Thursday, August 27, 2020

Autism Research: Synchrony 2019

<15 min read> 

The public day of Synchrony 2019 conference was in November of last year.

The conference was run by Brain Foundation, which is a unique parent-run organization based in Pleasanton, CA. It funds research to develop treatments and create awareness for medical co-morbidities and disabilities associated with Autism Spectrum Disorder (ASD).

A couple of moms and I went together from the Bay Area in the morning to hear the day’s presentations on research updates. We had to leave around 4 PM, but we heard quite a few talks and I would like to share some of them in this post. 


Pramila Srinivasan, President of Brain Foundation, gave the introductory address. She mentioned how the foundation is collecting ‘cloud data’ from 400 cities, from 3500 autism patients, This is to gather information on the co-morbidities in ASD. The foundation supported research from a fund of 400K in 2019 and hopes to raise 1.4M in 2020.

1. The first talk was by Sarkis Mazmanian, Professor in Microbiology at Caltech University.

His research is on the Gut-Brain Axis. He spoke on “Microbiome and Autism- basic research to clinical trials”.

Summary: The brain does not work in isolation. Our microbiome has 10^14 bacteria, with >10,000 unique species. It is a like a second genome. There is a vast body of work in animals where microbiome alteration was shown to affect anxiety, learning & memory and appetite & satiety. 

This is because the microbiome regulates the immune system. 70% of our white blood cells are in our intestines, most of our immune cells are in our GI track. It is this connection that regulates our functioning through signaling. 

Most importantly, can we help autism by restoring GI bacteria? Can GI disturbances actually cause autism in some subsets? A transplant of gut bacteria from humans with autism into mice - was found to transfer symptoms of autism to the mice.

Prof. Mazmanian spoke of 4EPS -this was new to me- it is- 4EthylPhenylSulphate,  which is a biomarker for a leaky gut and is high in the blood of humans with ASD. His team is working on a drug that soaks up aberrant molecules from GI track like the 4EPS which interfere with signaling, while the drug itself doesn’t reach the brain. 

2. Micheal Merzenich, CSO, Posit Science Corporation, spoke about Brain Plasticity. His work is on “Brain Plasticity in ASD”.

Summary: The brain has neuro plasticity. We have to look at this neurologically, not psychologically or behaviorally. 

He defined plasticity as ‘about refining your brain connections, to serve your own useful purpose’. The plasticity creates our own special internal version of the world, and creates the ‘self’, a product of a massive schedule of associative self-reference. This ‘self’-creation grows and progressively evolves, specializing and adapting. 

Each one of us has the capacity to remodel our brains, at any age. The processes that express plasticity are reversible. 

Through simple forms of specific brain health training, his team was repeatedly able to show that we can 1. grow brain power and 2. restore neurological integrity in normal and struggling adult human brains. 

Coming to ASD, the tool sets are still incomplete. We need to - a. normalize attention control, b. re-establish and exercise cross-modal integration, c. re-balance and restore neurotransmitter expressions, d. drive and progressively elaborate expressive behaviors. 

However, he noted, there is continual antagonism to re-normalization strategies. 

3. Robert Naviaux, Professor in Residence, Medicine, at UCSD, presented on “Antipurinergic Therapy to decrease core disabilities in ASD”. 

Summary: The healing cycle in the body is broken in all chronic illnesses. It is broken because the Cell Danger Response is invoked by the body after an injury (cuts, infections, trauma, pollutants, pesticides, radiation, etc). This CDR (cell danger response) coordinates the mitochondrial response after every injury. 

Three kinds of mitochondria are needed to heal. Metabolism controls progression through the healing cycle by using metabolites called metabokines as signaling molecules. The healing cycle is a genetically programmed 3-step sequence used to ensure recovery after any type of injury. 

In autism, the healing cycle is broken at the 3rd step called CDR3. Stressed cells leak ATP, which serves as a signaler outside the cell. The lost ATP leaves the cells with insufficient ATP.

Professor Naviaux researched many drugs and found Suramin as a candidate to block this escape route of ATP from the cells in a therapy called ‘Antipurinergic therapy’.

The first human controlled trail of 5 children with a small dose of Suramin was conducted in 2017. The results were very promising. More studies are planned with 50 children. 

4. James Adams, Professor in School for Engineering, Rosa Krajmalnik-Brown, Professor in School of Sustainable Engineering and Daewook Kang, Research Scientist, from ASU, presented on “Microbiota Transfer Therapy for Children with ASD and GI Disorders: Summary of Phase-I and Follow Up”

Summary: Previously in a study by Adams et al, it was found that gut problems in autism were associated with higher symptoms. Treatment by Vancomycin, an antibiotic temporarily improved symptoms. 

Our microbial genome has more than 100 fold more genes than our human genome. Lower microbiome diversity is associated with less healthy gut. A lower microbial diversity was found in guts of children with autism. For example, Prevotella, one kind of bacteria, was dramatically lower in children with autism. This bacteria can serve as a biomarker.

For treatment, children with autism need a broad spectrum probiotic. However, commercial probiotics have only a few bacteria. 

The team at ASU studied 18 children (open label trial) with ASD, ages 7-16, with moderate to severe GI problems using a protocol - MTT (Microbiota Transfer Protocol). All children had GI problems since infancy. An 80% reduction in GI symptoms was seen, stable at 8 weeks post treatment. A 23% decrease in autism symptoms was seen, stable at 8 weeks post treatment. Microbial diversity improved to normal range. A followup study after two years showed GI symptoms improvement at 59% and autism symptoms decreasing by 47%.

Based on this research, MTT for autism has been granted a ‘fast track’ status by the FDA as a promising treatment. Randomized, double blind controlled studies with larger groups are underway. 

5. David Bick, CMO at Hudson Alpha Institute for Biotechnology, presented on “Genomic Testing in Autism Spectrum Disorder”.

Summary: DNA testing is everywhere. However, these tests are not designed to test for genes associated with ASD. In DNA testing, cytogenetic microarray has replaced chromosome analysis. This testing can detect duplications and deletions called CNV (Copy Number Variants). Clinically relevant CNV’s were found in 10% of ASD population (studied 1838). There’s a catalog that lists these CNVs.

Generally, ASD patients have 3 types of genetic testing: Cytogenetic microarray, Fragile X testing and NGS (next-generation sequencing) testing of a panel of genes that have been associated with ASD. This is generally covered by insurance. Two newer tests are being done- Exome and Genome sequencing. However having set panels for ASD can leave out newly discovered ASD associated genes, like the recent ones- variants of CSDE1 (Sept 2019), mutations in TANC2 (October 2019), ELMOD1 gene mutation (October 2019).

Whole Genome Sequencing (WGS) has advantages over Whole Exome Sequencing (WES) because WGS can sequence the exome more accurately and can detect a wider range of CNVs, among other benefits. WGS also finds mitochondrial CNVs. Pharmacogenomic variants can be added to a WGS test.

In connecting testing to treatment, some treatable disorders causing ASD symptomatology were found: ALDH7A1 deficiency causes pyridoxine dependent epilepsy and BCKDK deficiency causes seizures and intellectual disabilities which responded to branch chain amino acid supplementation. WGS and WES can find these disorders. 

He also spoke about possibility of using CRISPR technique for ASD.

6. Ronald Davis, Professor of Biochemistry and Genetics at Stanford University, presented on “The End ME/CFS Project”.

Summary: Like autism, Chronic Fatigue Syndrome (called Myalgic Encephalomyelitis in Europe) is diagnosed by symptoms. 

Professor Davis has a son with CFS so this syndrome is very close to home for him. 

Prof Davis has come up with a novel method to actually measure a biomarker for CFS and use that for cure and for prevention. This holds a strong parallel to autism measurement. 

Devices were fabricated on Silicon wafers and used as nano-needle biosensors. The device layers were SiO2 (100nm)/Au/Si/Au(50nm)/SiO2. Measurements were taken on blood samples with RBC removed and impedence measurements taken at rate of 200/sec.

The impedance was measured in 20 CFS patients and controls- before and after a ‘load’ was added in the form of salt. Because pumping out the Na needs energy, the CFS blood impedance rose way over the control. 

Copaxone, a drug was tested using the same measurements. The impedence from CFS patients samples decreased with the drug. 

He also spoke of microbiome, how those with affected guts are unable to make some necessary products in the guts, like Indole Proprionate. Several CFS patients have mutations in a gene called IDO2 and this, is like a metabolic trap, and can flip the body into a disease state. 

7. Hari Srinivasan, studying at Berkeley for his undergraduate degree presented on the challenges facing individuals with autism who are minimally speaking. 

This presentation and the presence of many other individuals- high schoolers and college students- who are minimally speaking autistic and type to communicate, brought the day-to-day experience of living-with-this-type-of-autism to the foreground.

8. Several other presenters talked about their work, mostly in clinical practice settings. 

My view:

My perspective, as an autism mom and as a person with research background (in non autism area) is on the various angles in the body of work presented on the public day.

  1. Gut-Brain connection: A lot of our kids have sensitive guts and related issues. Finding a drug that can soak up ‘aberrant’ molecules coming from the gut can be a life changer for many of us.
  2. Diversity of microbiome: I hope this angle, of low diversity of microbiome in individuals with autism, reaches mainstream medicine more, so no infant or toddler, or anyone in autism population is given antibiotics for conditions that can be managed without them. 
  3. As a parent, being at ground zero, we see how autism is not ‘static and steady’ but changes everyday within a range. We see amazing differences in how our kids function on a day-to-day level. Brain plasticity is real: “Cross-modal integration” training is what individuals with ASD need, along with the other background factors, which in a home setting, we call ‘we get more done on a good day when autism is low’. This brings to the forefront that there is no one type of autism- there are autisms. If autism is low, which is generally referred to as ‘high functioning autism’, it is indeed understandable to want to emphasize self-identity with a different neurology than typical. But when autism is moderate or high, there is incredible suffering with the co-morbidities for many, along with the core autism. To desire to alleviate the suffering is but natural. 
  4. Tying actual loss of ATP, or in other words, energy, in the cell to autism is very exciting. This body of work is actually not just research in autism co-morbidities but hints at the mechanism that may be behind autism.
  5. I wonder if the novel device used to measure the ‘energy levels' in blood samples of CFS patients can be used to measure the same in ASD individuals. If this is viable, it can potentially give a non-behavioral measurement for ASD, irrespective of the kind of autism. (Based on the earlier hypothesis that energy has a role in ASD and if loss of ATP in a cell translates to something that can be measured). Can you imagine the possibilities if this works? For one, we can have a biomarker for measuring autism and not based on symptoms alone. 

Please support the Brain Foundation to continue supporting research like the presentations above. It is a parent-run organization- parents like you and me, who are doing this while juggling life and schooling of their kids with autism (some of the parents homeschool their kids). 


No donated amount is too small, no amount is too big!

Here is a slide from Prof. Mazmanian's talk at the conference. It shows all the areas affected by autism and co-exist with it. 

Here is the link to many of the presentations on the public day of Synchrony 2019 and the dates of the upcoming virtual Synchrony 2020: Synchrony Conference