Robert Naviaux MD, PhD is Professor of Medicine, Pediatrics, and Pathology at the University of California, San Diego (UCSD) School of Medicine. He is the founder and co-director of the Mitochondrial and Metabolic Disease Center and former President of the Mitochondrial Medicine Society (MMS). He is an internationally known expert in human genetics, inborn errors of metabolism, metabolomics, and mitochondrial medicine. He is the discoverer of the cause of Alpers syndrome. Starting in 2008, Dr. Naviaux began investigating autism from a metabolic standpoint and soon came to view that the underlying mechanism of autism might be metabolic and regulated by the mitochondria.

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In 2013 Dr. Naviaux published the first of several papers about his cell danger response theory of autism and experiments in autism mouse models where he was able to reverse both the outward behaviors and biochemical abnormalities observed.  In 2017 he published results from his small-scale trial of suramin in children with autism.  Suramin continues to advance through FDA clinical trials.  

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Dr. Naviaux is a brilliant researcher with a prodigious grasp of biology.  N of One has been a close collaborator since its inception.  We are proud to have supported his early on and his more recent findings.

 

As part of our ongoing series to connect you with researchers describing their work in their own words we present:  A conversation with Dr. Robert Naviaux about his ground-breaking study of the blood chemistry of children at various ages and the insights it provides regarding the possible biological basis of autism.

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Full-Text Publication Available here

Interview

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N of One: "You and your team analyzed the blood from children at different stages in life.  Tell us about the groups and how and why you picked them?”

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Naviaux:  We wanted to ask the question, “Were there identifiable differences in the blood chemistry of children who developed ASD that could be measured at birth, and how did these compare to the differences we could measure at 5 years of age?”

One way to do the study would have been to take blood sample from children at birth and then follow them for many years periodically taking new samples.  The challenge with this type of study is that it takes many years and only about 2% of children develop ASD.  This means that to have a big enough study to include 100 children at birth who will develop ASD 5 years later, you need to enroll and follow 5,000 children for 5 years (100/0.02 = 5,000), and follow-up is very difficult.   

We asked the question a different way that was able to provide the insight faster and more cost-effectively.

We first began by looking at children’s blood at birth.  We did this in a “time machine” kind of way by recruiting families with Children born in California and asking if we could access their newborn dried blood-spots in held in storage by the State of California. [note: in the US and many other countries, newborns have a small blood draw via a heel prick that is then collected on a piece of paper aka “newborn dried blood-spot”]  Children between the ages of 3 and 10 were eligible.  Once we received parent permission, we “went back in time” to analyze the dried blood spots of those children that were collected at birth.  Some of these children would go on to develop autism, some would not.  Using the pre-natal blood spots, we could compare the differences between these two groups.

We recruited a total of 205 children for this part of the study.  Out of those 205 children, 120 were typically developing 85 had received a diagnosis of ASD later in life.  We called the groups TD and “Pre-ASD”, since no one actually had ASD at birth.

We also wanted to look a group of children with and without ASD all about the same age later in life.  So we also contacted families who were part of the CHARGE study (CHildhood Autism Risks from Genetics and Environment) at UC Davis and were able to get blood from 53 children in total (31 with ASD and 22 TDs).

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Then what?

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With those 4 groups:  Newborn:  (Pre-ASD/ TD) and 5-year-olds (ASD/TD) we began analyzing the blood chemistry to ask the question if we could identify meaningful, statistically significant difference in the blood chemistry among the groups both with respect to time and ASD diagnosis.

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You utilized some pretty sophisticated analysis techniques on the blood, what were you looking for, what did you find?

 

We first measured the concentration of about 450 compounds (the “metabolome”) in the blood using a commonly-employed technique called mass spectrometry.  By looking at all of these compounds at once, we can see the “big picture” of how the body is working and how the cells are communicating.

Since we had the four different groups, we were able ask how cellular conversation changed during the development of ASD from birth to 5 years of age versus how it changed in those who did not have ASD.

We found a number of interesting things, some of which we knew, some of which were new.

Using classical metabolomics techniques, we saw many of the things that have been known about ASD.  For example, we found abnormalities in mitochondria, the microbiome, and pathways related to inflammation that we call the cell danger response or the CDR.  

We also developed some new methods that allowed us look at different networks of chemicals.  Using these new methods, we found that of the ~50 biochemical pathways that we looked at, the purine pathway was most changed between TD and ASD groups.  “Purines” are the class of chemicals that include ATP used as the universal currency of energy in the cell, and to make DNA, and perform many other functions.

As we’ve published in our earlier work, purines, like extracellular ATP are the root regulators of the cell danger response (CDR).

We found that TD children naturally developed self-calming connections between the purines and other pathways that helped to prevent over-excitation in response to common sensory stimuli.  These self-calming connections were used to dampen spikes in calcium release that might otherwise overstimulate, or even kill a cell.

For background here, cells are exposed to non-injurious stimuli throughout life.  The reaction of each cell needs to be adjusted or tuned so that it does not overreact to non-injurious stimulation. When these safeguards fail to develop, cells overreact, and children develop sensory over-responsivity.  This affects how children with ASD respond to all kinds of sensory stimuli, from touch, sound, and sight, to chemical stimuli like normal metabolites such as ATP, and to environmental chemicals. Children with ASD did not develop these cellular adaptations that prevent sensory over-stimulation.

 

For decades, researchers have described an Excitatory/Inhibitory (E/I) imbalance as a common them in ASD.  What is that and how does your work relate to that?

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Neurons and neural pathways in the brain and nervous system are commonly thought of as being excitatory (they stimulate) or inhibitory (they calm). In humans, these systems need to be able balance each other.  What’s interesting is that pathways that are excitatory at birth, become inhibitory very early in life.

The Excitatory/Inhibitory imbalance hypothesis states that children with ASD have an excess of excitatory pathways and deficit in inhibitory pathways.  This was first described by Rubenstein and Merzenich in 2003. However, the basis of this balance between neural excitation and inhibition and its reversal during development was not known in 2003

The metabolic network results from our study strongly support the importance of a regulated change in excitatory to inhibitory (E/I) balance for neurotypical child development.  This change happens after birth and is highly active in the first 2 years of life during neurotypical development. Moreover, our work suggests that the reversal of eATP signaling between birth and 5-years of age (from excitatory to inhibitory), is the basis (or master switch) of the E/I reversal needed for neurotypical development

There's a long-running debate as to whether autism is "one thing" i.e., is there a common biology, or rather a collection of many different conditions. Does this study help answer that question?

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We now know that hundreds of different genes and environmental factors can each trigger the process that leads to autism.  Our research has focused on the final common denominator—the biological response found in all children with ASD -- which is the cell danger response or CDR that is regulated by extracellular ATP signaling.  
 

When the CDR is activated during the neuro-critical window that extends from pregnancy to the first two years of life, energy and metabolic resources needed for normal development are siphoned away and used to adapt to the triggering genes and environmental factors. 

 

The blocked excitatory to inhibitory (E/I) reversal found in children with ASD not only makes the children hypersensitive to classical sensory inputs like touch and sound, sight and taste, but also to internal chemical signals from eATP, chemicals made by the microbiome, and certain common environmental chemicals.

 

Could the findings from your paper lead to novel treatments or prevention strategies for neurodevelopment conditions like ASD?

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Yes. Since ASD is associated with an excess of excitatory ATP signals, a rational treatment would be to use a drug that can block these excitatory ATP signals. This class of drugs is called “anti-purinergic” drugs. Once the excitatory signals are attenuated with an anti-purinergic drug, the naturally present, but overpowered inhibitory signals needed to prevent over-excitation can be sensed more clearly and more normal development can be restored.  

So far, the only anti-purinergic drug available for testing in human clinical trials is suramin.  Suramin has been shown to be safe and effective in two small clinical trials. If suramin is proven to be safe and effective to treat autism in FDA-approved clinical trials, many other anti-purinergic drugs might be developed. 

 

I think we are on the cusp of a drug renaissance.  There are19 different purinergic receptors.  New drugs will target subsets of these to treat many different disorders from ASD to ALS.  There is even metabolic evidence that disorders like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long-COVID might also benefit.  A list of disorders that might benefit from anti-purinergic therapy can be seen at: http://naviauxlab.ucsd.edu/science-item/suramin/

 

What would you like to see happen next to further this research?

 

I’d like to see a number of things.  Most near term, I would like to see fast-tracked, rigorous Phase 2 and Phase 3 randomized clinical trials that the FDA needs to decide if suramin is safe and effective for ASD.  This is expensive and will cost over $50 million.

Additionally for suramin, I would also like to see a fast-tracked rigorous clinical trial of suramin in post-infection cases of ME/CFS and two or three other disorders, including Post-treatment Lyme Disease syndrome (PTLDS).
 
Beyond suramin, I would like to begin two new systematic anti-purinergic drug discovery programs. One of these would take advantage of existing natural product libraries prepared from plants from rainforests and coral reefs. The other would be a structural chemistry program to synthesize new antipurinergic drugs to target 1 or more of the 19 different purinergic receptors.
 
Finally, I would like to conduct a prospectively randomized, 5-year clinical trial of early infant and child resilience interventions compared to current well-baby care for the reduction in ASD risk in children born to mothers with a previous child with ASD.  This study would require coordination of at dozens of centers across six states to prospectively enroll about 2000 pregnant females who have had at least one previous child with ASD. If successful, this multi-state study would prove that early interventions designed to improve maternal and infant metabolic resilience can significantly decrease the risk of ASD.  The results of this study would show that like phenylketonuria (PKU), the core symptoms of ASD can be prevented by early interventions designed to bypass and strengthen weak links in metabolism and microbiome health.

 

Thanks for your time and contributions, Dr. Naviaux!

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