1. Introduction
Climate change has immeasurable impact on our planet. These repercussions occur not only as direct effects from climate hazards such as droughts, wildfires and heatwaves, but also as cascading downstream secondary, tertiary and long-term effects. This is not a theoretical future set of consequences and dominoes that are going to fall, they are falling now.
Importantly, while we don’t always see it, many of these cascading paths lead to impacts on human health, including morbidity and mortality. In fact, it is unequivocal that climate change impacts human health. Changes in temperature, rainfall and sea levels, changes in pathogen growth, survival and virulence, and changes to human and animal interaction through encroachment, overpopulation and migration are already leading to increased incidences of zoonotic transmission.[1] In addition, although the exacerbation of transmissible disease is the most oft mentioned consequence of climate change, the epidemiology of other non-communicable diseases are also shifting dramatically – respiratory diseases, cancer, auto-immune diseases and metabolic disease to name a few.[2]
2. Drug Development Historically
Science has made tremendous strides in the understanding of biology and the molecular basis of disease, and the global biopharma industry has developed many breakthroughs that address the developed world. Yet the current approach to developing new medicines is inadequate to globally address the speed and scale of the health implications of climate change.
With our current drug development approaches, it takes on average 10-12 years to develop a single new medicine.[3] In response to an emerging threat, this timeline is unreasonable. It can also cost up to $2 billion to develop a new medicine, a significant economic hurdle.[4] Further, despite the timelines and cost, 2 billion people globally still do not have access to essential medicines,[5] and even more don’t have access to critical but non-essential medicines.
One challenge to addressing these limitations of current processes is that the drug development industry continues to use nearly century-old approaches in some cases. For example, vaccine development is currently an arduous and time-consuming process that is still done in eggs, first in one, then in many. It takes nine months to develop a vaccine, and given the rapid pace at which viruses evolve, just 40% to 60% efficacy is tolerated depending on the year.[6]
These old approaches reflect a “discovery” process. The definition of the word “discover” is to find something unexpectedly or in the course of a search. The high-tech, industrialized version of an archeological search for a valuable relic, drug discovery is fraught with serendipity, trial-and-error. As a result, to get to a viable medicine, drug developers must consider a million, even a billion, different possible drug candidates. This is a burdensome process that takes significant time and money, two things that cannot be wasted in a climate-impacted world.
3. Drug Generation, Not Drug Discovery
3.1. Programmable medicines
A new paradigm of medicine can address these shortcomings of the historic drug development process: drug generation, rather than drug discovery. With a broader and deeper understanding of biology, advanced tools to analyze biological samples and computational power to interpret biological data, designing medicines at speed and scale, not discovering them, is possible.
Programmable medicines, or medicines derived directly from an understanding of a disease or threat that can be designed and deployed deliberately, as opposed to using serendipity and chance, are the future. If drugs are intentionally, purposefully and precisely generated, the cost and time it takes to develop new medicines dramatically reduces, making medicines more affordable and scalable for the global population.
3.2. Biological Programs
In order to develop programmable medicines, the various programs that drive biology must be understood. For example, the central dogma of biology is a program. In every cell in the body, the blueprint for all of our building blocks, DNA, exists. When reading this blueprint, DNA gets converted into RNA and then RNA into proteins, the workhorses of life. This program is relatively simple, and well understood (Fig. 1).
There are many different programs in biology, and some are much more complex than the central dogma, including those inside cells and across and among cells. These are only beginning to be elucidated due to their complexity. A computer and data are needed to train algorithms to understand and use this information. Only then can better, programmable drugs, drugs that are more likely to work on the first try and drugs that are safer, be created.
4. DNA and RNA as Programmable Medicines
DNA and RNA as programmable medicines take advantage of multiple biological programs, from the central dogma of biology to programs governing our complex immune systems. Equipped with an understanding of the central dogma of biology, it is known that if mRNA is delivered into a cell, the protein that mRNA encodes will be generated. This means drug developers have the code to make virtually any building block in the human body.
Moderna, a biotechnology company founded by Flagship Pioneering, and its COVID-19 vaccine is a well-known example of programmable RNA medicines. In this vaccine, RNA encoding parts of the SARS-CoV-2 virus were delivered to cells to trigger an immune reaction. Not only was this the first achievement of its kind, but it was achieved in under 48 hours from the moment the biology of the virus was described to the moment the first prototype medicine was generated. This speed is unprecedented and made possible only through the creation of a programmable medicine.
As the direct and indirect effects of climate change impact zoonotic transmission, programmable medicines will become more critical tools in the fight for protection.
5. Proteins as Programmable Medicines
Proteins are the building blocks of life. Pharmaceutical companies have harnessed proteins in the form of antibodies, which are natural molecules of the immune system, and turned them into medicines. While these medicines are crucial tools in the defense from pathogens, creating antibody therapeutics is historically an arduous and timing-consuming trial-and-error process.
Generate:Biomedicines, a Flagship Pioneering company, was founded to address this hurdle by leveraging artificial intelligence. Using the vast compendium of information scientists have gathered about protein sequences and their respective structures and functions, Generate has trained an artificial intelligence algorithm to learn the rules connecting the language of DNA to the language of protein structure and function. As a result, the computer can traverse the central dogma of biology between DNA and protein.
Armed with this capability, Generate can now develop a drug of interest by giving the computer a prompt. This is analogous to how large language models can go from English to Italian and back, or can create a paragraph out of a prompt. As a result, Generate has been able to shrink the paradigm of drug discovery for antibodies from on average 30-42 months down to 8-12 months, and can continue to get faster. Further, the candidates produced have a higher probability of success because they were programmed for a specific function (Fig. 2). Generate applied its model to more than 50 top industry targets, including a portion of the SARS-CoV-2 virus, in just 3 months.
Figure 2. Industry approach to therapeutic protein development (top) versus Generate:Biomedicines’ approach (bottom).
New technologies such as Generate’s allow for the design of better medicines faster, a necessity in the fight against the health consequences of climate change.
6. Small Molecules as Programmable Medicines
Small molecules are attractive as medicines in the age of climate change for many reasons, including the fact that they can be taken as oral pills, making them easy to deliver and scale. Programmable small molecules are therefore critical for increasing accessibility to essential medicines.
However, making small molecules programmable is no small feat. Cellarity, a Flagship Pioneering company, was founded to devise a computational system to understand cellular biology and decode it, thus elucidating the multidimensional changes that are occurring in health and disease. From there, artificial intelligence can propose the small molecules that are most likely to reverse cellular changes that occur in disease.
One example is in chronic obstructive pulmonary disease (COPD), a disease with no cure. There are clear differences between healthy and diseased cells, but a deep understanding of the multidimensional cellular changes is missing. Cellarity has encoded the molecular biology underpinning the health to disease transition and created digital maps of these changes. With these data, a network emerges from the platform outlining the multidimensional changes that are happening in disease, and finally, suggested small molecules that are likely to drive cells back towards health. In this case, the platform suggested three new potential medicines that had never been used before in the COPD setting (Fig. 3).
Figure 3. Cellarity map demonstrating differences between healthy and diseased COPD tissue (top) and three new potential medicines (bottom).
This approach is applicable to a range of diseases, anywhere cellular dysfunction is known to underly an illness, and will be a paradigm shifting way of designing and discovering drugs in a world where global access to essential medicines is of utmost importance.
7. Conclusion
Programmable medicines are here, and they represent an important solution to the health challenges that result from climate change. There is now technology to start revealing new biology, decoding molecular changes and using these insights to generate drugs as opposed to serendipitously discovering them. However, this is just the beginning. The last important step is deploying these medicines to people across the globe. Many pieces need to come together to take advantage of these technological revolutions.
Public-private partnerships are crucial. The work that allowed the rapid creation, testing, manufacturing and deployment of the COVID-19 vaccine could not have happened without a coordinated, multi-institutional, multi-disciplinary effort. Collapsing the time to detect the virus, sequence it, and make the first prototype through work similar to that described above is only the first step. Clinical testing and deployment of a medicine is another. It typically takes 73 months to deploy a new vaccine. However, with Operation Warp Speed that timeline was significantly compressed. This was a monumental effort, taking scientists, corporations, small companies, big companies, manufacturing companies, governments and global organizations to collaborate, align, speak different languages and more (Fig. 4).
Figure 4. Standard timelines (top) versus Operation Warp Speed timelines (bottom).[8]
It is now clear that efforts such as these are possible. The key now, however, is not to forget them and go back to old ways once threats are gone. This is what it’s going to take to address emerging health threats in the future, but as the theme and spirit of the conference demonstrated, to also develop and deploy innovation to tackle climate change.
8. References
- Mora, C., McKenzie, T., Gaw, I.M. et al. (2022). Over half of known human pathogenic diseases can be aggravated by climate change. Nat. Clim. Chang, 12, 869-875.
- World Health Organization. “Climate Change.” World Health Organization, 12 Oct. 2023, www.who.int/news-room/fact-sheets/detail/climate-change-and-health
- Agrawal, Gaurav, et al. “Fast to first-in-human: Getting new medicines to patients more quickly.” McKinsey & Company, 10 Feb. 2023, www.mckinsey.com/industries/life-sciences/our-insights/fast-to-first-in-human-getting-new-medicines-to-patients-more-quickly
- Congressional Budget Office. “Research and Development in the Pharmaceutical Industry.” US Congressional Budget Office, 8 Apr. 2021, www.cbo.gov/publication/57025
- Chattu, V.K., Singh, B., Pattanshetty, S., & Reddy, S. (2023). Access to medicines through global health diplomacy. Health promotion perspectives, 13(1), 40-46.
- Centers for Disease Control and Prevention. “Vaccine Effectiveness: How Well Do the Flu Vaccines Work?” Centers for Disease Control and Prevention, 8 Feb. 2023, www.cdc.gov/flu/vaccines-work/vaccineeffect.htm
- National Human Genome Research Institute. “Translation.” National Human Genome Research Institute, 3 July 2024, https://www.genome.gov/genetics-glossary/Translation
- U.S. Department of Defense. “Coronavirus: DOD Response.” U.S. Department of Defense, https://media.defense.gov/2020/Aug/13/2002476369/-1/-1/0/200813-D-ZZ999-100.JPG