This article was first published on Linkedin on 11th August, 2020
From reading the news you would think that people’s experience of COVID-19 is random, and down to chance.
How is it after all that two people of the same sex and of a similar age and social background can be affected so differently by the virus? One person might only experience very mild symptoms, if at all. Meanwhile the next might require hospital treatment.
COVID-19, like either disease, isn’t random of course. It comes down to individual lifestyles and other health conditions. For example, the relationships between COVID-19 hospitalization and obesity or diabetes among younger 18-49-year-olds is now well known.
In this article, I will look at the increasing role personalized or precision medicine (the two terms are used interchangeably) needs to play in the healthcare arena. This is an area COVID-19 has brought into the spotlight, but it’s something that will remain increasingly important once the worst of the pandemic has passed and we have widely available vaccines.
As part of the research for the article, I interviewed Dr. Purna Kashyap who leads Mayo Clinic's Microbiome Laboratory, as well as Dr. Gabi Meron, previously co-founder and CEO of Given Imaging, and currently CEO of HygeiaCare. Thank you for your contribution!
- The link between COVID-19 severity and chronic diseases drives renewed focus on precision medicine
- Precision medicine combines an understanding of genome and microbiome mechanisms to gradually increase value from diagnostic to therapeutic use cases
- Genomics alone are insufficient in chronic diseases, putting focus on the microbiome
- There are early-stage diagnostic microbiome products that can address these diseases
- Big data is a bottleneck in moving the needle towards actual microbiome therapies
- Overall, there is enough early-stage technology in precision medicine to be optimistic about products that can further curb chronic diseases
- Technology is only one side of the coin in treatment of chronic diseases; psychology and incentives are a big part, further explored in future editions of Priority Zero
The link between COVID-19 and precision medicine
You may have heard stories from friends or family about ways COVID-19 "creeps" through your entire body, testing organ by organ to find weak spots.
Without going too deep into a scientific tangent, the aggressive COVID-19 spread seems to be at least partially a result of the way the virus binds itself to our bodies via protein-receptors called ACE2 that are very prevalent in most key organs of our body.
If an organ already has an underlying disease, ACE2 "hack" can turn a previously slow-burning chronic condition or pre-disposition into a catalyst of severe or even lethal course of the disease .
As a result, we are now facing a reinvigorated level of scrutiny on how we can map uncorrelated and largely individualized factors to specialized treatments that can de-risk and alter the course of the disease for very different cohorts of patients.
Questions that we ask ourselves are:
- Is my previously innocuous underlying condition making me high-risk?
- What can I do to protect myself better from short and long-term risks?
- What individual risk or protective factors I have? My blood type? My blood sugar? My allergies? My weight?
- How can I account for these factors and pair them with an appropriate medical treatment pathway that will work for me?
These questions highlight the importance of the science of individualized medicine in tackling many of the tough to resolve medical problems
So what exactly is precision medicine?
Precision medicine is the tailoring of medical treatment to the individual characteristics of each patient. The approach relies on scientific breakthroughs in our understanding of how a person's unique profile makes them susceptible to certain diseases.
Precision medicine is not about a one size fits all approach. It involves treatment that is customized for individual patient treatments.
Its ultimate potential is to turn a dangerous disease into an equivalent of a well-managed common cold, allowing us to lead productive lives.
Beyond COVID19 vaccines will not cure costly chronic diseases such as obesity, diabetes, cardiovascular disease. Right now we treat the symptoms and rely on long-term behavioral discipline. This seems at best inefficient to reach the majority of people in an effective way.
How are precision medicine products developed?
Before we go any further, let’s look at what precision medicine actually means in more depth.
Each human is unique in only a few of major ways - there are others, but below are two most relevant for this discussion:
- Through the human genome: This is the complete roadmap of how to build and maintain a unique human organism, consisting of 3 billion DNA pairs, encoded throughout evolutionary processes of the past
- Through the microbiome: Here we are talking about the genetic footprint of over 100 trillion microbial combinations that exist symbiotically in our body as real-time byproducts of living, forming yet another unique genetic identifier to a human being
The intertwined individual profiles of both the human DNA and the DNA of the microbial population in our bodies are what drives the value of precision medicine.
Unsurprisingly, there is a hierarchy of levers that scientists and business people need to pull in order to produce valuable treatments that account for this individual variability. Here's what it could look like:
At the very foundation of getting anything done is actual data science. Far-far behind any solutions, data scientists must have the high integrity data to be able to understand the various associations between specific diseases and biomarkers (aka indicators or characteristics of a biological state or condition ) from genome/microbiome.
Once you establish a correlation between biomarkers within individuals and diseases, then you can start stratifying some predictable relationships between treatments and therapies.
You start understanding what drugs can cause more of an adverse effect on an individual's body, and what drugs can actually yield a better clinical response. This slice of precision medicine pie is called pharmacogenomics.
At this stage, even if we understand relationships between treatments and our unique genetic or microbiotic "fingerprint", helping to drive diagnostic value to apply to other existing therapies, we still do not necessarily understand the mechanism in which one or the other "drives" the progression of a disease.
Any new therapy can only be developed when a mechanism is clear, and even then it is not necessarily personalized, but rather a one size fits all solution.
The degree to which we understand the mechanisms, as well as the availability of high-quality data discerning all key cohorts of individuals - all of this would enable truly personalized therapies that cure a very rare and acute disease or a very multi-faceted chronic disease.
In chronic diseases, human DNA is insufficient - focus on the microbiome?
It is not surprising that most of the early focus within this emerging discipline has been on some of the most acute diseases such as cancer. Understanding monogenic (one single gene involvement) variations and creating earlier diagnostics drives the increasingly bullish case for curing many cancers:
Despite the positive trends in oncology, enabled by some of the precision medicine concepts, the same does not hold true in the progression of chronic diseases.
Below is a staggering example of diabetes that correlates quite well with the increasing rates of obesity in the population
The reason why metabolic disorders aren't displaying the same pattern is that they are extremely multi-factorial: multiple genes are involved, in combination with lifestyle and environmental factors. This is not a good target for the "sniper" tools deployed in attacking various cancers via stratification of precision drug response or novel therapies.
That's where the "second genome" of microbiomes may come in. There has been a lot of research and new activity in this space focusing on both some of the chronic and lifestyle diseases, as well as complementing oncology research.
Below is a good overview from the Mayo Clinic on what microbiome is all about:
So why are scientists excited about the microbiome as a way to attack some of these more complex disorders? In my discussions with Dr. Purna Kashyap who leads Mayo Clinic Microbiome Lab, I understood that there are several key advantages to the microbiome:
- Additional variability beyond human genomics
Analyzing the microbiome can offer a much more detailed look into the unique profile of a single patient. In fact, you can think of the microbiome as the next layer of the onion to peel as we try to understand individualized approaches.
Given that the complexity of the genomic base of the microbiome supersedes that of the human genome, in a situation where two people with an equivalent genomic profile respond differently to new diabetes treatment, the likely significant differences in their microbiome profiles can potentially explain the difference in response.
- Potentially modifiable
Although we're now starting to experiment with various techniques to alter our genetic profile (e.g. fascinating CRISPR gene editing), it is still nascent. Conversely, interventions into microbiome using probiotics or microbiome transplants seem to be a safer and simpler exercise.
This means that if mechanisms of microbiome effect on specific diseases are understood, the ability to change the microbiome to enable the mechanism is more feasible and accessible.
- Comprehensive predictor for lifestyle factors
Diseases such as diabetes require 30-40 input variables in order to show strong correlation.
This includes BMI, food consumption, and others. The complexity and sensitivity of the microbiome to these environmental and lifestyle variables makes it potentially a leading predictor to understand organism response to various interventions. This would make the microbiome a very powerful source of data that can simplify an otherwise extremely complex set of data and algorithms.
Can microbiome enable products that tackle obesity and chronic disorders?
There is some evidence that it can help.
The flagship study that is driving the excitement of both the scientific and entrepreneurial communities is the set of studies initiated in the Weizmann Institute of Science in Israel, that bring precision medicine into personalized nutrition.
These studies use individual microbiome analysis to predict a person's glycemic (blood sugar) response to consuming specific foods. Below is a useful walkthrough video that highlights the benefits of the study:
As a result, while fairly early stage, there is increasing research that suggests that analyzing the microbiome can create new insights and algorithms to strengthen and improve existing pharmaceutical and even behavioral treatments.
But when will the consumers actually see robust microbiome-centered products?
The hierarchy of levers I spoke of earlier is very much reflected in product-market readiness. The use cases that are based on drug or food intake response seem to be much more mature.
The studies that Weizmann Institute and Mayo Clinic have conducted have triggered business activities, as seen by the emergence of several highly promising personalized diet starts-ups such as DayTwo.
Other studies have shown proof points of a clear connection between adverse events from specific cancer therapies like irinotecan and responders' microbiotic profile.
In short, there are several clear investable concepts that can drive the early utilization of microbiome research.
For now, they are pegged to either very specific "companion therapy" concepts connected to pharmaceuticals, or early-stage personalized nutrition tools that can help nudge consumers towards more effective dieting. In both cases, outcome improvement is tied to the performance of associated drugs or behavioral compliance. In the current state of art, mirobiome does not yet drive independent, stand-alone outcome improvement value.
Is data as a bottleneck for more intelligent personalized therapies?
Novel microbiome-based therapies or diagnostics are far from being ready for commercialization. In my dialogue with Purna Kashyap and Gabi Meron, I gathered that there are still plenty of challenges to surmount to get to personalized therapies for many of the chronic metabolic diseases.
The benefit of the microbiome in terms of its strong and broad association with most chronic diseases is also one of its biggest challenges. The cause-effect conundrum is tough to solve for - is the microbiome driving a chronic disease or is it the other way around?
As such, the case for AI in the microbiome seems to be very strong. We need to find ways to leverage machine learning to absorb large and high-integrity data sets that combine and "stack" together microbiotic and general biomarkers to find new algorithms that further individualize treatments.
My colleague at Caresyntax, Dr. Enes Hosgor, leading AI and data science efforts, and I often muse among ourselves:
Healthcare AI is glorified plumbing.
Too often we underestimate the "upstream" work of bringing, curating and annotating good data and over-focus on the more exciting aspects of resulting algorithms and software down the line
Microbiome research is no different. In my discussions with Purna Kashyap and Gabi Meron, all of us agreed that the more microbiome data is available, the more robust and rapid new product introductions will be.
It does not escape me that microbiome samples are collected from fecal matter (the origin of the endearing label of "poop-tech" bestowed on entrepreneurs in this space). While fecal material would seem to be a widely available commodity, microbiome sampling is nowhere near the industrial scale of DNA sampling driving rapid advances in genomic therapies.
Dr. Kashyap's experience with broader studies with recruited patients may enable larger much more robust algorithms needed to tackle systemic diseases such as diabetes and obesity. Large data sets are a requirement if we are to truly make tools like personalized diet guidance a consumer tool.
Gabi Meron's company, HygieaCare takes the "closed-loop" approach, pairing colonoscopy preparation procedure with robust data collection opportunities, which may be lower volume, but of higher diagnostic value. This path is well suited for the more specific and clinical use cases in early diagnostics of pancreatic and other tough to beat cancers.
Personalized treatments to help tackle chronic disorders - PLAUSIBLE
There are various ways to tackle the data problem in this space, and after conducting the research for this edition, I confirmed my strong belief that personalized medicine can be significantly enabled by scientific advancements in understanding our genome and microbiome.
Of course, science is only one side of the coin.
Curbing obesity and diabetes, as long-term chronic diseases linked to lifestyles, is not only a matter of science but also that of psychology and incentives, which are key topics that I would like to explore in further editions of Priority Zero (subscribe to the newsletter via Linkedin)