Love Making Actually – the science of

Last week’s Enduring Sexual Dysfunctions post opens doors to new ways of thinking about these and other medical conditions but also to big questions such as Why We Fall in Love .

Robb Dixon, who was also at the meeting interviewed Will Powers, the guy who at the Congress, in last millennium language, shifted the enduring sexual dysfunction paradigm. In the Robb and Will interview, Will is at great pains to say he is doing little more than reorganizing a few sea-shells, but his contribution is more significant than this.

Then

When thinking medically about physical problems two centuries ago, we began with infections. We likely still have conditions not recognized as infections – duodenal ulcers were a great example of this and some cancers may turn out to be.

After infections, we moved to single gene disorders. Diseases we were born with. Causative genes like these are pretty rare.  The multi-billion dollar genetic research industry has found very little other than a host of contributory genes without finding a way to make sense of the hundreds of genes, increasingly called risk factors and viewed as interacting with our environment, that may contribute to us ending up with a medical condition.

After the first effective drugs came onstream in the 1950s our thoughts turned to enzymes and then receptors, which the drugs acted on and we figured repaired when these receptors got broken or degraded – or so we thought.

A helpful effect a drug produces by binding to a receptor might, however, be outweighed by its other actions. All small molecule drugs have up to 100 actions. This fits with a centuries old idea that drugs are poisons, and while we aim at bringing a good out of their use, we risk poisoning someone. SSRI muting of sensory input can help but SSRI activation of carbonic anhydrase can irritate and agitate. Finding the right balance is key to good treatment. The combination of muting with irritation can make an otherwise manageable hazard lethal.

In recent years our problems in moving beyond relatively simple models like these have been compounded by conditions like Mast Cell Activation Syndrome (MCAS) and Ehlers-Danlos Syndrome (EDS), which linked to inflammation or neuro-inflammation, can, not unreasonably, look like a penumbra to core conditions. Does this penumbra need treatment in its own right? Or could more treatment compound the core problems which might be linked to our growing polypharmacy?

We have also had a set of Black Boxes to fall back on.  We can invoke brains or epigenetics, these poorly understood regions, as the spot where the answer surely lies.  These invocations get in the way of finding the answers we need now.

Now?

Enter Will Powers. In his interviews and Reddit posts you will see or hear him talking about 15 lane highways and sheet-metal replacement conveyor belts. These make sense but are not the usual language of health and risk bamboozling most of us.

Among the details Will found in PFS cases was a loss of the cortisol circadian rhythm – our stress hormone. Having a persistently elevated cortisol level rather than one that changes through the day and can respond to stressors might happen because the circadian clock, which sets the rhythm for most of what happens within us, is dysfunctional, or we are jet-lagged – we have a temporary gene-environment mismatch. Or it might happen because a feedback loop is insensitive to the circadian signal.

Something similar can happen in hearts. The regular beating of our hearts hinges on a prompt from the Sinu-Atrial (SA) node to the Atrio-Ventricular (AV) node, which prompts the Bundle of His to tell heart muscle fibers when to contract. This gets them beating in sync. A malfunction at any point in the chain can lead to a fibrillating heart. There are several possible life-saving answers to fibrillation. One is rebooting the system with an electric shock – cardioversion – great TV drama. Another option can be ablation of a nerve. Or just managing downstream risks like clotting may be the best bet.

The smooth running of these complex systems requires both a finely tuned interplay and slack in the system to cope with time-zone changes, and extreme physical conditions or events.

Malfunctions involve some breakdown in a gate control process, as a result of which certain things do not initiate other events when they should or downstream processes become insensitive to signals.

Catatonia is the classic example of this.  In catatonia, the link between willing to act and the emergence of an action can abruptly fail to work. As a result, nothing happens or the person may even produce the opposite act to an intended one.  All the while the catatonic person is aware of what’s happening and can later report what was going on.

The catatonic state can feel very willful to an observer standing beside an affected person and the temptation is to view this as a higher order cognitive process. But seagulls and mice can be made catatonic – so we are not talking about higher human-only cortical functions. Catatonia can be triggered in us by physical illness, by drugs and by emotional shocks. A common factor to all of these triggers is that they result in too much happening at the same time. Systems that normally gate control things are overwhelmed and a person, seagull or mouse freezes.

What Will has found is that folk who end up with Post-Finasteride Syndrome have risk factors (genes), sometimes several, and throwing Finasteride into the mix can lead to an androgen or other steroid breakdown product (metabolite) pile up. The pile up of metabolites fools the system into thinking there must be an androgen or steroid shortage so more is released leading an ever increasing metabolite pile that cannot be disposed of, which displaces or creates a shortage of what is needed in key places.

It also creates another problem – what might look from the outside as an obviously good thing to do may in these circumstances make the underlying problem worse – making doctors more dangerous than they think.

The answer in fibrillating hearts can be cardioversion. In catatonia, ECT may be the answer (good TV drama also but not celebrated), or pulses of high dose benzodiazepines – these two options one pro-convulsive and the other anti-convulsive look contradictory on the surface.  With the muscle atrophy linked to PSSD or PFS – See Enduring Sexual Dysfunctions – shockwave treatment can help.

Basically, this is no longer trying to locate and fix a problem in perhaps Piezo proteins, until two weeks ago my favorite candidate for the broken bit. Nothing is broken, but the system needs rebooting back into shape or as it were unplugged.

In the case of PFS, one option is to turn off the tap – the pituitary gland – using Lupron to stop the flow of GNRH and LH which release androgens and estrogens or dexamethasone a high potency steroid that switches CRF (Corticotrophin Release Factor) off.

Will Powers’ investigation of genetic risk factors accurately predicted the metabolites PFS sufferers would show on urine tests.  He is hoping that a reboot of metabolite systems will work out.  We will likely know soon.

Given the difficulties in pinning down what has gone wrong in conditions like drug-induced treatment resistant depression, or indeed complex antidepressant withdrawal problems, but perhaps even more importantly in states like Alzheimer’s disease where metabolite build up is a good candidate for triggering cell-death, or Type 2 Diabetes where system components become insensitive, there is a new way of looking at things here that will hopefully contribute to progress in areas other than the enduring sexual dysfunctions

Paradigms

The idea of a scientific paradigm came from Thomas Kuhn in a 1962 book The Structure of Scientific Revolutions.  Kuhn challenged the idea that science involved careful and well thought out experiments that built our knowledge steadily like coral shells building a reef.

Kuhn called that ‘normal science’ – normal but not what drove science forward.  What really mattered was seeing things in a different light. Normal science aims at solving some of the problems a currently dominant scientific view has, but the efforts to solve these can generate more anomalies until someone spots the anomalies are evidence for a new way of seeing the problem.

Will didn’t suddenly see a pattern. He spent several years reading hundreds, maybe thousands of genomes before a possible pattern came into view.  A breakthrough like this doesn’t mean he is smarter than the average. It will often require a degree of stubbornness plugging away at an issue on the basis of something possibly even vaguer than a hunch.

Why pay any heed?  The pattern Will thought he might have spotted predicted the results of urine tests looking for a metabolite.  So far so good.  The next step is seeing if an unexpected, counter-intuitive, intervention makes a significant difference – for the better.  If there are hints of a difference but not quite a cure, normal science will resume – trying to sort out the anomalies.

PSSD will likely be a good test case for these PFS developments. SSRIs work on different systems to Finasteride.  How do we end up with very similar clinical pictures and will a treatment that might help PFS help PSSD?   Or will the anomalies build up until someone spots a new pattern?

Metabolomics?

There are likely people with a vague knowledge of PSSD or PFS who might have said that these sound like a metabolomic problem to me but, while not generally ruling out metabolomics, no-one within the tiny enduring sexual dysfunctions field has been specifically putting their money on a metabolomic option the way Will has.

What is metabolomics?  First of all, being an omic is the latest de rigueur scientific jargon. Proteomics analyzes all proteins, the proteome, rather than just one of them.  Ditto Genomics and the entire genome rather than just individual genes.  Metabolomics analyses the metabolome – all metabolites of amino acids, sugars and lipids, their substrates, and intermediates within biological systems.

Metabolomatologists (there’s no such word) claim it can reveal insights that genomics and proteomics cannot.

• It means discovering biomarkers, studying metabolic phenotypes, analyzing drug metabolism, and understanding responses to environmental factors.
• It often uses our new abilities to screen for hundreds or thousands of things at the same time looking for patterns – but this still needs something Will brought to the frame – spotting a likely operative pattern in this case.
• Metabolomics can be an untargeted, collect everything and pray something stands out, or targeted approaches – formerly called finding a biomarker – but simply crunching numbers won’t do it.
• All of this can lead to Multi-Omics! Explaining how genes, proteins and metabolites give rise to a clinical picture that accounts for metabolic derangements, offers new therapeutic targets, and helps us decide if a drug is working or not.

Unless there is a passion behind it, none of this jargon means much, other than these are the buzzwords – the M.O. – currently necessary to get grant support or other funding.  Jargon and procedures are the stuff of bureaucracies, in this case a scientific bureaucracy more likely to stultify a field than lead to breakthroughs.

Why Do We Fall in Love, What on Earth is our Place in this Universe and Why are People Deserting the One True Religion – Making People – are the passions that drive Science forward – not getting the paperwork right.