HIV caused gigantic waves through the biology community because it works in reverse: the virus contains the genetic material to make more of itself stored in an RNA form. Once inside a host cell, special enzymes take that RNA and turn it into DNA that gets inserted into the DNA of the host cells. The host cells then make more copies of the virus, which go out into the organism and infect more cells.

The most important thing about this from my perspective is that the virus is capable of inserting genes into a host cell’s normal DNA. Recognizing that this could be a powerful tool for biology, people have been working for the last 15 years or so on how to harness the properties of this virus. What we work with now are 3 or 4 engineered “chunks” of that viral genetic code that we can put into cells. These cells are then forced to produce a virus that can introduce itself into a host cell and place genes into their DNA, but can’t make more of itself. This precaution helps keep the experimenters safe in case there is accidental exposure.

Two or three of those chunks are the same no matter what you want your virus to do. They have what the virus needs to assemble itself into a functioning unit that can insert DNA into a host cell. The last chunk is the important one. It contains the gene you want to insert into the infected cells. This is why it’s a little like a Lego set – you can switch your components to change what gene you want to deliver.

The best thing about this brand of Lego from the viewpoint of mental health research is that we can test hypotheses about the contribution of genes to different aspects of various disorders. For example, we can test if a gene is involved in anxiety by putting that gene in a lentivirus and infecting an animal with it. Then we confirm that the gene and its products are present in higher amounts and test an animal for fearful behaviour. Similarly, there are other tools we can put into that last chunk of lentivirus Lego that prevent a gene from expressing its products. This is a very powerful approach to discovering how a specific gene might contribute to a given mental disorder.

Using approaches like this, researchers hope to develop methods to help patients at the genetic level. For example, altering the expression of genes involved in the stress response might be able to help patients with anxiety disorder, or manipulating genes important for memory may one day help those with learning disabilities. Similarly, these techniques could be used to help patients with purely genetic diseases like Huntington’s.

One caveat, however, is that mental disorders are almost never so simple that changing the expression of a single gene will solve any of the problems a patient might have. There is no gene for happiness, or schizophrenia, or even calmness for that matter. If it were that easy, there would be no more problems in mental health, and a lot of people like me would be out of a job. Sadly, we are all aware that this is not the case.

Still, understanding the contributions of different gene products to various behaviours is vital for improving strategies for the treatment of psychiatric disorders. The genetic Lego set provided by the lentivirus allows us to do just that – manipulate some of the base building blocks of life to open avenues for better understanding of the brain, and suggest new treatments in the field of mental health. I realize this is nowhere near so exciting as lightning storms and maniacal laughter, but please believe me when I say that the research community is more than willing to sacrifice a little excitement in the name of science. In fact, it’s a job requirement.

I do wish I had an Igor, though.

Sure, we have blue or brown eyes, black or blond hair, we’re taller or shorter. But looking at it from the point of view of a cell, which is to say looking at proteins and other molecules, we are more or less exactly the same. Slight genetic variations and living in different environments (as we learned about last month) combine at a basic biological level to make humans the diverse people we are now. We might be different, but the building blocks are largely the same.

One main source of the differences between you and me at the genetic level are changes lumped into a category we refer to as SNPs (pronounced “snips”). It stands for Single Nucleotide Polymorphisms, which aren’t really so complicated to understand as they might sound. Each of the A, C, T and G elements of your DNA are molecules called nucleotides. A polymorphism is a fancy-pants five-dollar word derived from greek meaning “many forms.” So a single nucleotide polymorphism is just one spot in our DNA where some people have a C and others have a G.

I said that you and I are about 99.98% identical. Which seems like a lot, and is possibly quite a nasty thing to say about you. But when you think about the numbers, it gets put into perspective. We have about 3.4 billion nucleotides in our DNA, which means we differ in almost a million places in our genomes. This 0.02% variability is still enough to give a practically infinite number of variations to the human theme.

Most SNPs are pretty minor changes. They don’t actually show up as an eleventh toe, bigger muscles, or an anxiety disorder. Most of them seem to do nothing at all, from what we can tell right now. Maybe a study will show that one form of a SNP increases your odds of skin cancer by 1.24%. A large number of these polymorphisms are probably completely inconsequential.

Some aren’t, though. Some can predict responsiveness to different drug treatments in cancer; maybe even change the composition of a protein and impair its function. Douglas researchers like Ridha Joober and Howard Steiger have found interesting associations between certain SNPs and psychiatric illnesses like major depression and eating disorders.

For roughly the price of a Playstation 3, you can buy a kit from a private company and send away some cheek cells to have you own DNA examined. For example, an outfit known as 23andMe will take your DNA and check it for thousands of known SNPs. This isn’t going to give you the actual 3.4 billion nucleotide sequence that makes up your DNA, but it is going to tell you about some key places where your genome might be different from someone else.

Just don’t expect it to show that you have an anxiety disorder or you’ll develop cancer. Even people who work in this seemingly serious biological industry say that “the 23andMes of the world are more in the entertainment realm…” Like insurance companies, we can calculate the probability that a given SNP will increase a person’s chances of skin cancer by age 55. But we can’t look at this data for a given individual and know they’ll have cancer or undergo a major depressive episode in their 36th year of life.

Even if we could, there’s nothing we could do about it at the genetic level. SNPs aren’t diseases, and there’s no way to “cure” a SNP. Which one is the “right” one? Genetic variation is good for us as a species, and frequently has benefits that aren’t immediately apparent – sickle cell anemia, for example, is a heritable genetic disorder very common in some areas of the world because it hampers the ability of the malaria parasite to survive in the host.

So, as always, it’s true what our mothers used to say: even down at the genetic level, we’re all unique and special in our own way. Less true is what my father used to say – that me and my friends are a bunch of little monkeys…

But they do. Not so much in a disembodied voice kind of way, which would indeed be cause for worry, but our environment is always telling us things. It tells us when it’s cold, when we might be damaged by something, when there’s something big and heavy coming our way. This is no mistake, all organisms from lowly bacteria to humans have evolved over millions of years to be able to hear the things our environments say so that we can survive.

Our environments talk to us by biological mechanisms. It’s easy to understand this in terms of moment-to-moment changes registered by our eyes, ears and noses. It’s less obvious that these signals all go into the brain and start off their own chains of signals inside brain cells at the levels of proteins and genes. Accepting this as true, it makes sense that more complicated things about our environments – a loving family, proper exercise, a good education, eating right – also affect these basic biological processes.

Dr. Michael Meaney‘s research here at the Douglas Institute has done a great deal to advance these ideas and our understanding of the biology that underlies these changes. Through studying maternal behaviour in rats, we have learned that babies who receive a lot of attention from their mothers grow up to have less anxiety-like behaviours than babies who receive very little attention. We have also shown that a rat taken from a mother who doesn’t much care for her pups and given to a more attentive mother also grows up to be less anxious.

This is an amazing finding for two main reasons. Firstly, it confirms in a scientific manner something we have all suspected, namely that your parents are to blame for all the terrible things you’ve done in your life. Secondly, because the differences are based on the mother’s care, we know that it’s parenting and not genetic information passed down from the mother and father. Because we have done some pretty complicated and elaborate experiments, we have a good idea why the high maternal care pups are less anxious and have gained some insight into the mechanism by which this happens.

In my last post, I mentioned that a gene is a piece of DNA that “codes” for a protein, which go on to do the work inside cells. The elements of your DNA – the millions of A, C, T and G molecules – are inherited from your parents and you’re stuck with them for the rest of your life. Unless you dose yourself with a huge amount of radiation, which I don’t recommend. Unlike in the comic books, you will almost certainly not be gifted with superpowers.

The DNA inside every one of your cells is the same, but there is an incredibly wide variety of different kinds of cells in your body – brain cells, skin cells, liver cells. They are specialized to perform specific functions, and they can do this because they produce the proteins that allow them to do their jobs, and other genes that aren’t needed are shut off. The actual content of your DNA is the same between cells, but the way that the DNA is organized is vastly different. Proteins are capable of restructuring your DNA to control genes in a process we call epigenetics.

The DNA gets organized by signals that come from outside the cell. During development, specific biochemical signals force stem cells to make brain cells or spleen cells, and proteins inside the cell organize its DNA accordingly. What you might find surprising is that researchers are finding out that even very routine events in the brain, like forming new memories, seem to involve precise epigenetic DNA reorganization events in certain brain cells.

Should it be any more surprising that maternal care can produce epigenetic changes? Dr. Meaney’s research shows that rats that received high amounts of maternal care organize their DNA differently than their low-maternal care cousins. The DNA coding for a protein called glucocorticoid receptor is more easily accessible for the proteins that sort of “turn on” the gene in a specific area of the brain. This increased amount of glucocorticoid receptor can help the high-maternal care offspring inhibit some of their stress response, which in turn makes them have less anxious behaviours.

Which brings me back to my initial point: our environments speak to us. Even if we haven’t been listening, the various environments of our lives have been chatting with our DNA in secret, deciding things about our fates in backroom deals like crooked politicians. It’s not easy to decode what the DNA has agreed to do in response to the environment whispering in its ear, however. It’s even more difficult trying to understand how exactly the message got through in the first place.

Listening in on and understanding these messages is a large challenge in biology, but it’s very important. Psychology has had a notion of “nature vs. nurture” for a great many years, where some traits are solely genetic and some are environmental in nature. This is becoming a largely meaningless debate, as we are beginning to understand that there is an ongoing discussion between genes and environment that impact who we are, the things we do, and even our mental health.

Which in turn, is why I don’t think I’m crazy for talking so much to my environment. I look at it more as just trying to get my two cents’ worth into the conversation…

Now, if you’ve seen a George Romero movie, you’ll know that zombies are all about brains. In fact, some of us Douglas zombies are actually after brains, and we’re not the only ones. Most of working in research at the Douglas study brains. Naturally, this requires actually having brains to study. Our options for studying brains in living humans are quite limited – needless to say, ethics committees frown upon us looking TOO closely at the brains of living subjects.

What we are left with are scans and models. Scans can tell us interesting things about the brain, but the questions you can answer are limited in scope. We can ask about blood flow, which might be an important indicator of brain activity. We can ask how much of a certain chemical is being released by specific brain areas. However, not all of the millions of questions we have about brains and how they work can be answered through scanning.

Sometimes we can take a closer look at things like protein levels, electric signaling, or gene expression by using animal models of human biology. There are many interesting and important questions about brains, genes and behaviour that can be answered using rats, flies, and even slugs. But to paraphrase the statistician George Box, “some models are useful, but all are wrong.” That’s what makes them “models” as opposed to the actual systems we want to work on. Which is why it is so important to get real human brains for efforts like the Douglas Institute Brain Bank.

The ability to analyze brains in great detail is key to understanding mental health, psychiatric diseases and the actual events in the brain that underlie these states. Using our very own brain bank, Douglas Institute researchers like Dr. Gustavo Turecki have gained important insights into depression and suicide by studying differences between the brains of suicide victims and other patients. These studies will contribute to the development of new theories of depression, which will in turn open the door to new treatments for this complex psychiatric disorder.

Unlike depression, some brain disease is relatively easy to understand and even treat. Nobel Prize laureate Eric Kandel refers to these diseases as “neurological disorders,” and can be characterized as being restricted to a certain area of the brain, limited to a small number of systems in that area, and having the same set of symptoms across all patients. A great example is Parkinson’s Disease – we know that cells dying in a specific area of the brain cause the tremors and disturbances in movement (even if we’re not yet sure why they die). We know ways that it can be treated, and although there is no cure as of yet I am highly confident that stem cell research will provide one in my lifetime.

Psychiatric disorders do not follow such simple rules. Depression and schizophrenia, for example, have widely variable symptoms – no two patients are quite alike. They seem to affect wide areas of the brain and many different “sub-systems.” Our hope is that examination of molecular targets, like those I talk about below, will help us to better define the causes of complex diseases and develop better identification of the problems that can give rise to disorders like depression.

Proteins: Proteins are the workhorses of your cells. Enzymes are proteins that make chemical reactions happen in your body. Receptors are proteins that catch signaling molecules and let cells receive information from other cells and their environments. If there’s a job to do in a cell, there’s better than a 99% chance it gets done by a protein. Often we study receptors, and the proteins they use to pass their signals into a cell; but my experiences suggest that you can find at least one neurobiologist that studies any protein that’s ever been discovered in the brain.

Genes: We hear a lot about the “genetic code” and how important it is. What is meant by this is that genes are the pieces of DNA that lay down the codes for cells to make proteins. Genes in DNA are transformed into a sort of middleman called mRNA in a process called gene expression. mRNA is then translated into proteins, which go on to do the real work.

Promoters: In order to be expressed, genes need to be “read” by a set of proteins that make the mRNA. This set of proteins assembles at the start of a gene in a region called the promoter. The cell can control gene expression by controlling the proteins that assemble at a promoter site for a given gene.

In future posts, I will expand on these topics by talking mostly about genes and promoters, the methods we use to study them, and their importance to different aspects of mental health. So I guess you could say that there will be a test on this later. In the meantime, maybe you want to have a closer look at Dr. Turecki’s research, the Brain Bank maintained at the Douglas, or check out this excellent Nature article on the importance of brain banks and some of the scientific advances we can credit to their existence. I hope you’ll even think about donating your own brains to the Douglas zombies – whenever you happen to be done with them, that is. We promise not to eat them.