Autism is popularly considered as a disorder of the brain which manifests itself via behavioral and social difficulties. Recently, however, researchers have started to realize that profound gastrointestinal and metabolic abnormalities may be inextricably linked to patient behavioral symptoms. In the midst of this new frontier of autism research, scientists like John Slattery are engaging in multi-disciplinary approaches to develop tools for treating patients.
As the founder and CEO of BioROSA Technologies Inc. and a longtime collaborator with top autism researchers like Dr. Richard Frye, Slattery has a history of making valuable contributions to autism research. By investigating new diagnostic methods and with the hopes of partnering with companies that are developing novel compounds that have the potential to treat the microbiome and metabolic pathways of patients, Slattery is pioneering a new diagnostic paradigm unlike any before. This approach can potentially lead to enhanced understanding and allow industry to have novel biomarker tools to assist in therapeutic developments.
Slattery’s company is developing a diagnostic test which, upon successful validation, could complement the autism diagnostic evaluation. BioROSA would do this through biological investigations in addition to behavioral and clinical evaluations which would greatly improve the diagnostic process and decrease diagnostic bottlenecks and hurdles which currently plague clinicians and parents alike, impeding access to the early interventions known to produce better outcomes. In addition to his role as Founder & CEO of BioROSA Technologies, which aims to create a biologically-based standard of care for ASD, is also a member of the scientific advisory board at Tesseract Medical where his extensive experience in conducting clinical trials is invaluable.
In this interview, Slattery discusses the clinical and epidemiological value of the new test as well as his views on the most promising developments in the field and how they might be used to reduce the impact of autism worldwide.
A New Approach to Autism Leads to New Diagnostic Methods
At present, doctors must diagnose autism by observing patient behavior and assessing reports from caregivers. Unfortunately, behavioral diagnosis of autism relies on diagnostic methods which may be inconsistent from clinician to clinician. There is currently no objective biomarker-based methodology to allow clinicians to determine whether they are making the correct diagnosis. For example, if a cardiologist wants to assess cardiac function there are many biological tools at their disposal to assess how the heart is functioning and which interventions may be needed. This is not possible today with autism. There are no lab-based biomarkers for clinicians to use. Furthermore, doctors can’t assess the risk of developing autism.
Slattery and his colleagues have discovered a compelling method which may sidestep some of the aforementioned complications that accompany subjective assessments and opens up the possibility of better diagnostic methods. “Within the next four years, my company, if successful, will have developed a way to diagnose autism through a lab-based test,” he says. By examining biomarkers rather than behavioral symptoms, the test will allow for easier and more accurate diagnosis. Such a diagnostic test would facilitate earlier and more accurate identification of autism and lead to earlier diagnostic timelines, reduce diagnostic bottlenecks, and allow for earlier interventions.
However, the value of biomarker testing goes beyond diagnosis. “There are a lot of treatment strategies which are, frankly, ineffective or dangerous,” Slattery explains. “Patients and their families may not need to be practicing these alternative treatment strategies. Hopefully we can create an objective standard of care which industry and clinicians alike can use to evaluate whether treatments are working.” Currently, much like with diagnosis, doctors are left to subjectively assess behavioral criteria in response to treatment. These criteria are difficult to sample effectively and efficiently, as doing so requires significant time and cooperation which within a clinical setting is almost impossible. This is complicated further by the fact that such assessments of behavior are often not a part of the care model because they don’t lead to insurance reimbursement, as there are currently no FDA approved interventions that have efficacy for ASD. By providing doctors with a tool to measure the impact of interventions, it will be possible to create objective rubrics to help doctors assess which intervention may be appropriate to use for a given patient and track treatment efficacy at a physiological level.
Metabolic Disorders: Are They a Consequence of Autism? Or a Cause?
To assess a patient’s metabolism and use that assessment for diagnosis, Slattery needed to identify a biochemical property which correlates with developing autism. In Slattery’s Redox Oxidative Stress Analysis (ROSA) test, oxidative stress related metabolic pathology is that property. Oxidative stress is the process by which byproducts of metabolism interfere with cellular function, causing cellular damage and disrupting proper cell function. This phenomenon is particularly damaging to the mitochondria of cells, which are responsible for producing energy to power other cellular machinery. Patients with autism have been repeatedly shown to exhibit very high levels of oxidative stress compared to typically developing peers, indicating that their body’s cellular machinery is not working properly, substantially impairing mitochondrial function and leading to other significant physiological concerns.
Using machine learning and laboratory techniques like mass spectrometry, ROSA can determine whether a patient’s cells are experiencing high levels of oxidative stress which impedes cellular function. Higher levels of oxidative stress correlate with more severe behavioral symptoms of autism and may also correlate with more severe gastrointestinal symptoms as well as other medical symptoms that have been reported in ASD such as impaired immune system function. Importantly, researchers like Slattery have discovered molecules which act as markers for ongoing oxidative stress. In particular, the molecule known as glutathione is critical for assessing oxidative stress because its purpose in the body is to prevent oxidative stress from damaging cells. Malfunctional glutathione utilization is thus a major indicator of autism. As Slattery explains:
Patients with autism have significant problems with glutathione production and also glutathione utilization. If you look at the metabolic pathways, you can look at all the biochemical steps above glutathione and find that patients with autism have abnormalities with every step along the way. Of course you’re going to have problems with glutathione when those steps are banged up. Improving glutathione could, therefore, potentially have tremendous implications for correcting the biochemical problems of autism and also improving behavior and investigations into the precursor for glutathione production N-acetyl-l-cysteine (NAC) has shown promise in ASD and other neuropsychiatric conditions. I have actually just published a book chapter on this work with my colleague, Dr. Richard Frye.
But Slattery’s perspective on how metabolic issues and oxidative stress relate to autism symptoms is broader than abnormal glutathione metabolism alone. Indeed, oxidative stress impacts many different interconnected physiological systems, but all stem from the metabolic action of the mitochondria. “Mitochondrial medicine is a relatively new field in medicine, although, amazingly, the mitochondria were first described as early as the 1840s,” Slattery says. “It’s really only been around conceptually as a medical discipline since the 1980s, but it wasn’t until recently that we had the technology to explore it more efficiently and effectively.” This new field of medicine has enormous implications for the treatment and diagnosis of autism, especially in light of new research implicating the gastrointestinal tract and microbiome in autism-related dysfunction and how these systems in the body seem to be evolutionarily conserved and interconnected in many complex ways.
The Advent of Mitochondrial Medicine
Rather than examining autism purely through the lens of neurology and psychology, understanding it in light of the role of mitochondrial dysfunction opens up new possibilities for not only diagnosis, but also for treatment. In terms of the possible scope of these new treatments, Slattery doesn’t try to conceal his excitement:
Restorative treatments may be possible. All of these metabolic pathways that are interconnected are not performing properly. Can we, in a hypothetical world, identify these pathways and use the right interventions to be leveraged to push those pathways to normal levels to allow more normal physiological function and improve patient symptoms to a point where the patient could recover? Potentially. That is the future that we think is possible, and that is where we want to go. That’s what we’re going to try and aim to achieve.
So, what might metabolic-targeted therapies involve? Slattery has a number of ideas on the topic, including treatment with compounds like methyl-B12 and folate. One chemical is especially promising to Slattery, however: butyrate.
Innovation Drives Effective Treatment
Slattery emphasizes that butyrate is a compound of great interest within mitochondrial medicine and the field of the microbiome. “Therapies such as butyrate can have a tremendous effect at limiting oxidative stress to the mitochondria,” he explains. Butyrate is particularly appealing for researchers because it is known to be bioactive; it is used by the body to regulate immune cells in the gastrointestinal tract.
Treating the mitochondria of patients with autism with butyrate can be challenging due to its unique characteristics, however. Butyrate is the chemical that gives vomit its characteristic smell, which makes it extremely unpalatable to most patients and introduces practical barriers to administration. “Butyrate is a gross compound to deal with,” Slattery says. “Trying to get patients with autism to consume butyrate is not a small task unless you’ve been able to mask the taste and encapsulate it so that the patients don’t know they’re consuming butyrate.”
Some researchers have addressed this challenge by creating tolerable pill formulations for butyrate supplements—a major innovation which vastly broadens the landscape of potential therapies. Tesseract Medical, which works with cutting-edge therapies for neurological and gastrointestinal conditions, has produced two such supplements: ProButyrate and AuRx. “The thing that Tesseract has done that sets them apart from anyone else in the field is that they’ve developed a palatable supplement,” Slattery explains. This means that butyrate can be administered in a therapeutic capacity unlike ever before and could be a massive boon to patients. However, taste is not the only challenge to butyrate use; butyrate suffers from significantly poor bioavailability, which means that only specialized nutraceutical delivery mechanisms have a chance at providing a therapeutic benefit.
Butyrate is naturally produced by the body, and the body readily metabolizes any additional butyrate consumed orally as a result. This prevents it from accessing the areas of the body that it needs to act on in order to produce symptom relief. To work around this obstacle, Tesseract has developed highly bioavailable delivery systems which are thought to deliver intact butyrate directly to the physiological target. “You have to deliver butyrate throughout the GI tract, but in particular, the colon,” says Slattery, “It is not an easy thing to do, but Tesseract has accomplished that.” By delivering butyrate to the colon, the compound can exercise its antioxidant defense capabilities on the cells that need the most assistance in patients with autism.
Though Dr. Richard Frye and Shannon Rose’s in vitro research (of which Slattery was a collaborator and co-author) on butyrate showed promising preliminary results, it should be noted that the laboratory findings are far from the goal of clinical utility. A definitive result of butyrate efficacy on ASD symptomatology awaits the completion of clinical studies. “The stage has been set for a clinical trial testing butyrate in autism. That’s the next step. The fact that Tesseract has developed ProButyrate and AuRx is a significant piece of that.” While Slattery’s company is not involved in ASD therapeutic research, Slattery views the ROSA testing platform as a natural potential companion to any significant ASD therapies. In the future, clinicians could administer the ROSA test and receive a positive result for ASD diagnosis. In turn, hypothetically, they could follow up with a treatment (such as butyrate therapy), monitor any effects on oxidative stress, determine if the treatment is reducing oxidative stress, and correlate the effects with behavioral symptoms. This clinical pairing would be a major improvement in the field of autism treatment, as it would link treatment to an objective measurement of efficacy.
A World Without Autism?
New testing and treatment paradigms have a massive potential to help patients. But could ROSA or butyrate supplementation be a tool to reduce the prevalence of autism? Is total prevention possible? “Maybe,” Slattery says cautiously before his tone changes to aspirational. “If you can reduce the incidence of cases by even 1%, there’s a significant economic return [from preventing the need for medical services] and you can also potentially change that patient’s life and their family’s life forever.” Slattery contends that while his ROSA technology has potential to open new avenues for diagnosis and treatment monitoring, therapies like butyrate supplementation will have to be tested to assess their ability to improve symptoms. In this framework, Slattery thinks that the next twenty years of autism research can reduce symptoms, but that the road to an autism-free world still extends over the horizon with much research and validation from diagnostics and therapeutics necessary to achieve these lofty goals.
Nonetheless, Slattery is confident about the future of autism therapeutics research. “We’re optimistic that all is possible if the resources are put into the space and the work that needs to be done can be funded and put to the test through innovative academic-industry collaborative efforts,” Slattery says. “We’re about to be ready for the race. I think we’re still stretching right now … [but] I am optimistic and think things are about to take off like they never have before.”
Slattery notes that all mentioned compounds need to be carefully evaluated in clinical trials and that none of these comments have been evaluated by the FDA and that the remarks he makes are strictly research-based without any implied or explicit warranties related to the use of any of these interventions for patients with ASD. He stresses that families must consult with a physician before attempting to treat their child with any therapy, irrespective of presumed safety or efficacy).