Pollution Must Be a Pharma Problem
Exploring a field that is deeply under-appreciated relative to its impact
Consider two large problems that share a non-obvious link:
16% of human deaths globally are directly attributed to pollution today and 12% of radiative forcing will be due to industrial bi-products by 2050. Yet, despite these chemicals being tied to some of the biggest disease burdens of our era, there is relatively little direct effort to cure or reverse the diseases linked to these chemical injuries.
As long as it is maximally profitable for a company to generate toxic externalities, the company is mandated to continue that activity. CEOs are personally liable to operate in shareholders’ interest, whereas the corporations are liable for environmental impacts.
If these two points seem unrelated, it’s because there is currently an Accountability Gap between the cause and effect of industrial byproducts. What if we lived in a world of perfect molecular information in which every molecule is accounted for and every downstream cascade is perfectly observable?
New technologies are needed to bridge the Accountability Gap: Solving the challenges of discovery and resilience could form one of the biggest fulcrums yet to drive global economies toward cleaner, more sustainable practices.
Intro: Shaping the problem
Human health is an under-appreciated lever for planetary health. When people study pollution now, generally via government research grants, they tend to study it from an epidemiological perspective. These grants become correlational studies with the assumed end goal of informing new policy. Frankly, I think this is slow, indirect, and worst, only going to decrease in efficacy as industrial technology outpaces regulatory infrastructure. We need to tap the power of the billion-dollar biotech machinery to go molecules-up on large-scale mechanistic studies to invent interventions to directly address the presence and effects of pollution. Success could be both profitable and impactful.
In the recent boom of ClimateTech, there has been an intense focus on building innovation engines to mitigate the three big sources of radiative forcing: carbon dioxide, methane and nitrous oxide. The technical challenges of management of these three gasses have increasingly actionable surface area and, specifically around CO2, rapid mobilization and innovation in funding has created hundreds of companies within just a few years. This nascent ecosystem has made huge progress (see my essays on gaps in early stage climateTech funding and a first rough draft on climateTech benchmarks), and I worry that blindspots are forming. Take the graph below as an example: It explains why CO2, CH4 and N20 are rightfully prioritized, but I also see 17+ gasses that make considerable contributions. What this graph does not show is that, on a per molecule basis, some of these “other”1 chemicals can have 100-10000x the warming potency of CO2. Importantly, this “other” category is increasing in magnitude and poorly understood in other biosphere impacts. So, generalizing beyond greenhouse effects, what about all the other industrial byproducts that haven’t yet received the same mass mobilization effort as CO2, CH4 and N2O?
The independence from policy and regulation made Negative Emissions Technologies (NETs) a perfect nucleation point for builders. Without being tied to the slow Sisyphean rocks of bureaucracy and population-scale decision making, NETs innovators have enjoyed a freedom to step in and chase scalable approaches to physical limits (e.g., toward the <$100 ton CO2 capture goal). Because of this freedom and the accessible technical challenges, carbon capture is a gateway drug2 for technologists to search for a match between their abilities and the big, meaningful problem of “Climate”3. Now, with the critical mass of funding support and growing community of activated practitioners in ClimateTech, we can explore other challenges that, in contrast to NETs, are intentionally intertwined with existing systems4. This means now is an opportune time take more technical risk, providing the contours of the chosen problem can fit existing gears of industry.
A prime first example of one such highly interconnected problem is the negative externalities of small molecule byproducts of industry, AKA pollution.
When I talk about pollution and biotech, I use the clickbait-ish phrase “Pollution is a Pharma Problem.” I’m being intentionally loose with the word “Pharma” to be broadly inclusive of the new reaches of industrial medical bioengineering5. More importantly, I’m showing respect for the enormous levers of biotech innovation around human health. My optimism is that we can discover ways to steer these billion-dollar biotech levers toward impact on planetary health.
Four interconnected subindustries
On its surface, the challenge of managing small molecule waste6 seems impossibly hard: tiny molecules in unknown states of degradation interacting in unknown mixtures with unknown biological effects in a variable timeframes in unmeasurable situations. Which slices of these dimensions are productive to access, what technologies are we lacking and how much data do we need?
The high level challenge for the biosphere is that industries will innovate and deploy novel chemicals faster than governments can discover and regulate them. Especially as we’re in the early stages of a boom era of computationally generated molecules, and in mid-late stages of regulatory incapacitation (eg, “inert” ingredients don’t need to be declared except in California), I only expect the problems caused by toxicants to get worse. Even in the most optimistic futures, we must be prepared for the biosphere’s longterm cohabitation with anthropogenic chemicals, which will mean developing methods for resilience. For example, we all have the teflon precursor “forever chemicals” in our body now:
Even though there are active government efforts, and important new policy proposals, and mature efforts for bacterial/viral diseases, it is essential to also discover free market solutions to small molecule externalities. Due to significant technological advances in biology over the past decade, the time is right to develop industries around this challenge.
I see four industrial opportunities that can be partitioned into highly synergistic verticals and together represent a TAM in the hundreds of billions:
Forensics: How might we significantly increase the scale, speed and generalizability of small molecule detection? Possible markets might be legal discovery and expertise (e.g., the $10.9BB Roundup lawsuit) and consumer exposure tracking. Projected profitability is low, impact to other businesses are high.
Remediation: How do we remove the toxin once we’ve identified the harms and the molecules? Total TAM is currently ~$100 Billion with CAGR of 9.8% (source). Environmental remediation was specifically identified in the Biden “Build Back Better” bill, with $9BB just for lead in water supply alone (link).
Neutral Alternatives: How can we accelerate the development and validation of bio-neutral alternative chemicals? Can a modern forensics pipeline that detects bad molecules also be used to develop cleaner replacement molecules? If so, are there IP licensing opportunities or other viable businesses?
Therapeutics and prophylactics: Can we build on the biotech playbook of rare, monogenic diseases to create a medical industry around mono-toxigenic diseases? The monogenic disease playbook has been played out for dozens of billion-dollar biotech companies, what is missing to bring environmental toxicology into this world? Similarly, can we re-purpose the pipelines and tools that the pharmaceutical industry has developed?
When laying out these four industries, one can imagine many possible connections between them. For each industry, I will ask some questions that could plausibly be answered by biotech today. Perhaps in a later piece I’ll articulate that gaps that explain why so few of these challenges are currently attempted by industry (let me know if you’re interested). But first, I want to give a brief sampling of the issues out there today to motivate the incredible efforts needed in the future.
A brief history of gross chemicals and human health
In 2012 I was driving on highway 101 listening to the radio and heard the writer Florence Williams as she went on NPR to explain her new book “Breasts, a Natural and Unnatural History”. I was, and still am, captivated by her story. She wanted to understand why girls as young as 9 were prematurely developing breasts, so she and her daughter sought to rid themselves of all exogenous chemicals. Even with measures such as wearing old clothes, only bathing with Dr. Bronner’s, and avoiding plastic food containers, there were chemicals in their blood that could not be removed. Furthermore, she references studies on how the composition of breast tissue makes it a concentration site for toxins. She talks about many chemicals that are now familiar to us such as Bisphenol A (BPA) and PFAS. The lingering question is: what other chemicals are in us now and what effects are they having?
In a curiosity similar to Florence Williams in 2010, Professor Edward Kolodziej in Washington in 2018 was puzzled why the Coho salmon died every time it rained. Coho Salmon are keystone species, meaning they are an essential layer of the food pyramid, risking collapse of the forest and marine ecosystems if the Coho are irretrievably lost. After two years a heroic effort of analytical chemistry (for any mass spec nerds out there, six fractionation steps!), they discovered that a tire preservative was responsible for killing juvenile fish. Even more difficult, it wasn’t even a known chemical that had been registered with the EPA that caused the damage. The tire preservative 6PPD degrades to 6PPD-quinone, which is highly toxic for just the juvenile fish. The study was published in Science, caused a big splash, but two years later, 6PPD is still irreplaceable because there are no known alternatives.
Most people think that we know what chemicals are toxic, and all we have to do is control the amount of those chemicals to make sure water quality is fine," said co-senior author Edward Kolodziej of UW. "But, in fact, animals are exposed to this giant chemical soup and we don't know what many of the chemicals in it even are." (source: NSF)
Forty-seven percent of the 86,405 chemicals registered with the United States Toxic Substances Control Act (TSCA) inventory as of June 2020 are actively manufactured, processed, or imported. Furthermore, according to the non-profit Environmental Working Group, the federal standards for safe drinking water have not been updated for 20 years (for context, that was when Snake was the only phone app). And, even if we could assume that all existing industrial chemicals were registered, as we saw in the CoHo salmon case, chemicals degrade in the natural environment, creating downstream unregulated toxic molecules to unexpected corners of the biosphere.
Here is a quick list of some the best known and studied chemicals in our environment:
Antibiotics in agriculture: The overuse of antibiotics for both industrial terrestrial farming and aquaculture has produced measurable amounts of antibiotics in critical waterways. Beyond antibiotic-resistant pathogenic bacteria, these chemicals are associated with cancer, bone marrow disease and immune dysfunction (see: the EU’s maximum residue limits and the health effects listed in the chemicals associated with fish farming ).
PFAS: The PFAS family is enormous (well known from Teflon production), containing over 5,000 different compounds with well-documented health efforts (see: the PFAS-Tox database). 97+% of Americans have PFAS in their blood and now one science team is claiming all rainwater in the US is undrinkable due to PFAS.
Fracking chemicals: One 2017 paper from Yale Med studied the carcinogenicity of 1177 water pollutants and 143 air pollutants: 55 of which were known carcinogens, 20 of which had leukemia/lymphoma risk.
Phthalates: the “plasticizer” chemicals found in beauty products, foods, mechanical oils, etc.
Organic solvents: TCE is a chemical known to directly impact the nervous system, yet is known more for its carcinogenic properties when it contaminates drinking water (source).
Concentrated metals: Heavy metals are essential for industry and unfortunately have the ability to spread, only to be re-concentrated up the biological food chain or pristine forest. Mercury can be spread over the air and rain down to concentrate in unexpected places like pristine forest. Lead is the most well known of all: “The State of Michigan considers all children in the City of Detroit to be at-risk [of lead poisoning].”
Insecticides. Organochlorine, for example, has been the most studied and, while banned in developing countries, it continues to increase in usage around the world . There have been a few exciting new biotech companies founded in the past few years beginning to address this space (eg, Greenlight Bio)
Phthalates and other EDCs in consumer goods: Phthalates are the “plasticizer” chemicals found in beauty products, foods, mechanical oils, etc. and one of the big Endocrine Disrupting Chemicals in the world today. The CDC says detectable phthalate metabolites are “widespread throughout the general population”. “EDCs can impact the endocrine system and subsequently impair the development and fertility of non-human animals and humans” and includes “ disinfection byproducts, fluorinated compounds, bisphenol A, phthalates, pesticides, and estrogens” (Gonsioroski, Mourikes, and Flaws 2020). An unexpected canary in the coal mine could be the unfortunate polar bears, which have been impacted by the hormonal waste of humans that are transported by ocean currents, creating a high rate of hermaphroditism (Nature blog, 2003).
To give a sense of how little is understood about the health effects of small molecules, consider that while herbicide glyphosate does not directly cause obesity in rats, nor their offspring, it does cause obesity in their grandchildren and great-grandchildren (who had no direct exposure). This is very strange and shows us how little we actually understand about biological systems. But by understanding the effect of harmful small molecules, it’s an optimistic possibility we could also learn to work with positive small molecules. For example, certain microbial metabolites in the gut are linked with human lifespans of over 100 years. The rapidly growing strengths of bioengineering will continue to broaden the scope of addressable problems and opportunities, it just needs the right focal points.
Fertility is one example of a humanity-scale critical problem with strong links to pollution exposures. We know that there is a net decrease in testosterone of about 50% over the past 40 years, including a 25% drop from just 2000-2016. Furthermore, studies of sex hormones have shown direct links to small molecule exposure. Phthalates, for example, have been linked to a 24-34% decrease in testosterone among young boys ages 6-12 . BPA is detectable in 92% of the US population and also associated with a significant decrease in testosterone. Malformation of penises in utero are also associated with endocrine disrupting chemicals. For an extensive overview of exposures and male reproductive health, refer to this 2018 review, ItStartsWithTheEgg.com or MillionMarker.com.
This list of chemicals and diseases is of course non-exhaustive, and I think many of us have been saturated by these headlines. So where is our sense of technological optimism and entrepreneurial energy ?
To spur conversation, I’m going to ask technical questions inside each of the four industries and rank them by how technically far away we are from them today. “Easy” means we are technically able to do it today, “hard” means we would need a concerted effort to accomplish an answer. And recall the opening two thoughts to this essay: 16% of global deaths are caused by pollution and there is a wide gap of accountability, so our goals here are to imagine futures in which the economics of pollution could be meaningfully changed.
Industry 1/4: Forensics
How might we massively increase the scale, speed and generalizability of small molecule detection?
Easy: “Are specific Chemicals A, B and C in my water? Is A, B or C in me now?” (examples: MillionMarker for consumer testing, MatterWorks for AI + Mass Spec).
Medium: “If direct detection of the molecules is either prohibitively expensive, too time sensitive or insufficiently robust, what are associated biomarkers like RNA or stable proteins that are easier to probe? Can it tell me if I was recently exposed?”
(examples: serum markers for PFAS exposure, LifeExtension.com sells a $150 urine test for 8 exposure metabolites)
Hard: “What are all the unexpected molecules in my McDonalds cheeseburger?”
(examples: one example of potentially rapid progress happening in untargeted mass spec, but the scope of the challenge is enormous)
Bonus: Can we create molecular fingerprints to pinpoint the original source of the pollutants? If fingerprints are combined with ways to rapidly discover causation of disease from a pollutant, do we create a fundamentally new legal path to holding polluters accountable?
(examples: tracing PFAS soil pollutants to the source, Phylagen’s supply chain monitoring, the $11B RoundUp lawsuit came down to proving causality, and the incredible story of Robert Bilott which became the 2019 movie Dark Waters)
Industry 2/4: Remediation
How do we remove the toxin once we’ve identified the harms and the molecules?
Easy: How do we remove chemical X from a point source?
(examples: removing the irreplaceable 6PPD-quinone from urban runoff or glyphosate from farm runoff. Epoc Enviro has an elegant PFAS filtration method, now licensed by Allonia)
Medium: Can we make a product that removes chemical X from a natural environment, rather than selling a CapEx intensive cost-plus service?
(examples: plants are metal hyperaccumulators, Gerben Stouten’s Platicacumulens microbe eats trash)
Hard: How do we get rid of PFAS from environments or organisms?
(examples: according to the Secretary of the US Navy, there are no known methods of getting PFAS out of the human body and across the food web some PFAS chemicals are biodilutive while other are bioamplified. )
Industry 3/4: Neutral Alternatives
How we declare or invent a molecule to be completely bioorthogonal?
Easy: Does known molecule X have any interaction with Druggable Protein P7?
(example: organophosphate pesticides bind to acetylcholinesterase )
Medium: Does candidate molecule X have any interaction with any druggable protein or other mechanisms of bio-concentration?
(example: the Warner Babcock Institute for Green Chemistry or the SaferMade portfolio )
Hard: Does candidate molecule X, and any degradation product of X, have any interactions with the known biosphere?
(example: virtual screening has been longstanding effort in the pharma industry, VirtualFlow as one example, but instead of screening billions of candidate drugs onto one protein, it would be one molecule and its derivatives against the addressable proteome)
Bonus: Are there first-principle criteria by which future industrial molecules could be designed in order to create minimal biological impacts?
Industry 4/4: Therapeutics
How do we heal people that have unavoidable exposures to bad chemicals?
Easy: How can I minimize damage from a known molecule with a known toxicity mechanism that causes a known disease8?
(example, bioclearance is well-studied by pharma companies and clinical pharmacology labs)
Medium: How can I rapidly and repeatably discover the molecular-scale pathogenesis of diseases caused by a mixture of one or more toxicants?
(example: exploring Parkinson’s Pathogenesis in Drosophila)
Hard: How can we build the field of toxicogenic diseases9 in the same way that rare monogenic diseases and subtyped cancers became the foundation of the the $100Billion+ precision medicine industry?
(example: gold standard datasets and tools such as the offerings from the Broad Institute or OpenTargets have been an essential resource)
Conclusion (for now)
There is obviously much more to say than the kernels planted here. The point is that there is tremendous much room for impact: beyond “just” helping us clean up our current environment by solving today’s accountability gap, building the biotechnologies to increase our resilience is a subtle but essential foundation to optimistic futures such as space travel.
There is a community we can build around the current efforts on toxicology and environmental remediation. There are practitioners who will read this and immediately see answers to these industry questions. There are knowledgable leaders who may have insights to the magnitude of gaps ahead in order to build the translational field of toxicogenic diseases. There are also clinicians that have patient populations with currently unaddressable illnesses. I’d love to talk with all of you and see new networks form around this opportunity space: if anybody wants to go deeper on any of these directions, comment below or reach out to me via Twitter with request for a follow-up piece or discussion.
And if we do nothing? I contend that government efforts are essential but alone will not be able to keep up with the rapid pace of chemical innovation from industry. The status quo path is that we will co-exist with chronic perturbations that will certainly have the most impact on today’s youth (see the image below and this EA Cause Exploration Prize). If we do nothing, the massive boom of new biotechnologies goes under-utilized on today’s narrow scope of industrially addressable problems. This could be one of the biggest and most direct opportunities for the biotech/pharma industry to achieve both positive environmental and social justice impact, and I aim to see this potential fulfilled.
Acknowledgements
Huge thanks and appreciation to all the amazing people who have discussed this with me over the past year Jenna, Josh, Ethan, Tony, Scott, Georgia, Loren, Sam, Sam, Erika, Adam, Anastasia, Milan, Tatyana, David, Daniel, Bob, James, John, Alexander, Henry, Carly, Brett, Elliot, Willy, Jenny, and many more. Special thanks also to Hanny for playing the role of friendly editor on this piece and finding many opportunities for improvement.
Historians of climate might immediately think of the CFCs which led to the Montreal Protocol in 1987. This is one of the biggest wins in Climate history, and a highlight is that when the chemical companies criticized Greenpeace for just whining about the problem, Greenpeace created a better refrigerant called Greenfreeze within months that was an enormous market success, funding the organization for decades.
To explain this reference for readers not in the US: a gateway drug is an old idea that an easily accessible drug like marijuana will suck a person into going into harder substances like heroin. In startup land, we might also say beachhead or wedge.
“Climate” in quotes because it’s such a broad word that simultaneously has much buzz but so little specificity. Still, there is a huge swell of very talented people who want to work in “Climate” so I continue to use this word but at some point I hope we improve our language.
Clean Energy is the obvious and important example, and has been well traveled for decades.
Bioengineering does also have enormous applications from past, present and future - I will cover these in another essay.
“Small molecule” here is roughly used to describe the space of non-biological materials, such as heavy metals, engineered compounds, or waste products. “Toxin” is a biological material that can be poisonous, “toxicant” is a human-made small molecule. David Wishart would call anything under 1,500 Da a metabolite.
We’d of course like to search for proteome-wide interactions, but if 90% of the proteome is undraggable (quoted from Professor Dan Nomura’s website), then we turn an already-hard problem of docking prediction etc into an intractable one. Similarly, olfactory receptor selectivity has been an exquisite mystery of biology, with potential breakthroughs happening in recent years.
The classic phrase in toxicology is “The dose makes the poison.”
There may be a better word for it, I’m all ears if you have a better suggestion.
Absolutely outstanding overview + I'm really happy to see this out in the world. I shared it with a ton of people!