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Nanobubbles isn’t a punchline, it’s actual science: A closer look at the Harvard, Oxford, and NYU studies on the benefits of nanobubbles

Japanese Scientists Create Worlds First Fatherless Mammal Photo by Koichi Kamoshida/Getty Images

In August 2015, Rolling Stone published an article about Russell Wilson which included this now infamous passage:

Wilson is an investor in Reliant Recovery Water, a $3-per-bottle concoction with nanobubbles and electrolytes that purportedly helps people recover quickly from workouts and, according to Wilson, injury. He mentions a teammate whose knee healed miraculously, and then he shares his own testimonial.

"I banged my head during the Packers game in the playoffs, and the next day I was fine," says Wilson. "It was the water."

Wilson stood by his claim, sending out the following tweet:

Sports writers were quick to pounce. Barry Petchesky at Deadspin didn’t interview any neuroscientists, but still called it a scam. Michael David Smith at ProFootballTalk didn’t cite any peer reviewed studies, but still called it snake oil. From there it was easy for readers to latch on; after all, “nanobubbles” sounds funny and when you hear it you probably think of champagne or a carbonated soft drink. Nearly two years after the Rolling Stone article it continues to be a punchline for fans and even journalists on television and social media.

I decided to do what no journalist bothered to do: I actually read the peer reviewed science on nanobubbles. And I learned that anyone who thinks nanobubbles are a scam, snake oil, or just pseudoscience is completely ignorant of what they actually are. That’s okay, that’s why I am writing this now. Let’s learn the reality of what you’re saying when you say “Must be the #Nanobubbles.”

Since 2010, oxygen nanobubbles have been the focus of studies and clinical trials at institutions like Harvard, Oxford, Rush, and NYU, for conditions across the neurological disease spectrum, including Alzheimer’s disease, Parkinson’s disease, ALS, and multiple sclerosis. Positive results have been reported in vitro as well as in transgenic mice and human subjects, in everything from brain activity to muscle recovery to the treatment of cancerous tumors. Much of the research on nanobubbles was presented at the Society for Neuroscience Annual Meeting in 2014, and I’ve highlighted some of the most relevant findings below:

Hyperphosphorylated tau protein is a hallmark finding of traumatic brain injury (TBI)

In December 2012, Dr. Ann McKee, an expert in neurodegenerative disease at Boston University School of Medicine who was featured in the FRONTLINE documentary League of Denial, published the study “The spectrum of disease in chronic traumatic encephalopathy” after analyzing the post-mortem brains of 85 subjects with histories of repetitive concussions. She found that one of the hallmark pathological findings of concussive hits was the accumulation of toxic or abnormal proteins - particularly hyperphosphorylated tau protein:

“There is an ordered and predictable progression of hyperphosphorylated tau abnormalities through the nervous system in chronic traumatic encephalopathy that occurs in conjunction with widespread axonal disruption and loss.”

Dr. Bennet Omalu reported similar findings in his 2005 study, “Chronic traumatic encephalopathy in a National Football League player,” when he found “diffuse amyloid plaques as well as sparse neurofibrillary tangles and tau-positive neuritic threads in neocortical areas” of the brain. Pathological aggregation of tau protein has been observed in a host of neurodegenerative brain diseases as well as post-TBI/concussion.

In addition, an October 2016 study published in Neurology found that in athletes who had suffered a concussion, those who took longer to return to play had higher levels of tau protein in their blood following the trauma than players who were cleared to return to play sooner.

Nanobubbles reduce tau protein phosphorylation in a mouse model of Alzheimer’s disease

In August 2014, Khushbu Modi, PhD and Arundhati Jana, PhD at the Rush University School of Medicine Department of Neurological Sciences were the primary authors of the study “A Physically-Modified Saline Suppresses Neuronal Apoptosis, Attenuates Tau Phosphorylation and Protects Memory in an Animal Model of Alzheimer's Disease” in the peer-reviewed journal PLoS ONE. They found that RNS60 (Revalesio Corp.’s oxygen nanobubble formulation - the same stuff found in Recovery Water) inhibited tau phosphorylation in human neuronal cells in vitro, and attenuated tau phosphorylation in the hippocampus of transgenic Alzheimer mice when administered via intraperitoneal injection:

“Given the evidence that phosphorylated tau protein can lead to the destabilization of microtubules, impaired axonal transport and eventually neuronal death, it is generally believed that inhibition of tau phosphorylation induced by Aβ may be a useful therapeutic strategy for the treatment or prevention of Alzheimer’s disease. Here we demonstrate that RNS60 is capable of attenuating tau phosphorylation in Aβ-insulted cultured neurons and in vivo in the hippocampus of 5XFAD mice.”

In other words, researchers in this study demonstrated that the active ingredient in Recovery Water helped prevent the same pathological process - the hyperphosphorylation of tau protein - that is a hallmark of mild traumatic brain injury.

Oxygen nanobubbles inhibit the expression of neuroinflammatory molecules in a mouse model of Parkinson’s disease, and cross the blood-brain barrier

Saurabh Khasnavis, PhD at Harvard Medical School in March 2014 was the primary author of the study “Protection of dopaminergic neurons in a mouse model of Parkinson's disease by a physically-modified saline containing charge-stabilized nanobubbles” in the peer-reviewed Journal of NeuroImmune Pharmacology. He found that RNS60 inhibited the expression of proinflammatory molecules both in cultured microglial cells as well as in the substantia nigra region of the mouse brain in vivo. In the study’s abstract, Khasnavis writes, “these results strongly suggest a promising therapeutic role of this simple modified saline in Parkinson’s Disease and other neuroinflammatory disorders.”

But perhaps the more important research finding in this study as it pertains to Wilson’s claim is that oxygen nanobubbles cross the blood-brain barrier:

“Within 3 hours of intraperitoneal RNS60 administration, we observed the activation of class 1A PI3K and the upregulation of IκBα, signature events of RNS60, in vivo in the nigra. Therefore, it is likely that RNS60 enters the brain.”

Oral administration of oxygen nanobubbles reduces tumor hypoxia in a mouse model of pancreatic cancer and attenuates muscle damage in human subjects

In December 2016, researchers at Oxford University published the study “Reducing Tumour Hypoxia via Oral Administration of Oxygen Nanobubbles” in PLoS ONE. They found that oral administration of oxygen nanobubbles resulted in a reduction of 75% and 25% in the transcriptional and translational expression of the HIF1α gene in pancreatic tumor mice, a gene which is normally only expressed at high levels in hypoxic conditions. In June 2013, Paul Borsa, PhD at the University of Florida published the study Oral consumption of electrokinetically modified water attenuates muscle damage and improves postexercise recovery in the peer-reviewed Journal of Applied Physiology. Borsa found that plasma concentrations of creatine kinase and high-sensitivity C-reactive protein were significantly lower in the study group who had consumed Reliant Recovery Water compared to the placebo group. (These two studies aren’t quite as relevant to Wilson’s claim as it relates to concussions, but I included them anyway since they give important insight into how nanobubbles affect cell signaling and gene expression.)

In December 2016, the ALS Foundation announced $1 million in funding to support a clinical trial testing the efficacy of RNS60 on reducing neuroinflammation. Nanobubbles even caught the attention of Rodolfo R. Llinás, MD, PhD, chair of the Department of Physiology and Neuroscience at the NYU School of Medicine, who has been called “a founding father of modern brain science.” Llinás, like most people, was initially “highly skeptical” of nanobubbles, but after conducting his own study, reported in 2014 that RNS60 increased ATP production, enlarged mitochondria, and improved synaptic transmission in squid neurons.

Llinás hypothesizes that nanobubbles create this ATP production boost by crossing the outer cell membrane as well as the mitochondrial membrane, then releasing their oxygen directly into the organelle’s interior, preventing the creation of toxic free radicals in the cell. His lab at NYU is now conducting a human Phase II clinical trial to measure the effects of oral consumption of Reliant Recovery Water on brain activity (Phase I clinical trials to determine safety of RNS60 were completed in 2011 and 2012).

Elite athletes frequently turn to novel therapies to gain an advantage. Kobe Bryant would fly to Germany in the final years of his career for a non-FDA approved treatment called Regenokine.
Photo by Stephen Dunn/Getty Images

Russell Wilson is not the first elite athlete to turn to a novel therapy in order to gain a competitive advantage. Obviously there are questions about nanobubbles that still need to be answered, but the initial science is significant, the broad range of ongoing clinical trials shows great promise, and Wilson’s claim clearly isn’t as crazy as a lot of people still seem to think.