As you have heard from the other speakers today, there are numerous health risks associated with global climate change. The Union of Concerned Scientists has analyzed this question and concluded that: “Rising temperatures will likely lead to increased air pollution, a longer and more intense allergy season, the spread of insect-borne diseases, more frequent and dangerous heat waves, and heavier rainstorms and flooding. All of these changes pose serious, and costly, risks to public health.”1 Global climate change is clearly under way, and human society may or may not take actions to mitigate it. From the perspective of preparing for the consequences to our species, we must be investing in science and new medical technologies for those areas of human disease we know will be impacted or increasing due to the effects of climate change. In this talk, I will discuss the role of technology as a tool to mitigate the health impacts of climate change. I will illustrate with both concrete examples using technology that is available today, and I will also speculate a bit about where new technologies can be developed to address these challenges.
We are living in a time of rapid technological change, and there are many revolutionary technologies that can be put to work solving the health challenges which are arising due to global climate change. To set the stage for some of the discussion which is to follow, let me outline some of the important technologies I see playing a role. One technology which you will see coming up again and again is that of genomics and DNA sequencing. We are living in the genome age where biology has become an information science, and this transition was driven by the invention of incredibly powerful sequencing machines. These machines are amazing tools that have dropped the cost of sequencing by orders of magnitude and increased the throughput of sequence data, which we can acquire also by orders of magnitude.2 These trends are comparable to that of Moore’s law in the semiconductor world. As a result, we now have genomes of many major organisms—not just humans but also many of the pathogens which afflict our health. We are able to rapidly sequence novel genomes as pathogens mutate and new pathogens emerge. And we are able to analyze human biology with a power that was only dreamed of a few short decades ago.
An important application of genome sequencing relates to technologies that are used to sequence the genomes and transcriptomes of single cells.3,4 This has allowed us to gain a much deeper understanding of the diversity of cell types in the human body, and also to use the response of the human immune system as a discovery tool for new therapeutics—several examples of this will be described below. We are also able to use high throughput sequence data to monitor the emergence of new pandemics and even new pathogens which have never been characterized before. These experiments can be done with all sorts of human samples: blood, saliva, biopsies, cerebrospinal fluid, and so forth. One of the most useful in my own research has been to use blood samples to study circulating cell free DNA and RNA. These are small fragments of the genome and transcriptome which provide information not only about the health of the individual but also about the microbes and infections that may be colonizing a person.
Another set of technologies, which I believe are going to be important in the battle against global warming related health crises, are electronic and computer technologies. The ability to monitor physiology through wearable or implantable devices, and to have these devices networked to the internet and cloud computing, will provide numerous new approaches to coping with the health challenges which will accompany more extreme weather events.5 For example, global climate change is expected to produce more frequent and more intense heat waves. The challenge here is that the elderly and young are disproportionately affected and often don’t realize they are dangerously dehydrated and overheated. There are many examples of fatalities due to this in recent years in the developed world; for example, during the heat wave that struck Europe in the summer of 2003, more than 70,000 people died due to overexposure. This could in principle be helped by better physiological monitoring—wearable devices such as the Fitbits and Apple Watch can have sensors and apps designed to alert individuals, their families, and caregivers that they are in a dangerous condition. These devices will take advantage of automated cell phone and internet communication to share physiological updates either with the affected individuals or those responsible for caring for them. As an extension of this, research into implanted sensors could yield new devices which are permanently part of our bodies and which don’t require separate accessories or charging.
The same emissions that cause global warming also increase levels of air pollution, which is a problem that human society already has extensive experience with and data from.6 Cities such as Los Angeles, Mexico City, Athens, and Beijing all have a history of dealing with air pollution and its health consequences, and there is by now substantial data on the effect of air pollution on human health. It is known that the increased ozone levels, which are a consequence of air pollution, end up causing increased levels of respiratory disease, exacerbate asthma, and cause cardiovascular problems. Some of the consequences of increased air pollution can be managed by reducing exposure—filters and masks will become ubiquitous, and we expect that this will motivate development of new technologies to improve air quality, particularly indoors, and to protect individuals from unhealthy air in the outdoors. There are opportunities for geo-engineering here—massive air filtration systems placed on top of buildings which scrub the air in entire neighborhoods, for example. Another option may be the construction of large domes which enclose entire towns and provide filtered air for the occupants. At the level of individual homes, one can expect that people will begin to live in sealed environments and each home will have its own air quality control and filtration system. Possibly some of these will be bio-engineered and use living organisms such as bacteria, algae, or plants which have been engineered to improve air quality.
These efforts to control exposure will help manage the consequences of increased air pollution, but it seems inevitable that levels of respiratory disease will increase and that we will see increasing populations of individuals with compromised breathing and damage to lung tissue. Therefore, there is also a need to develop new treatments for pulmonary disease. This suggests that increased investment in regenerative medicine—to understand the basic biology of lung development, the cell types, pathways, and molecules involved, and how they can be manipulated to promote repair of damaged tissue—should be a societal priority. We can imagine that advances in regenerative medicine will play a role in mitigating the effects of these diseases—for example by finding ways to reverse oxidative damage to lungs and perhaps repair cardiovascular damage, thus lowering the burden of disease due to global warming.
Asthma is an already widespread respiratory disease whose incidence and severity will increase dramatically. We will need better treatments for asthma as well as new diagnostic monitors to know when to be taking medicine, perhaps even proactively based on environment or early symptoms. These are all opportunities for the development of new bioengineered devices, new therapeutics, and better understanding of the clinical aspects of the disease.
Another direct health consequence of global warming will be a dramatic increase in environmental allergies. The Union of Concerned Scientists explains it this way: “Three main factors related to climate change fuel increases in allergens. Carbon dioxide, the heat-trapping gas that is the primary cause of our warming planet, increases the growth rate of many plants and increases the amount and potency of pollen. Rising temperatures extend the growing season and the duration of allergy season. And an extended spring season alters the amounts of blooms and fungal spores that are known to exacerbate allergy symptoms.”1 While this increase in environmental allergies is not expected to be life-threatening, it will have an enormous economic cost. Currently, it is estimated that about 60 million Americans are affected by allergic disease, making it the third leading chronic disease for the under-45 age group. The costs of allergies in the United States reach nearly $20 billion per year and result in roughly 6 million school and work days lost per year as well as 16 million doctors visits per year.7 If allergies increase ten-fold, this becomes $200 billion per year—well above the peak yearly cost of the Iraq War.
Currently we lack all but the simplest understanding of how allergies are caused. Treatment has largely been empirical and is based either on treating the symptoms or by controlled exposure to the allergens for desensitization. Therefore, it would be prudent to invest in basic research in immunology as well as in clinical studies related to allergies. There are hints of novel treatments already, which should be further explored and brought to market. One dramatic example of this is a novel biologic drug developed by the biotechnology company Regeneron. Regeneron has developed an antibody-based therapeutic against the environmental allergen cat whiskers. Allergic individuals treated with these antibodies showed a dramatic decrease in allergy symptoms and allergic response.8 These results, while the result of only a small clinical trial, provide a blueprint for a class of therapeutics aimed at treating allergies and reducing the economic cost of allergies in the world economy.
The key to expanding such a program of novel anti-allergy therapeutics is the development or discovery of antibodies against the important environmental allergens. Here we have the opportunity to apply emerging technologies such as single cell genomics to analyze the antibody-producing cells of individuals. The philosophy is that the solution lies within the disease—the very antibodies which cause allergic disease can be used to help cure it, if only they can be identified and produced in a slightly different molecular form. Kari Nadeau and I have taken this approach and developed a way to isolate the cells which produce the allergy-causing antibodies from allergic individuals.9 This has enabled my student Derek Croote to discover numerous antibodies which cause food allergies, and we are now engineering those antibodies to turn them into therapeutics which might cure allergies. While it is still quite early, we believe this provides a potential roadmap to making a broad new class of therapeutics.
Another expected consequence of global climate change is heavier rainstorms and increased flooding. The World Health Organization has found that floods can potentially increase the transmission both water-borne disease and insect vector-borne disease.10 Examples of water-borne diseases include typhoid fever, cholera, leptospirosis, and hepatitis A. These diseases all have effective vaccines, but only a small fraction of the global population is fully vaccinated. This suggests that resources be invested into a global vaccination campaign to preemptively protect against the expected increase in outbreaks. It would also be prudent to invest in the development of a new generation of vaccines which will be longer lasting, have longer shelf life, and be more broadly protective. The situation is more complicated for insect vector-borne diseases, such as malaria, dengue and dengue haemorrhagic fever, yellow fever, and West Nile Fever. Vaccines exist for only a few of these pathogens, and therefore we should invest in the development of new vaccines against this class of diseases. Many of these already present a substantial health burden on human society. For example, dengue infects 400 million people annually around the world in more than 100 different countries, and there is no particularly effective vaccine or specific antiviral therapeutic treatment. There are also challenges in diagnosing some of these diseases. For example, in the case of dengue infection, only a subset of infected individuals proceed to severe dengue. If we had diagnostics not only for dengue infection, but which had the ability to predict who was going to go on to severe dengue, we would be better able to know who should be treated in the hospital or receive intense medical attention. There are also opportunities to develop novel small molecule therapeutics to treat these diseases, especially from the perspective of blocking host (i.e. human) proteins, which the viral infections are dependent on.
As an example of how to develop new vaccines and therapeutics, I will again turn to the observation that humans who have survived an infection will often make antibodies that protect them. If only we can identify and produce those antibodies outside the body, they could be administered either as treatment or as prophylactic vaccines to protect people from the pathogen. There are some excellent examples of this in the scientific literature; one of the most dramatic is the discovery of broadly neutralizing antibodies against HIV. HIV is a pernicious virus which attacks the immune system to prevent the body from regulating it, and it also seeks to evade the immune system through constant mutation. However, some people’s bodies are able to make what are called “broadly neutralizing” antibodies, which is to say that their antibodies neutralize all the various mutant forms of HIV. Scientists have managed to clone these antibodies, which is to say that they have discovered and sequenced the gene which makes the antibody, and then have produced protein versions of the antibody which can be used as an anti-HIV vaccine or as a therapeutic to treat HIV. There has been proof of principle of these approaches using mouse models as well as non-human primates, which have been promising enough that the first human trials are now underway. There is a large vaccine trial in sub-Saharan Africa supported by the NIH currently underway, and there have been small proof-of-principle therapeutic studies with positive results.11
The HIV broadly neutralizing antibodies are the result of decades of research, and it is natural to ask if they provide any useful lesson for emerging pandemics, which might require a more rapid response. We can look to the Ebola outbreaks in recent years for an example on a more rapid time scale. In the 2018 outbreak in Congo and Central Africa, three antibody-based therapeutics were tested in the field and were shown to roughly halve the Ebola fatality rate from 68% to 32%.12 While the results are still early and much work remains to be done, this is an example of how such therapeutics can be deployed in outbreaks and on times scales substantially shorter than decades. One of the therapeutics was developed in 2014 in the space of just a couple of years—six months for development followed by a phase I clinical trial. It was then produced and shipped over a period of 21 days for the 2018 outbreak.13 This is a dramatic improvement in time scale from the development of HIV broadly neutralizing antibodies, and it seems reasonable to expect even more compression as technologies improve over time.
While there are multiple approaches to generating therapeutic antibodies, I am particularly enthusiastic about using the human immune system as the source. I discussed an example of this earlier in the context of allergy therapeutics, and a similar approach works for infectious disease. Modern single cell transcriptomics technologies continue to accelerate the field, and what was heroic in the case of HIV or Ebola a few decades ago is now becoming commonplace. As an example, a recent collaboration between my lab, Leslie Gu at the Chan Zuckerberg Biohub, and Shirit Einav at Stanford demonstrates how this approach can be used in the context of Dengue. Shirit established a patient cohort in Colombia, which was undergoing an outbreak of dengue fever. Working with colleagues at a hospital there, patients who were admitted in the local hospital with evidence of dengue infection were enrolled in the study. Their blood was sent to Stanford, where my postdoc Fabio Zanini performed single cell transcriptomic analysis of immune cells.14 We discovered clues that some of the antibodies might be connected to the response to dengue, and we cloned and expressed those antibodies. It turns out that one of the antibodies is broadly neutralizing against all four strains of dengue, with better efficacy than anything reported thus far in the literature. It is therefore a strong candidate to be used either as a therapeutic or as a vaccine.
Single cell transcriptomics of blood cells from infected patients can also be used to discover new diagnostic signals. In the case of dengue, the majority of symptomatic patients experience flu-like symptoms. Five to twenty percent of these patients progress to severe dengue, manifested by bleeding, plasma leakage, shock, organ failure, and sometimes death. Early administration of supportive care reduces mortality in patients with severe dengue, however, there are no accurate means to predict which patients will progress to severe disease. The currently utilized warning signs to identify dengue patients at risk of progressing to severe disease are based on clinical parameters that appear late in the disease course and are neither sensitive nor specific. This promotes ineffective patient triage and resource allocation and continued morbidity and mortality. Our single cell transcriptomic study with Shirit Einav described above enabled us to discover what we think might be a sensitive diagnostic tool which enables us to predict which patients will progress to severe dengue and therefore to provide them with supportive care before they become severely ill. While the patient numbers were small and more work needs to be done to understand if this can become a practical diagnostic tool, it does illustrate the power these technologies bring to the challenges of handling emerging infectious diseases.
I would now like to turn from the question of diagnosing individual patients to the larger question of how to recognize the causes of pandemics and infectious disease outbreaks that affect public health more broadly. This is an area which is ripe for technological revolution, particularly by incorporating hypothesis-free approaches based on genomic sequencing to public health surveillance. While sequencing hardware has become mature and inexpensive, the software and database tools required to make this technology useful in public health has lagged behind. As part of a collaboration between the Chan Zuckerberg Biohub and the Chan Zuckerberg Initiative, my colleague Joe DeRisi has led the development of a cloud-based software tool called IDseq, which enables anyone to compare their sequence data to the collection of all known genomes of infectious pathogens. The beauty of this approach is that you do not need a hypothesis or a preliminary diagnosis—you are testing for all possible pathogens at the same time, including those that are rare or unusual.
As an example, which shows the power of this approach, Joe led the application of IDseq to understand the causes of a meningitis outbreak in Bangladesh.15 Globally there are 10.6 million cases of meningitis and 288,000 deaths every year, and the majority of meningitis cases occur in low-and middle-income countries. At least a quarter of survivors suffer from long-term neurological consequences. In a World Health Organization-supported meningitis surveillance study in Dhaka, Bangladesh, Joe’s collaborators collected 23,140 cerebrospinal fluid (CSF) samples from patients with suspected meningitis and were able to detect a bacterial etiology in only 20% of these cases despite the use of multiple diagnostic tools including culture, serologic and antigen assays, and pathogen-specific qPCR. Such low rates of microbiological diagnosis are common in many settings globally, hampering implementation of evidence-based policy decisions for optimizing local empiric treatment protocols and disease prevention strategies. The challenges of obtaining a microbiological diagnosis may be due to a combination of multiple factors, but one of the most consequential is that meningitis is is caused by a wide variety of microbes, some of which are uncommon and lack diagnostic assays.
In analyzing 66 samples with known infectious cause, IDseq found 83% concordance with conventional testing. In 25 idiopathic cases (i.e. without known cause), IDseq identified a potential etiology in 40%, including several bacterial and viral pathogens. There were three instances of neuroinvasive Chikungunya virus (CHIKV). The CHIKV genomes were >99% identical to each other and to a Bangladeshi strain only previously recognized to cause systemic illness in 2017. Molecular testing of all 472 remaining stored CSF samples from children who presented with idiopathic meningitis in 2017at the same hospital revealed 17 additional CHIKV meningitis cases. Therefore, IDseq revealed a previously unrecognized outbreak of CHIKV caused meningitis.
Although IDseq is very powerful, it has the limitation that it is only as good as what is in the database—which is to say that it can only be used to detect known pathogens. With increasing global warming, we expect new pathogens to emerge and in particular to jump from one species to another. How do we detect those? Fortunately, the combination of sequencing technology and computation offers a solution. Mark Kowarsky in my lab led the analysis of more than 1,000 patient samples whose blood had been drawn and the circulating cell-free DNA purified and sequenced.16 He mapped all of the sequence reads to all known genomes—human, microbial, and viral—and then discarded them. He wanted to focus on what was left—the sequence reads that don’t map to anything in any known database. He then took all of those sequence reads and tried to assemble them like a jigsaw puzzle. In doing so, he discovered something amazing—the remnants of genomes from several thousand organisms, many of which appear to by new microbes and viruses whose evolutionary history is quite divergent from everything studied to date. Among the torque teno virus family, we discovered numerous new species that were quite divergent from all other related viruses which infect humans, and in fact were closer in relationship to ones which only infect non-human animals.
Mark then applied the same approach to non-human primates in an attempt to get a sense of which potential pathogens might be ready to jump species. In collaboration with Nathan Wolfe from Global Viral, we assembled and annotated non-host sequences derived from cell-free DNA from blood samples of 221 individuals from an assortment of both Great Apes (two species) and Old World Monkeys (15 species) from three wildlife refuges in the West African nation of Cameroon.17 Multiple sequences were detected from the Apicomplexa phylum, which includes the parasites Plasmodium, which causes malaria, and Babesia, which causes babesiosis. In addition, many fungi including known pathogens in the Tremellales order (such as cryptococcus) and fungal orders containing highly prevalent genera such as Candida, Cladosporium, Aureobasidium, and Saccharomycetales also had novel and divergent sequences present. The majority of viral families known to infect primates were found in the de novo assemblies including: adenoviridae, anelloviridae, hepadnaviridae, herpesviridae, parvoviridae, polyomaviridae, and retroviridae. Thirty-nine individuals across ten species were observed with hepatitis B virus, and this study provided the first sequence-based evidence that eight species in the Papionini and Cercopithecini tribes can be infected with HBV. The ability to observe high coverage of viral diseases such as HBV, while providing new lineages and infection patterns, demonstrates a benefit of applying an untargeted approach to microbiome sequencing.
I hope that these vignettes have helped to give a sense for the role technology might play in mitigating the effects of global warming on human health. While I wish we lived in a world where there was a stronger collective commitment to prevent global warming, I think it is only prudent to prepare for what might be the inevitable result of short-sighted policy decisions. There are clearly both short-term and long-term investments that can be made in basic science and technology research which could act as a hedge against the effects of global warming and prepare humans to live in quite a different world.
Stephen R. Quake is the Lee Otterson Professor of Bioengineering and professor of applied physics at Stanford University. He is also the co-president of the Chan Zuckerberg Biohub.
