Future Health: DNA is one thing, but 90% of you is not you

One of my pet hates is seeing my wife visit the doctor, getting hunches of what may be afflicting her health, and this leading to a succession of “oh, that didn’t work – try this instead” visits for several weeks. I just wonder how much cost could be squeezed out of the process – and lack of secondary conditions occurring – if the root causes were much easier to identify reliably. I then wonder if there is a process to achieve that, especially in the context of new sensors coming to market and their connectivity to databases via mobile phone handsets – or indeed WiFi enabled, low end Bluetooth sensor hubs aka the Apple Watch.

I’ve personally kept a record of what i’ve eaten, down to fat, protein and carb content (plus my Monday 7am weight and daily calorie intake) every day since June 2002. A precursor to the future where devices can keep track of a wide variety of health signals, feeding a trend (in conjunction with “big data” and “machine learning” analyses) toward self service health. My Apple Watch has a years worth of heart rate data. But what signals would be far more compelling to a wider variety of (lack of) health root cause identification if they were available?

There is currently a lot of focus on Genetics, where the Human Genome can betray many characteristics or pre-dispositions to some health conditions that are inherited. My wife Jane got a complete 23andMe statistical assessment several years ago, and has also been tested for the BRCA2 (pronounced ‘bracca-2’) gene – a marker for inherited pre-disposition to risk of Breast Cancer – which she fortunately did not inherit from her afflicted father.

A lot of effort is underway to collect and sequence the complete Genome sequences from the DNA of hundreds of thousands of people, building them into a significant “Open Data” asset for ongoing research. One gotcha is that such data is being collected by numerous organisations around the world, and the size of each individuals DNA (assuming one byte to each nucleotide component – A/T or C/G combinations) runs to 3GB of base pairs. You can’t do research by throwing an SQL query (let alone thousands of machine learning attempts) over that data when samples are stored in many different organisations databases, hence the existence of an API (courtesy of the GA4GH Data Working Group) to permit distributed queries between co-operating research organisations. Notable that there are Amazon Web Services and Google employees participating in this effort.

However, I wonder if we’re missing a big and potentially just as important data asset; that of the profile of bacteria that everyone is dependent on. We are each home to approx. 10 trillion human cells among the 100 trillion microbial cells in and on our own bodies; you are 90% not you.

While our human DNA is 99.9% identical to any person next to us, the profile of our MicroBiome are typically only 10% similar; our age, diet, genetics, physiology and use of antibiotics are also heavy influencing factors. Our DNA is our blueprint; the profile of the bacteria we carry is an ever changing set of weather conditions that either influence our health – or are leading indicators of something being wrong – or both. Far from being inert passengers, these little organisms play essential roles in the most fundamental processes of our lives, including digestion, immune responses and even behaviour.

Different MicroBiome ecosystems are present in different areas of our body, from our skin, mouth, stomach, intestines and genitals; most promise is currently derived from the analysis of stool samples. Further, our gut is only second to our brain in the number of nerve endings present, many of them able to enact activity independently from decisions upstairs. In other areas, there are very active hotlines between the two nerve cities.

Research is emerging that suggests previously unknown links between our microbes and numerous diseases, including obesity, arthritis, autism, depression and a litany of auto-immune conditions. Everyone knows someone who eats like a horse but is skinny thin; the composition of microbes in their gut is a significant factor.

Meanwhile, costs of DNA sequencing and compute power have dropped to a level where analysis of our microbe ecosystems costs from $100M a decade ago to some $100 today. It should continue on that downward path to a level where personal regular sampling could become available to all – if access to the needed sequencing equipment plus compute resources were more accessible and had much shorter total turnaround times. Not least to provide a rich Open Data corpus of samples that we can use for research purposes (and to feed back discoveries to the folks providing samples). So, what’s stopping us?

Data Corpus for Research Projects

To date, significant resources are being expended on Human DNA Genetics and comparatively little on MicroBiome ecosystems; the largest research projects are custom built and have sampling populations of less than 4000 individuals. This results in insufficient population sizes and sample frequency on which to easily and quickly conduct wholesale analyses; this to understand the components of health afflictions, changes to the mix over time and to isolate root causes.

There are open data efforts underway with the American Gut Project (based out of the Knight Lab in the University of San Diego) plus a feeder “British Gut Project” (involving Tim Spector and staff at University College London). The main gotcha is that the service is one-shot and takes several months to turn around. My own sample, submitted in January, may take up 6 months to work through their sequencing then compute batch process.

In parallel, VC funded company uBiome provide the sampling with a 6-8 week turnaround (at least for the gut samples; slower for the other 4 area samples we’ve submitted), though they are currently not sharing the captured data to the best of my knowledge. That said, the analysis gives an indication of the names, types and quantities of bacteria present (with a league table of those over and under represented compared to all samples they’ve received to date), but do not currently communicate any health related findings.

My own uBiome measures suggest my gut ecosystem is more diverse than 83% of folks they’ve sampled to date, which is an analogue for being more healthy than most; those bacteria that are over represented – one up to 67x more than is usual – are of the type that orally administered probiotics attempt to get to your gut. So a life of avoiding antibiotics whenever possible appears to have helped me.

However, the gut ecosystem can flex quite dramatically. As an example, see what happened when one person contracted Salmonella over a three pay period (the green in the top of this picture; x-axis is days); you can see an aggressive killing spree where 30% of the gut bacteria population are displaced, followed by a gradual fight back to normality:

Salmonella affecting MicroBiome PopulationUnder usual circumstances, the US/UK Gut Projects and indeed uBiome take a single measure and report back many weeks later. The only extra feature that may be deduced is the delta between counts of genome start and end sequences, as this will give an indication to the relative species population growth rates from otherwise static data.

I am not aware of anyone offering a faster turnaround service, nor one that can map several successively time gapped samples, let alone one that can convey health afflictions that can be deduced from the mix – or indeed from progressive weather patterns – based on the profile of bacteria populations found.

My questions include:

  1. Is there demand for a fast turnaround, wholesale profile of a bacterial population to assist medical professionals isolating a indicators – or the root cause – of ill health with impressive accuracy?
  2. How useful would a large corpus of bacterial “open data” be to research teams, to support their own analysis hunches and indeed to support enough data to make use of machine learning inferences? Could we routinely take samples donated by patients or hospitals to incorporate into this research corpus? Do we need the extensive questionnaires the the various Gut Projects and uBiome issue completed alongside every sample?
  3. What are the steps in the analysis pipeline that are slowing the end to end process? Does increased sample size (beyond a small stain on a cotton bud) remove the need to enhance/copy the sample, with it’s associated need for nitrogen-based lab environments (many types of bacteria are happy as Larry in the Nitrogen of the gut, but perish with exposure to oxygen).
  4. Is there any work active to make the QIIME (pronounced “Chime”) pattern matching code take advantage of cloud spot instances, inc Hadoop or Spark, to speed the turnaround time from Sequencing reads to the resulting species type:volume value pairs?
  5. What’s the most effective delivery mechanism for providing “Open Data” exposure to researchers, while retaining the privacy (protection from financial or reputational prejudice) for those providing samples?
  6. How do we feed research discoveries back (in English) to the folks who’ve provided samples and their associated medical professionals?

New Generation Sequencing works by splitting DNA/RNA strands into relatively short read lengths, which then need to be reassembled against known patterns. Taking a poop sample with contains thousands of different bacteria is akin to throwing the pieces of many thousand puzzles into one pile and then having to reconstruct them back – and count the number of each. As an illustration, a single HiSeq run may generate up to 6 x 10^9 sequences; these then need reassembling and the count of 16S rDNA type:quantity value pairs deduced. I’ve seen estimates of six thousand CPU hours to do the associated analysis to end up with statistically valid type and count pairs. This is a possible use case for otherwise unused spot instance capacity at large cloud vendors if the data volumes could be ingested and processed cost effectively.

Nanopore sequencing is another route, which has much longer read lengths but is much more error prone (1% for NGS, typically up to 30% for portable Nanopore devices), which probably limits their utility for analysing bacteria samples in our use case. Much more useful if you’re testing for particular types of RNA or DNA, rather than the wholesale profiling exercise we need. Hence for the time being, we’re reliant on trying to make an industrial scale, lab based batch process turn around data as fast we are able – but having a network accessible data corpus and research findings feedback process in place if and when sampling technology gets to be low cost and distributed to the point of use.

The elephant in the room is in working out how to fund the build of the service, to map it’s likely cost profile as technology/process improvements feed through, and to know to what extent it’s diagnosis of health root causes will improve it’s commercial attractiveness as a paid service over time. That is what i’m trying to assess while on the bench between work contracts.

Other approaches

Nature has it’s way of providing short cuts. Dogs have been trained to be amazingly prescient at assessing whether someone has Parkinson’s just by smelling their skin. There are other techniques where a pocket sized spectrometer can assess the existence of 23 specific health disorders. There may well be other techniques that come to market that don’t require a thorough picture of a bacterial population profile to give medical professionals the identity of the root causes of someone’s ill health. That said, a thorough analysis may at least be of utility to the research community, even if we get to only eliminate ever rarer edge cases as we go.

Coming full circle

One thing that’s become eerily apparent to date is some of the common terminology between MicroBiome conditions and terms i’ve once heard used by Chinese Herbal Medicine (my wife’s psoriasis was cured after seeing a practitioner in Newbury for several weeks nearly 20 years ago). The concept of “balance” and the existence of “heat” (betraying the inflammation as your bacterial population of different species ebbs and flows in reaction to different conditions). Then consumption or application of specific plant matter that puts the bodies bacterial population back to operating norms.

Lingzhi Mushroom

Wild mushroom “Lingzhi” in China: cultivated in the far east, found to reduce Obesity

We’ve started to discover that some of the plants and herbs used in Chinese Medicine do have symbiotic effects on your bacterial population on conditions they are reckoned to help cure. With that, we are starting to see some statistically valid evidence that Chinese and Western medicine may well meet in the future, and be part of the same process in our future health management.

Until then, still work to do on the business plan.

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