by Lone Frank
“WE HAVE HAD some technical problems, but now the assay is up and running again, and your test results have now arrived from the laboratory. If you are interested, please call me.”
This laconic e-mail has arrived from Birgitte Søgaard, the head of Lundbeck’s department for translational medicine. Her department is the one that is supposed to translate the results of research into something that can be used outside the sheltered laboratory environment. On real patients. I have not been in contact with Søgaard before – I just delivered my blood test to a lab technician, who sent it on to the research team in New Jersey – but I call at once. Of course, I’m interested.
“Hello,” chirps Søgaard, who sounds like she’s in an especially good mood. Without further ado, she informs me, rather too cheerily, that my test places me solidly in the group of depressed research subjects.
“What?” I’m a little confused by this. I didn’t feel depressed when I offered up my vein, and I don’t now. This does not bode well for their test, I should think.
“You don’t have any symptoms?”
The usual dissatisfaction and occasional frustration with my immediate circumstances, but nothing abnormal.
“Okay. I want to stress that the test here is in its early development phase and that your result need not be a mistake. Not at all. But, perhaps, you should come out here and get a more detailed explanation.”
I agree at once, but unfortunately I won’t be able to meet with Søgaard herself, who is about to leave on a trip to the New Jersey offices. After some negotiation back and forth, her colleague Jennifer Larsen, who is a biologist involved in this major test project, makes herself available for that afternoon. All I need to do is show up.
Several hours later, I step across the threshold into the special domain of the pharmaceutical industry. This is top-flight research in business class. There is no trace of the eternal struggle against the poverty and cutbacks that permeate the halls of academia and give universities a telltale atmosphere of anxiety. Here, there is room and money enough.
Through the yellow buildings in Valby, you are sluiced into a gigantic glass lobby, which opens into another hall as high and wide as a train station. It is empty of people except for two receptionists, who are situated in a sort of screened-off playpen, where they look like discarded Lego figurines. Equipped with a guest pass, I traverse the reception hall to one of the luxurious chairs plunked into the corner designated as a waiting area, where a high-end Bang & Olufsen flat screen television supplies the news of the day. The floors are silky dark shale, punctuated by vases as tall as a man, positioned here and there to provide a feeling of security as well as decoration. Even a granite sculpture of a human brain does not seem nerdy but aesthetically elegant – and expensive.
“May we speak English?” I hear from behind me.
Jennifer Larsen is Canadian, and even though she has lived here for five years and can easily speak Danish, she doesn’t like to listen to her own grammatical mistakes. How she feels about my treatment of her native tongue, I don’t ask. Instead, I confess my confusion about Lundbeck’s famous test and ask for an explanation. Why does my genetic activity proclaim that I am depressed, when I’m not? What is it that’s being tested?
“How about a little background first?”
As we move through the wide hallways and pass offices notable for their order and congruent colors, Larsen shares the tale of the pharmaceutical industry’s biggest problem. The company executives know they can’t go on producing new products that are actually only slightly modified – or “gussied-up” – versions of old friends. Plus, there are lots of unmet needs to be dealt with. But to develop something new or significantly better, the industry’s scientists must first uncover and identify a disease’s mechanisms. In the psychiatric area, it is just incredibly difficult to get hold of these mechanisms.
“A general problem is that diagnoses are subjective,” says Larsen, wringing her hands. When it comes to depression, which is a really big market, they’ve gradually come to the conclusion that, in reality, the relevant diagnosis – major depressive disorder or MDD, as the psychiatric manuals term it – covers more than one disease. This intuition had been gnawing at the specialists for years. In particular, they know that a third of patients with an MDD diagnosis do not react to antidepressive SSRI drugs, though the rest do. It’s just that no one has been able to find the criteria to identify which patients fall into which group in advance.
“We’ve finally had to admit that there are probably different biological mechanisms involved. There is a difference in the patients’ sleep patterns, in which some sleep a lot, while some wake up early in the morning, just as there is a difference in whether the stress hormone cortisol is elevated or lowered. If we separate the different groups on the basis of biology, we also stand to find out whether we should treat them differently. Depressed is not just depressed,” Larsen confesses with an audible sigh. “And we would very much like some biomarkers to distinguish them.”
She is speaking on behalf of an entire industry. Everyone in “Big Pharma” is working to find biomarkers. Entire conferences address the topic; the market demands it. In a recent report on the future of the pharmaceutical industry, analysts at PricewaterhouseCoopers predict that, by 2020, it will be difficult to sell drugs without, at the same time, having a diagnostic test to verify which precise medicine the individual patient should receive.
“But we have a problem in the psychiatric field. Cancer researchers can easily search for biomarkers in tumors, but we cannot go in and take a biopsy of your brain to look at its biology, right?”
I understand that. On the other hand, I don’t quite get how they figure on finding markers for depression and personality disorders in white blood cells, which are the storm troopers of the immune system.
Larsen is eager to illuminate me. “Depressive patients show a number of changes in the immune system, and many believe that the disease may have a component that has to do with inflammation. We may not be able to see the whole picture in the blood, but we may find something relevant to measure.”
It sounds more like a fishing expedition than a scientific hypothesis, I think.
“Listen, for the last fifty years we have used animal models and tried to extrapolate from animal to human, but this has great difficulties in brain diseases. You can hardly ask a rat whether it feels sad or has hallucinations. It is obvious that we have to begin with patients, but we cannot take brain tissue from living people. On the other hand, we have lots of patient blood from our major clinical trials, and our starting point is that it is better to look at the blood from a patient than at the brain from a rat.”
I give in. But I still want an explanation of how in the world you find out which genes you’re supposed to measure in the patients’ blood. After all, there are over twenty thousand, and who knows which are relevant?
“We have experts for that,” says Larsen, abjuring any personal responsibility, “but I know it began with literature surveys.”
Specialists in the company’s US research department put on their reading glasses and spent six months digging through all the studies that postulated an association between depression and one gene or another. Then, they whittled their way down to a set of twenty-nine genes that seemed likely to play a part. Interestingly enough, these are not genes that have anything to do with the brain’s signaling pathways. The receptors and transport proteins we normally hear about are conspicuous by their absence.
“It’s a mixed bag,” Larsen admits. “There are some genes that regulate the activity in cell nuclei, and a number of genes that are involved in the function of the immune system. But I can’t reveal more, because we don’t have a finished product yet.”
What she can reveal is that, in their initial experiments, they have measured the activity of these twenty-nine genes in blood samples from several hundred carefully chosen people enrolled in clinical tests in Denmark, the United States, and Serbia. These wom
en and men were either healthy controls or people diagnosed with an untreated depression that had lasted for at least three months. Finally, they included some patients diagnosed with either borderline personality disorder or post-traumatic stress disorder. Why those? Borderline patients have fundamental difficulties regulating their emotions and thus display a number of symptoms in common with depression. Post-traumatic stress, on the other hand, is completely different from the other two conditions and could serve as a control for whether the effect the researchers eventually find in the blood is a standard reaction, a signal from the immune system that something unspecified is wrong.
The gene’s activity – or gene expression, as it is called – is determined by measuring how much RNA is transcribed from the relevant genes. The measurements are next transferred to a computer, where the whole kit and caboodle is combed by various pattern-recognizing algorithms to find characteristic and statistically sustainable patterns. All tasks done by machines.
“The whole project could have ground to a halt right there,” Larsen stresses, her voice shivering. “We could have been facing absolute chaos, pointing in every direction. Just imagine it.”
But there are patterns, patterns that clearly separate the different groups into distinct piles, the healthy from the borderline from the post-traumatic from the depressed. Across the three illnesses, some genes are more or less active in relation to the control condition, but there is a way to distinguish among them. In depression patients, for example, a specific subset of the twenty-nine genes shows less activity. Further analyses exposed possible subgroups among the depressed: patients whose gene expression looked more like each other’s than anyone else’s. But it’s not quite clear if these are biomarkers that could be treated or simply interesting patterns, a description rather than a diagnosis.
“We don’t know yet what the test will be able to do,” Larsen says. “It’s possible that what we’re seeing is an acute reaction to the disease itself and that you can identify patients in this way. But, first, we’re examining whether the gene activity is normalized when the patients are treated. A major experiment is going on now, where we are testing the twenty-nine genes in patients’ blood before, during, and after treatment with two different antidepressive drugs. But it takes time. We’re talking about thousands of samples.”
In the meantime, they’re exploring another possibility, namely that the patterns in the blood are not just acute reactions but an expression of epigenetic changes. And this seems to fit well with my personal test result. I’m not depressed but I have been.
“It is definitely possible that we have captured an epigenetic change that happened a long time ago but still remains. Maybe, this pattern itself is the expression of what we normally call ‘sensitivity’ to depression. But if that were the case, it is not necessarily bad news for the test,” says Larsen, with a conspicuously broad grin. “It can be used as a handle to find out whether something can be done about the disease and the sensitivity if you can normalize the gene activity in the blood cells.”
“I DON’T KNOW the details in the test, but from what you’re telling me, it sounds likely that we’re talking about stable changes,” says Moshe Szyf over the phone from his office in Montreal. “That is, not just acute changes but something epigenetic. And, generally speaking, I’m convinced that, when epigenetic changes happen in the brain, it has an effect on the whole system. The immune system speaks directly to the nervous system. So, it is highly likely that changes in the brain will show up in white blood cells.”
There is a short pause.
“But it’s not other people’s work you want me to talk about.”
No, most definitely not. I’d spent five minutes waiting on the line of an international call to hear about the potential for the field of epigenetics from one of its leading figures – and one who specializes in the brain. I fully understand that my test from Lundbeck is not his top priority.
“Yes, now we get attention,” says Szyf. “Some of us have been working with epigenetic modifications of the genome for thirty years, while everyone was totally indifferent.”
But now there’s enthusiasm, I remind him cautiously.
“Yes, because it’s finally clear that epigenetics can provide explanations for quite a few of the questions that have baffled us.”
Szyf himself has inserted epigenetic theories into some of those questions. He is convinced that we will find an explanation for the huge health gap between rich and poor in epigenetic effects. A person’s socio-economic status puts its mark on the genome, he argues, and this results in conspicuous differences in individual health outcomes within our otherwise affluent Western society. As preliminary evidence, he points out that it is not just that people in lower social classes die earlier, or that they are more frequently struck by the major lifestyle diseases. No, even the course of their illness, and the prognosis, is typically worse than for the economically better off with exactly the same disease. “This difference can hardly be due to the fact that the poor have different genes from the rich. It is so obvious that something epigenetic is going on here, but no one has looked at it,” he says.
To test his theory, Szyf and his team recently acquired access to a research goldmine: a huge and representative group of Canadians who have been medically tested and followed ever since they came into the world fifty years ago. So far, doctors have examined white blood cells to study whether there are individual differences in how many and what genes have been epigenetically inactivated by small methyl groups. Szyf is checking to see if any of the observed differences have a connection with the person’s socio-economic status early in life.
“And there seems to be something to it!” he says without, however, being able to reveal the final results just yet. I take a chance and ask whether his team might have been able to see epigenetic changes in any interesting individual genes? I’m thinking that the social health differences we typically hear about relate to cancer, diabetes, and cardiovascular diseases. Szyf moans softly.
“Of course, we know about special genes that play a role in those diseases. That speaks for itself.”
Yes, but have any of these genes been turned off or are they, perhaps, extra active in either the rich or the poor?
“The patterns we’re seeing are spread across the entire genome, and my guess is that there are quite a few genes involved here. We’re not getting lost by concentrating on just a few at this point.”
I certainly beg his pardon, then.
“But a good deal of the enthusiasm in the field also relates to the fact that no matter where the epigenetic changes are found, it is possible to manipulate them, okay?” he adds, in a slightly more friendly manner.
He’s quite right. You just have to pin down the biochemical processes. There is a palette of different enzymes in cells that can deactivate genes by attaching methyl groups, or that can open or close access to DNA strands by manipulating histones. And all these nice enzymes can, in principle, be regulated by well-chosen chemical compounds.
Szyf has demonstrated these mechanisms in action in a group of poor rat babies he allowed to be raised by inattentive mothers. As adults, these badly raised rats were plagued with nervous temperaments because of their geared-up stress reaction, but this could be corrected with one good shot of the chemical compound trichostatin A, or TSA. When the rats received injections of TSA directly into the brain, the chemical erased the epigenetic signature that had branded their conduct as infants. The damaged animals suddenly relaxed and, from then on, displayed completely normal reactions to stress.
“We already know a handful of recognized drugs that work on epigenetic changes,” Szyf says. He mentions valproate which, like TSA, inhibits the histone deacetylase and is used to treat depression. “There are also clinical tests going on of similar drugs for the treatment of psychoses. And now, when we are finally, hopefully, seeing some serious investments in this field, a lot of new drugs will be coming out over the next few years.”
But how does he imagine the treatment of patients will work in practice? After all, you can hardly stick needles into the brains of mistreated children. Epigenetics generally involves making chemical modifications that might only take place in one particular tissue – blood cells, say, or the brain. If a drug affects the epigenetic patterns in all the cells of the organism, you might well disturb completely healthy gene activity and create unintended side effects. It can’t be easy to hit just the right cells.
“Nobody said it was going to be easy,” Szyf shoots back, somewhat offended. “We have to find out which enzymes are the most important for different tissues and design drugs that are aimed at each enzyme.”
But is chemistry even necessary? Couldn’t you imagine doing something in a more natural way via simple changes in behavior? If a miserable upbringing and the way people treat us can influence our genome, then can we also influence it the other way? I think again of the tough skin on a sensitive psyche.
“You’re probably right,” Szyf admits, surprisingly cordial. “I even think that behavioral and psychological interventions will end up proving better than drugs. Because they play directly on the biological mechanisms that we’re already dealing with. But I’m not a behaviorist, so don’t ask me for specific examples.”
I don’t ask.
“But the path has been paved for them. If we know the epigenetic signatures and markers – for abused children, for example – we can design behavior therapies, talking therapies, or whatever, and study whether they work. Determine whether they remove the markers in question. Today, psychologists are doling out all sorts of therapies without knowing what they actually do to people, but we can test them in the same way they do clinical tests on drugs. We can develop therapies that are tailor-made for different problems.”