Innovation - A Hallmark of Simmaron’s New Research Team
Ten years in, it's a new Simmaron Research Foundation (SRF). When Gunnar Gottschalk PhD – the foundation’s longtime research manager - returned from graduate school to the SRF he brought two things with him: (1) a better understanding of neurological diseases and greatly expanded technical expertise including understanding how small molecule drug discovery works, and (2) Avik Roy PhD - Simmaron Research Foundation's new Chief Scientific Officer (CSO). Roy has done extensive research on Parkinson's disease and other neurological diseases, and was just named as Associate Editor of the Journal of Alzheimer’s Disease.
Gunnar Gottschalk returned from medical school with a Ph.D., a new partner, and a new set of skills.
When I asked Roy what attracted him to ME/CFS, he said his interest in the molecular mechanisms of inflammation, the mitochondrial stress response and cognitive deficit in neuronal diseases made ME/CFS with inflammation, muscle fatigue, and cognitive problems an excellent match for his scientific experience. Dr. Peterson's extensive array of ME/CFS samples - perhaps unmatched in the ME/CFS world - were a significant draw as well.
Avik Roy’s interests in inflammation, the mitochondrial stress response, and cognition led him to ME/CFS and Simmaron.
While the Simmaron Research Foundation has always done some in-house research, it's mostly been known for its extensive clinical collaborations with researchers like Ian Lipkin, Mady Hornig, and Maureen Hanson. While those collaborations remain, Simmaron is now producing its own novel and exciting research. In fact, it's extending itself into heretofore unexplored research areas in ME/CFS and long COVID.
For instance, nobody, so far as I can tell, is actively ferreting out and testing small molecules that may be able to help in ME/CFS. Simmaron is now doing that. The blog below touches on just some of the exciting approaches Simmaron’s small, but innovative research department is exploring.
The Coronavirus Pandemic Hits
Gunnar Gottschalk returned from his five years at medical school with an MS in Biotechnology and a Ph.D. in Integrated Medical Biosciences with a focus on Neuroscience. Now Simmaron's Executive Director of Research, he returned not long before the pandemic hit, and like so many other researchers it became his first priority. His and Roy's first project set the stage in terms of creativity and innovation for others to come.
Dr. Peterson's Incline Village practice never shut down during the pandemic. With the low availability of nasal swabs holding up testing, the Simmaron team developed a novel way to use urogenital swabs to test for the virus in collaboration with Konstance Knox Ph.D. at Coppe Labs. Since receiving the first emergency use authorization for coronavirus testing in the US in Feb. 2020, they've tested over 5000 people in the Incline Village and surrounding areas.
Knowing that a long-COVID cohort was likely to follow, they developed consent forms which allowed them and Dr. Peterson to track the positive COVID patients and develop their own carefully characterized long-COVID patients. They've been following many of them for over a year.
Dr. Peterson potentially has a leg up with long-COVID patients because of his ability to provide Ampligen and his track record using the immunomodulator for his ME/CFS patients. Peterson's been gathering data on Ampligen's effectiveness in ME/CFS for decades and is now attempting to do the same for the long haulers.
The Development of a Coronavirus Blocker
Along the way, they've developed an ACE-2 receptor modulator called the ACIS KEPTIDE, received a patent for it, and published two papers concerning it.
It turns out SARS-CoV-2 virus that causes COVID-19 doesn't just enter human cells via the ACE-2 receptor, it also greatly upregulates the production of these receptors — leaving cells in the lungs, kidneys, and other areas saturated with them.
Cell and animal studies suggest the keptide may be able to block the coronavirus from attaching to the ACE-2 receptors on our cells
They've been working with Konnie Knox, Ph.D. (Chair of Simmaron’s Scientific Advisory Board) and her CDC reference laboratory (Coppe Labs) to test their invention using the live virus. That work showed that intranasal administration of the keptide could indeed block the live virus from entering the cells of humanized mice expressing the ACE-2 receptor. Next they worked with a veterinarian in Wisconsin who helped them determine: a) if the peptide could prevent infection in humanized mice (it could); and b) if it harmed the mice (it did not).
First, they administered the keptide intranasally and then doused the mice with the coronavirus. The heart rate, 02 saturation of the infected animals which did not receive the keptide tanked, their lungs were damaged, they lost weight and then died. The animals which received the keptide maintained normal heart rates and 02 saturation, their lungs were undamaged, and they survived. The keptide also stopped the explosion of new ACE-2 receptors that the virus produces.
The modulator they developed then appears to have two significant effects; it rappels the spike protein away from the receptor, and as it does so, it prevents the upregulation of the ACE-2 receptors. Their next step is to show that the keptide has the same effect on the delta variant in primates.
The potential is to produce a nasal spray that would provide complete protection from the virus in a risky environment such as going on an airplane.
There's more, though. The Simmaron team’s next finding could turn our understanding of how the SARS CoV-2 coronavirus creates illness on its head.
Infection Not Needed? A Coronavirus Paradigm Shift…
"One most important highlight of this paper is to identify a new mechanism of SARS-CoV2- mediated death, which is entirely independent of its infective property". The authors[CA1]
Remarkably, given the immense amount of study devoted to the virus across the world, the researchers also highlighted a possibly new and potentially significant way the virus causes death. Noticing the dramatic effect the virus has on the ACE-2 receptors, they probed the impact of an inactivated virus which attached to the receptors but which didn't actually infect any cells.
In what they called "a paradigm shift" regarding our understanding of the impact the virus has, the authors showed that the coronavirus can cause substantial pathology and even death when it's no longer able to infect the cells. All it has to do is attach itself to the ACE-2 receptor.
The finding that the virus may be able produce substantial pathology without actually infecting cells potentially opens a new window on our understanding of how the virus causes harm.
Intranasal inoculation of the inactivated virus killed 28% of the 7 animals it was given to within 24 hours. The mice that died were all female. The other animals looked very much like they'd been infected with a live virus: their body weight, temperature, oxygen saturation, and heart rate all dropped.
The authors propose that the simple action of the virus binding to the ACE-2 receptor alters the receptor in such a way as to cause injury and death. This, of course, brings up the question of how much of the pathology we see in COVID-19 is due to the virus binding to the ACE-2 receptor, and how much is due to its actual infection of the cell. Much more study needs to be done, but if the authors are correct and the virus is altering the ACE-2 receptor in ways that are pathological, then researchers need to be focusing intensely on that receptor.
Possible COVID-19 ME/CFS Link
That could be a good thing for ME/CFS, as the ACE-2 receptor has shown its own quirks in this disease as well. Two studies suggest that the activity of the ACE-2 enzyme which transforms Ang II to Ang (1-7) and angiotensin to Ang (1-9) is reduced in ME/CFS. The inability to transform the pro-inflammatory and vasoconstricting Ang II to the anti-inflammatory Ang (1-7) could potentially be a big deal.
In fact, Nuno Sepulveda’s paper “The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in myalgic encephalomyelitis/chronic fatigue syndrome: A meta-analysis of public DNA methylation and gene expression data“, suggests that the ACE-2 issues found in ME/CFS might leave people with ME/CFS at a greater risk from a coronavirus infection. This is because reduced ACE-2 expression could cause the blood vessels to narrow (vasoconstrict) and increase oxidative stress and inflammation.
The reduced expression of the ACE2 gene in ME/CFS might also be able to help explain why the renin-angiotensin-aldosterone system could be reducing blood flows, impairing blood volume, inhibiting mitochondrial functioning, and others in ME/CFS.
The authors of the Sepulveda paper concluded that more research into the activity of the ACE-2 receptors in ME/CFS and allied diseases is needed – particularly in epithelial/endothelial cells – but also in other cells the virus may be able to invade.[CA2]
Conclusion
Innovation and creativity have been hallmarks of the Simmaron Foundation’s new research efforts.
With its production of several novel findings, the small research team at the Simmaron Research Foundation is clearly punching way above its weight class.
First, they produced the first emergency authorization coronavirus test kit in the U.S. - allowing Dr. Peterson to follow long-COVID patients as they appeared early in the pandemic. Then they developed an intranasally administered keptide which cell and mouse studies indicate may be able to block the coronavirus from entering the cell - thus potentially laying the groundwork for an effective anti-coronavirus nasal spray.
After showing that the coronavirus triggers a massive upregulation of the ACE-2 receptors, the group assessed the potential effects of ACE-2 alteration alone by providing an inactive virus to a small number of mice. To their surprise, they found that simply administering the inactive virus caused a massive pathology, including the rapid death of several animals. That suggested that the coronavirus may cause a great deal of pathology in a heretofore unknown way simply by changing the functioning of the ACE-2 receptor.
Reduced functioning of that same receptor, interestingly, has been found in ME/CFS and has been linked to the "RAA paradox" that contributes to the low blood volume, the blood vessel vasoconstriction, and potentially the mitochondrial problems found in ME/CFS. In fact, a recent ME/CFS study warned that problems with the ACE-2 receptor may leave people with ME/CFS more vulnerable to the coronavirus than others.
That's not all. The new Simmaron research team has more interesting stuff up its sleeve. Stay tuned as new papers roll out on ME/CFS and long-COVID findings. As Simmaron Research Foundation’s 10-year anniversary approaches, the Foundation is ushering in new approaches to research that are aimed squarely at finding treatments for ME/CFS and potentially long COVID.
