The tipping point
The tipping point

The tipping point

possibleA tipping point is the moment everything changes. That is true for science, science builds knowledge slowly, progressing from ideas and inventions into innovation. It is a tipping point when a critical mass of information reveals an answer, usually to more than one individual. Tipping points are easily identified with hindsight. Predicting a tipping point doesn’t happen often. That said, we predict a tipping point in the treatment of patients with amyotrophic lateral sclerosis, ALS we are optimistic that can happen in the next 10 years.

Why are we optimistic? Three things are available to make that ALS innovation. The investigative tools used by knowledgeable, hardworking researchers are present, check two things off the list. What’s missing is recognizing and removing information silos. From where we sit there is a lack of global sharing. Meeting and discussing ALS issues will surely reap rewards, that is our innovation to reach an ALS tipping point.

Spoiler alert! There will not be one treatment, one small molecule that targets one pathway isn’t the solution. There will be several drugs and treatments that will be selected on the stage of disease and the disease processes that are manifest in an individual. Recognizing available tools to diagnose the manifest disease process in an individual could be a tipping point.

The pace of tool discovery is exponential. One example is the ability to create organoids from skin biopsies. Organoids are test tube brains produced from stem cells found in skin biopsies. The laboratory mini brains are in a fetal development stage and applications using them are in still their infancy. It will take innovative thinking and yet-to-be technology to transform these rudimentary cells into a three-dimensional brain with neurons that can connect to other neurons and finally, muscle cells. There are some labs ready to make organoids and put them in the brains of Alzheimer’s patients. Proving that these short connections are possible is an innovative step that will eventually lead to replacing the neuron that innervates muscles. That can make a difference in ALS. It is this type of in vivo modeling that is needed to cure ALS.

It will take unusual thinkers that abandon their deeply held, framed expectations and habitual thought patterns for new, cognitive thinking and alternative framing of the ALS disease processes. Throughout history there were accidental, world-changing inventions. These paradigm shifters were discoveries like quinine, x-rays, microwaves, radioactivity, and penicillin. More common history changers were the culmination of incremental, plodding improvements. Fire was accidental and sporadic, until it was harnessed. Increasing the size of man’s brain is attributed to harnessing fire by some people, fire made more foods available.

Marcus Vitruvius Pollio, a Roman architect and engineer in the 1st century BC wrote about the meticulous processes to produce concrete flooring and concrete pillars that hardened in ocean waters. It is hard to imagine concrete was an accidental find. Two thousand years ago, in the Parthian empire, vinegar filled clay jars were equipped with iron rods and copper wire, electroplating a silver coating onto common surfaces, perhaps the birth of deception to the unwary. Similar history changing discoveries, the wheel, the compass, the Copernican view of the cosmos, the internal combustion engine, all share their inspiration because there was a bedrock of information that was gathered by many people over time. And then the tipping point arrived, the moment that everything changed. A prepared mind in the right environment.

It is possible the tipping point for ALS is here? In a sentence, ALS is the selective loss of motor neurons. More than twenty-five ALS-associated genes are described in the literature. Each of these genes can be an ALS-relevant trigger. Human fALS genes that are over expressed in mice induce cellular processes mimicking aspects of human disease, and some genetically altered mice develop ALS. The processes present in heritable (fALS) presentations of ALS are also present in sporadic (sALS) cases.

Muscles that are resistant to the ravages of ALS are known, extra ocular, pelvic sphincter, and slow twitch limb muscles. Eighteen genes are differentially expressed between resistant and susceptible muscles. A unique difference between vulnerable fast twitch muscles is expression of the metalloproteinase 9 (MMP-9) gene. How does one put this together to reconnect the motor neuron to a muscle in people? In other words, using this information how does one design a treatment? SOD1 ALS-mice had delayed muscle denervation when scientists reduced the expression of MMP-9. We envision targeting respiratory muscles, swallowing muscles, and the big jump to limbs. We envision a roadmap of enzyme pathways that trigger and perpetuate inflammation– and finding the molecular shut off valves that will stop the process. We can envision one drug that hits multiple targets, a master switch for this and other aspects of the ALS syndrome.

Another widespread disease relevant pathology in fALS and sALS is mitochondrial dysfunction. Dysfunctional mitochondria suffer from oxidative stress. Logically, one would think that increasing mitochondrial function, or decreasing oxidative stress, would be useful in human ALS. ALS was improved in animal models of ALS using coenzyme Q10, creatine, vitamin E, and minocycline. This is a conundrum because improvement wasn’t seen in human trials. Why not? Multiple causes of mitochondrial dysfunction at different stages of disease at play in ALS can’t be addressed with a single therapy. We must find those checkpoint valves and then know if they should be switched on or turned off. And paradoxically, some molecular switches are toggles, the same molecule can turn on one pathway and turn off another. Researchers will have to decide if oxidative stress is primary or secondary to designate a targeted therapy in an individual.

Our approach is finding innovative researchers and bring them together in a Zoom room and discuss ALS relevant pathologies on multiple platforms. In addition to organoids and enzyme pathways dysregulated by mitochondrial oxidative stress, we are investigating peptide array technology, adipose stem cell secretome, modulator proteins in neurogenic muscle atrophy, dysfunctional axonal transport, altered lipid metabolism, checkpoint signaling, markers for stressed tissues…genetics, epigenetics, metabolomics, and more. Our collaborative efforts will be published and hopefully we will find that tipping point in ALS.

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