I am interested in environmental influences on gene expression, specifically phenotypic changes in infants at birth.
Dr Kraepelin was interested in Darwin’s theories and he was an amateur naturalist, as was his brother. They admired Darwin tremendously. They were interested in evolutionary biology. Dr Kraepelin became a doctor and a psychiatrist and his brother became a botanist. They were both very interested in science and in the importance of observation and measurement in scientific research. Dr Emile Kraepelin would have agreed with you regarding Polygenic Risk Scores in psychiatry.
Kraepelin identified the physical signs of what he called manic depressive insanity. This part of his work has been forgotten. I think that modern knowledge of molecular biology and phenotypic variation can help shed light on what he discovered.
I rediscovered Kraepelin’s work when I started to work with my friend and co-worker Paula. Paula found out in a basic first aid class, that her breathing rate at rest, in health is too slow. Paula and I have been trying to understand this for the past 20+ years.
I am not a scientist. I have [re] discovered something very interesting. [bradypnea and tachypnea at rest was originally described over 100 years ago….in healthy adults [JS Haldane and others] and in adults who were ill [E. Kraepelin]
Interestingly- In the early twentieth century, JS Haldane and other early physiologists found that there was a great deal of variability when it comes to respiratory rates at rest [set by the brain stem].
In a normal healthy adult population, they found that respiratory rates ranged from as low as 3 breaths per minute [like Paula] to as high as 28-30 breaths per minute [like Paula’s nephew].
My work with Paula reminded me of Kraepelin’s hypothesis of metabolic dysfunction in bipolar illness. Paula has mostly been very healthy throughout her life but she did experience an 18 month attack of bipolar depressive insanity. She experienced the anguish and the cognitive impairment in much the same way that Kraepelin describes.[her experience was nothing like anything described in the DSM]. And her breathing was very low, in health, but also after the virus which precipitated this syndrome. Breathing rates go up with the stressor of physical illness usually, along with blood pressure and heart rate. Like Kraepelin, we found BP and HR to be raised. Breathing rate never caught up; it never changed at all-it remained at 3 breaths per minute during illness and clearly had become inadequate.
She recovered after 18 unpleasant months.And has been fine ever since. And we have been discussing this ever since.
We discovered during our research that Paula was born not breathing, her airway obstructed by meconium. She had to be resuscitated, then transfused. She thrived after that. She is now 65.
You might ask “what does Paula have to do with Kraepelin’s work?
Kraepelin found breathing rates that were too slow in patients with bipolar depression- a form of bradypnea at rest when awake . [The same patients had too fast breathing when manic.]
Patients complained of great anguish [a form of dyspnea] accompanying the bradypnea. It seems pretty clear that Kraepelin thought that these young adults were suffering from a form of respiratory failure. What he found fascinating was not their cognitive impairment, or anguish, or even their euphoria [when manic]. He found it fascinating that most of these patients spontaneously recovered without [for the most part] permanent brain damage, even if the attacks lasted for years. And only some died [usually of cardiorespiratory collapse].. No other patients in the asylum did as well over periods of their life. [patients with other conditions declined physically over time, eventually dying].
I think that Kraepelin’s findings of bradypnea and Paula’s discovery of her own [unfelt, invisible] bradypnea reflects the importance of environmental influences on gene expression. It seems that some people can be completely fine with bradypnea and when their metabolism is overwhelmed when sick, they tend to recover from long periods of delirium [all motor subtypes] intact.
This is where evolutionary conserved mechanisms regarding genes can explain what might be happening.
“Gene Regulation
Each cell expresses, or turns on, only a fraction of its genes. The rest of the genes are repressed, or turned off. The process of turning genes on and off is known as gene regulation. Gene regulation is an important part of normal development. Genes are turned on and off in different patterns during development to make a brain cell look and act different from a liver cell or a muscle cell, for example. Gene regulation also allows cells to react quickly to changes in their environments. Although we know that the regulation of genes is critical for life, this complex process is not yet fully understood.”https://www.nature.com/scitable/topicpage/gene-expression-14121669/
We figure that genes have been turned on or off in an “evolutionary conserved way” somehow, giving people like Paula some kind of “superpower” when it comes to ventilation, provoked by the birth experience of anoxia, then hyperoxia and having foreign blood products circulating throughout the body.
And Dr Kraepelin found thousands of young adults with too slow breathing, with attacks similar to Paula’s. It seems logical that if these people, like Paula, do not sense their “different” method of ventilation and others cannot see it either and if they look younger and healthier and fitter than most, maybe because of taking in less air than most, it makes sense that neither we or they will understand what is happening to they when their superpower runs into difficulty and they experience some level of ventilatory failure and stop behaving normally.
Depending on the difficulties encountered during birth, I imagine different genes are turned off or on.
I think this is what happened to my friend Paula. Paula has some unusual traits that are not obvious unless one measures her respiratory rate.and volume].
We think that Paula is an example of a phenotype we should learn more about. Like Paula, Kraepelin’s patients thrived till adulthood, until they didn’t. and then [after years of incapacity and illness] then suddenly would spontaneously and surprisingly recover with no lasting damage.
Paula…and Kraepelin’s patients do not seem to require as much air as other people to stay alive [when healthy or when ill]. But we think that they cannot possibly be clearing the amount of carbon dioxide in the blood that is necessary. They do seem to have normal levels of oxygen in their blood. Kraepelin was impatiently waiting for arterial blood gas analyzers to be perfected at the very least for his continued research. No one has continued his research. Except for us, with one significant subject,
We think that Kraepelin’s patients, and Paula [during her attack] were suffering from attacks of [mild [hidden] respiratory failure. These patients, in retrospect, could have used some of our modern treatments [antibiotics, non invasive breathing support and bronchodilators and the like]. These treatments were not yet invented in Kraepelin’s time..
I have been working with Paula for 20 years and we are both interested in her biology. Paula should be experiencing respiratory failure but she is not. Her oxygen levels are normal and we have no easy way of obtaining her PCO2. Her 02 levels were normal during her 18 month long attack.
I guess what I am trying to say is that knowledge of molecular biology and genes and phenotypes and vital signs [in particular ventilatory rate and depth – the minute ventilation] can inform each other and further our knowledge of the real world effects [superpower and conditions under which they fail eg kryptonite for some- just a metaphor] on real humans.
By the way, Paula’ s depth of breathing is normal [her lungs are fine]. Her breathing rate is 3 breaths per minute at rest when awake and her tidal volume is .5 L so she is taking in 1,500 L of air per minute rather than the usual 6-8 L. [this is her minute ventilation].
.5L times 3 breaths per minute = 1,500 L minute ventilation. [in health]……[.and it does not seem to increase in illness]
Only molecular biology can explain this, we think.
I am having trouble getting doctors interested in this topic, or physiologists. They are not curious. [they are freaked out].
This has not been explored since Haldane and Kraepelin and no one remembers their findings.
Plus, I think that Kraepelin saw depressed patients as having ventilatory defective mechanisms [since they could have repeat attacks] where as Haldane and I see this as a ventilation superpower [because of healthy adults needing less air to function [albeit, a superpower with specific failure parameters that can now be treated].
“Clinical psychiatry has lagged behind other fields of health care in its use of new technologies and routine clinical data for research. Now is the time to catch up.” JAMA Network, Review October 14, 2020 Could Polygenic Risk Scores Be Useful in Psychiatry?A Review Graham K. Murray, MD, PhD1,2,3; Tian Lin, PhD1; Jehannine Austin, PhD4,5; et al
Of Sound Mind 