Would you prefer to be told that your newborn is likely to grow up into a psychopath? Or that they may develop schizophrenia? What if, after receiving a positive result, it would be possible to prevent this from happening?
Prognostic factors for psychopathy and schizophrenia can be observed in human brain cells already in the second trimester of pregnancy. In principle, newborns could be tested and their risk of developing a disorder assessed. Whether such testing would engender too much suffering is another matter.
“Regardless of the disease, the easiest and least expensive way of reducing suffering is prevention or alleviation in advance,” says Professor Jari Koistinaho, director of the Neuroscience Center.
Nevertheless, testing would be associated with risks and difficult questions.
From the skin to cortical cells
Koistinaho's group is investigating brain diseases with the help of stem cells. The brain cells of living patients are off limits. Instead, skin samples collected from them can be converted, via a stem cell stage, into the kinds of brain cells the patients used to have before they were born.
At the beginning of the process, a piece of skin is turned into a cell culture. Then, four genes are introduced, for example, by using a viral vector, which make the cells pluripotent. These cells correspond to the cells of a few-day-old embryo. Due to their status as stem cells, they have the ability to develop into any cells found in the body.
Subsequently, neurons are derived from the stem cells by employing growth factors. Manufacturing cortical cells takes roughly three months. Motoneurons found in the spinal cord are quicker to develop, while the differentiation of the brain's supporting cells takes six months.
Koistinaho's group is culturing neurons, supporting cells and microglial cells.
“Brain diseases alter the functioning of all of these cell types, and they are associated with genetic risks of developing a disease,” Koistinaho notes.
Twins are not the same
The brain cells thus generated can be used to investigate the functioning of genes and proteins, as well as to draw up related diagrams. Comparing these diagrams with those taken from healthy individuals, differences may be apparent at a glance in certain areas.
“For instance, we noticed that patients suffering from schizophrenia differed markedly from non-schizophrenic people in terms of their genes and proteins.”
The risk of developing schizophrenia is affected by hundreds of genes, with the heritability rate of the disease estimated at 64–83%.
A schizophrenia study carried out by Koistinaho's group used as its dataset five pairs of identical twins. In each pair, one was suffering from schizophrenia and the other was not. Furthermore, five control subjects were enrolled in the study. Those suffering from schizophrenia clearly differed from their non-schizophrenic twin, who, in turn, were different from the control subjects.
“It was interesting to see that identical twins were not that similar after all. The expression of their neuronal genes was different,” Koistinaho says.
The sample was small, but corresponding American studies comparing schizophrenic patients and healthy individuals have yielded similar results.
“Still, it would be difficult to say who will eventually develop the disease and who will not,” Koistinaho underlines.
Even if the risk of developing the disease were 90%, there would always be people who would remain healthy in spite of their genes.
Under the skin of killers
Today, psychopathy is not classified as a disease but as a personality disorder. And yet, the related predisposition appears to be perceivable in brain cells already in the second trimester of pregnancy.
In a study on psychopathy, Koistinaho's group investigated five psychopaths who had committed several homicides. In addition, the study involved five individuals with substance abuse problems who were not psychopathic, as well as five control subjects. Again, the differences were clear: the psychopaths and healthy individuals were at the opposite extremes, while the addicted were, in many ways, in the middle ground.
In the psychopaths, differences were seen, for example, in genes associated with the functioning of opiate receptors and glucose metabolism. However, most of the changes were found in genes whose effect so far remains unknown.
Adult psychopaths have no wish to change
The research conducted by Koistinaho and his colleagues indicates that certain pharmaceutical agents could be helpful in treating psychopathy, as they impact the onset of feelings of gratification and reward.
“One significant problem is that adult psychopaths lack the motivation for undergoing treatment. They do not see the need to change,” Koistinaho says.
Children could be more receptive. The combination of drug therapy and upbringing could nudge them in the right direction. Teaching empathy is not easy, but teaching desirable modes of action is possible.
Incapacity for empathy associated with psychopathy is a common trait. Most people with psychopathic traits do not commit crimes. Such traits can even be beneficial, as certain relevant traits have been identified in business managers. Only the most extreme cases cause trouble.
Miniature brains for mice
Koistinaho's group investigates the cells it produces in cell culture dishes and three-dimensional gels. The cells are also turned into miniature brains the size of a few cubic centimetres.
“The miniature brain is just a small lump of tissue, but a cortex, the ventricles of the brain and the hippocampus are discernible in it.”
The miniature brain or brain cells can be transplanted into a living immunocompromised mouse that does not reject tissue transplants. Supporting cells from the brain of patients with Alzheimer's disease or schizophrenia have been transplanted into mice models. In memory tests, the behaviour of the mice that received cells from an Alzheimer patient changed, while the mice that received cells from a schizophrenic were no longer able to build a nest like healthy mice.
“Supporting cells known as microglia, tasked with removing cellular debris and non-functioning synapses from the brain, may have an effect on the development of schizophrenia. In patients with schizophrenia, these cells erroneously clear out the wrong synapses. In other words, the brain is maintained too effectively or incorrectly,” Koistinaho explains.
Research provides information on whether a certain drug or diet could be useful as part of treatment. Certain pharmaceutical agents targeted at other diseases may prevent the onset of schizophrenia, for which no preventive therapy currently exists.
More benefit or harm from testing?
In the end, would testing for schizophrenia or psychopathy in advance cause more harm than good? How would parents see their child after receiving a positive result from a test?
People predisposed to developing a disease could be marginalised. Key to this is who would be aware of the genetic risks and whether such information would be useful: would there be any preventive therapies available?
The preconditions for screening people with a heightened risk of developing schizophrenia or psychopathy are there, but further research on prevention is needed.
Should the relevant treatment options advance further, the risks associated with identifying the relevant genes may become smaller than those associated with not finding out. Koistinaho puts it like this:
“If the mechanism of a brain disease has been identified and if it can be treated or prevented, should screening be carried out?”
At the core of neuroscience
At the University of Helsinki's Neuroscience Center, the focus is on the development of the healthy human brain and function, as well as what can be done in the case of related disorders.
Among other activities, research on brain plasticity is conducted at the center. A number of cerebral diseases could potentially be cured or alleviated by increasing plasticity. The brain is studied by utilising imaging techniques as well as stem cells and mice models.
A total of 60–70 scientists work at the center headed by Professor Jari Koistinaho. Now, the aim is to bring together all fields active in brain research at the University of Helsinki. For this purpose, an application has been submitted for a profile-building grant, with the results expected later this year.
The article has been published in Finnish in the 6/2020 issue of the Yliopisto magazine.