After 4 decades of classical academic research, once retired, I have shifted to applied research in 2011 and I briefly review below the ads and complexity of this shift.
“There is no applied research but applications of basic science” this famous statement of Pasteur is certainly valid but not that easy to achieve. It often fails because of the huge complexity of the shift in terms of conditions, aims, implications and difficulty to abandon the academic way of thinking to one dedicated to developing novel treatments. To succeed in this endeavour, it is mandatory to rely on solid conceptual issues that can substantiate therapeutic aims. In my case, this link can be summarized in 3 words: the Transmitter GABA, brain development and brain disorders born in the womb.
Early on- already in 1989- once nominated head of a large INSERM unit in a maternity hospital, we made discovered that the inhibitory transmitter GABA excites immature neurons because of intrinsic high intracellular levels of Chloride. This famous “GABA” shift was then confirmed in all animal species from insects to mammals and humans indicating that it has been preserved throughout evolution rendering the topic exciting and highly challenging. In parallel, working on epilepsies, we discovered the mechanisms underlying the famous saying “seizures beget seizures” via a phenomenon of reactive plasticity with the formation of novel aberrant synaptic connections that generate seizures. These two apparent unrelated observations will unconsciously direct the passage to private science.
It turned out that in many brain disorders- including autism, epilepsies, Fragile X, Rett syndrome, but also Parkinson or Alzheimer disease, Brain trauma, Cerebrovascular infarcts, chronic pain and various cancers including brain tumours, there is a reversed shift as if brain disorders are a return to immaturity with neurons endowed with immature features generating aberrant patterns that perturb behaviourally relevant patterns.
The Checkpoint concept developed with my colleague Nick Spitzer (TINS 2010) suggests that genetic information operates with activity and environmental cues to direct brain development, nothing is automated. The Neuroarcheology concept that I developed (TINS- 2008) suggests neurons remain endowed with immature features following in utero insults that are the final cause of the disorder. Therefore, there is no direct link between the insult and the deleterious sequels, treatments must be based on agents capable of blocking selectively immature but not adult patterns. It rapidly became obvious that in many disorders, an excessive activity of a well-known co-transporter called NKCC1 leads to high (Cl–)I levels and excitatory GABA. Hence the need to use an inhibitor of this co-transporter to restore low (Cl–)I levels and inhibitory actions of GABA.
The next steps were conceptually easy but very difficult in practice; it implied to learn he pharmaceutical approach to treatments with the need to rely on lawyers, patent and drug development experts etc. Not a simple sequence requiring years to avoid making important mistakes and learning the patience needed to do clinical trials. This explains why this shift so often fails!
Despite these difficulties, we first demonstrated that indeed Autism is born in the womb. Analysing by Machine learning maternity data of children that are -or not – autistic, we succeeded to identify at birth babies who will or not be autistic later allowing an early use of behavioural therapies that are indeed more efficient when initiated early. This “pelargos “project is presently generalised to make France the 1st country in the world in which such an early prognosis is possible.
In parallel, treating children with Autism using an inhibitor of NKCC1 was successful in large trials (phase 2) with > 1050 children having their syndrome attenuated and this was validated in many trials performed in different countries. A final phase 3 failed – and this was largely expected considering the heterogeneity of the disorder. Using Machine learning re-analysis of the data, we identified 30-40% of children responding to the treatment within the failed phase 3! We are now searching funds to perform a final trial that we are convinced will successfully treat many children with Autism. At any rate, this illustrates the importance of subdividing children with autism in populations with similar clinical features to succeed in large trials.
More recently, I became convinced that brain tumours have similar “problems”. Recording directly fresh tissue removed form patients with brain tumours, revealed high (Cl–)I levels & excitatory actions of GABA. Parallel studies published in the last 4 years revealed that the tumour establishes aberrant synaptic connections – a form of “reactive plasticity” – that aggravates the syndrome and causes the relapse. Clearly, targeting only tumour cells and not the environment will not succeed, underlying the failure of immunological and more recent tools to attenuate the severity of associated clinical signs and augment significantly the life expectancy of patients. We therefore tested the effects of a combo composed of 2 drugs – one to kill tumour cells (an antiparasitic agent) and one to inhibit NKCC1 and neuronal hyperactivity. We have validated this approach in human brain surgical resections from patients with Glioblastoma, Glioma or brain metastasis.
In sum, a solid conceptual background is instrumental to succeed shifting from basic to applied science. This conclusion is important considering the trend in many countries including France, of young researchers to work in or create novel startups dedicated to develop novel treatments.
