#3 The Compound Eye
Securitsation of Climate Change, AI joins search for new antibiotics, Stem cell therapy for Type-I diabetes
Welcome old and new subscribers. This is the new version of the health and life-science policy newsletter started by Shambhavi Naik. We have new contributors on board. They are Priyal Lyncia D’Almeida, Harshit Kukreja, and Ruturaj Gowaikar. We have expanded our coverage to include Health systems and climate & environmental issues .
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Securitisation of Climate Change
-Ruturaj Gowaikar @RuturajGowaikar
What happened at the UN Security Council?
India recently voted against an interesting draft resolution at the Security council of the United Nations (the body of the UN charged with ensuring international peace and security). This draft resolution sought to put climate change at the centre of issues related to international conflict at the UN. Ireland and Niger were the two countries that introduced the draft while it was co-authored by 113 countries ! However, this draft resolution failed because Russia- a veto bearing member voted against it. China too, voted against this draft resolution.
India’s justification for voting against this draft was the flawed composition of the UN Security Council that might result in unilateral solutions towards climate change mitigation. The Security Council has permanent members with veto powers and no representations from developing countries. As climate change is a global issue, developing countries should be part of the solutions to deal with the effects of climate change.
The resolution failed due to one of the very features of the Security Council that was objected to by India, China, and Russia i.e. unilateral powers in the hands of permanent members. This draft was however the only second such attempt to formally include climate change in discussions related to international conflict and security. So it is interesting to look at some of the points this document acknowledged and some action items it sought to include.
What’s in the draft document?
The draft starts with highlighting the fact that the UN General Assembly had passed a resolution 63/281 in 2009 titled ‘Climate change and its possible security implications’. This was arguably the first formal attempt to link climate change and global security. Ever since that, the Security Council has repeatedly stressed the UN, regional organisations, and member states to consider the security implications of climate change in affected countries/regions like Lake Chad Basin, Somalia, Darfur, South Sudan, Mali, Democratic Republic of Congo, and Western and Central Africa, Cyprus and Iraq. But these discussions have been in a sporadic, ad hoc manner.
The draft then goes on to highlight the fact that small island nations face an existential threat due to climate change related rise in sea levels and higher frequency of extreme weather events. That the Security Council must encourage involvement of regional organisations and the scientific community with local expertise and promote open data sharing when it comes to data on climate change.
The draft also recalls that the Security Council had stressed UN peacekeeping missions to be aware of the environmental impact of their missions. It also recalled the need to include personnel trained in understanding security implications of climate change in these missions. These can be modelled on the United Nations Assistance Mission in Somalia (UNSOM) that has a dedicated capacity for climate change.
After acknowledging and rehashing some of the earlier discussions and observations the draft then lists action items. Some of which have been listed below.
Action items:-
take into consideration comprehensive conflict analysis and conflict management strategies incorporating information on the security implications of climate change.
integrate climate-related security risk as a central component into comprehensive conflict-prevention strategies of the United Nations to contribute.
the Secretary-General to submit a report on the security implications for relevant country or region-specific contexts on the Council’s agenda of the adverse effects of climate change.
member States and the scientific community and the development of online-platforms for supporting real-time access to climate related data and information products.
encourage relevant special political missions, peacekeeping operations and United Nations country teams, to incorporate, within their existing mandates, the security implications of climate change in their assessment, analysis and activities to prevent relapse into conflict.
Perhaps the well meaning effort was doomed from the beginning. The presence of a veto vote in the Security Council, and absence of India and China as co-authors undermined the draft. The statement of the representative of Niger best summarises this, “the force of veto can block the text but cannot hide the reality”.
Helping Humanity Survive: Artificial Intelligence finding new Antimicrobials
-Harshit Kukreja @harshitk43
Antibiotic resistance. We have all been hearing about it. About how our continuous improper usage of antibiotics will lead to an end of their effectiveness. This is only partly true. The whole truth is even scarier. Even if we show perfect Antibiotic Stewardship (follow evidence-based prescribing, in order to stem antibiotic overuse, and thus antimicrobial resistance.), we would still run out of antibiotics in some decades. Newer antibiotics are being created at an insufficient speed, newer classes are being discovered at an even dismal rate.
Two major breakthroughs have happened which are helping in speeding up this process.
MIT used neural networks to identify newer antibiotics that were dissimilar in structure to existing antibiotics. They named the forerunner "Halicin", after the fictional artificial intelligence(AI) system from “2001: A Space Odyssey,”. Halicin has been previously investigated as a Diabetes drug. In the lab, it killed many pathogens which are proving to be increasingly problematic. It worked against drug-resistant pathogens like Clostridium difficile, Acinetobacter baumannii, and Mycobacterium tuberculosis. Giving us new weapons to fight these nasty, hard to treat infections. Researchers used machine learning algorithms and looked out for potential candidates in preexisting chemical libraries. They also hope that AI can be used to create entirely new drugs.
First, the researchers designed their model to look for chemical features that make molecules effective at killing E. coli. They trained the model on about 2,500 molecules, with diverse structures and a wide range of bioactivities. After Training the model, they tested on Broad Institute’s Drug Repurposing Hub (a library of about 6,000 compounds). The model picked out Halicin and they tested it on a different model to rule out toxicity to human cells. Initially, Halicin was so novel that the researchers could not understand how it works. Afterwards, they found out Halicin works by disturbing electrochemical gradients across the organism cell membrane. The organism can have great difficulty in developing resistance to this mechanism.
The University of Pennsylvania used AI to look up for human peptides (fragments of proteins) that can kill pathogens. The AI gobbled up the entire human proteome and gave a preliminary list of 43,000 peptides. They searched and found 2,603 antibiotic candidates of which the team tested, the most promising 55, and a majority of them eliminated bacteria. They included pathogens such as Pseudomonas aeruginosa (MIT's halicin doesn't work against this) , Acinetobacter baumannii, and Staphylococcus aureus. A lot of these peptides seemed unrelated to our immune system and were from all over the body. A few peptides stood out, including SCUB1-SKE25 and SCUB3-MLP22, which they further tested. They compared the SCUBs to an already existing antimicrobial polymyxin B and found that after 30 days of exposure, the bacteria could tolerate doses of polymyxin B that were 256 times higher than the original amount, but the SCUBs remained effective at the same dose. Although they point out this doesn't mean that the bacteria will never develop resistance to the SCUBs.
Why is it important?
Researchers try to find antimicrobials among organisms that live in the soil and the sea. Almost all our existing antibiotics have been found this way or are derived from a molecule that was found this way. This method is not yielding a lot of strong candidates for quite some time. Even if we have perfect antibiotic stewardship, antibiotic resistance will eventually develop. We have been using decades old therapies for diseases such as Tuberculosis. These drugs have remained largely the same with the same adverse effects since the last 40 years. We have to find newer molecules to treat them better. Then there is the case of newer "Superbugs" which are resistant to existing antimicrobials. We have to be ready for the possibility of a future pandemic caused by a pathogen that doesn't respond to our existing drugs.
AI can also help us in paving the way for antimicrobials that are targeted and individualized to the patient. It is also economically unfeasible to search for newer molecules in our existing libraries by our conventional methods.
I hope that AI can help us get better therapeutics faster.
Read More
1. Stokes, Jonathan M., et al. "A deep learning approach to antibiotic discovery." Cell 180.4 (2020): 688-702.
2. Torres, Marcelo DT, et al. "Mining for encrypted peptide antibiotics in the human proteome." Nature Biomedical Engineering (2021): 1-9.
Stem-Cell derived cell replacement therapy for Type-I Diabetes
-Priyal Lyncia D’Almeida @LynciaPriyal
Interim findings from a multicenter clinical trial show that the engrafted cells produce insulin in type 1 diabetic patients. The implants which consisted of Pancreatic Endoderm Cells (PECs), and their safety, tolerability, and effectiveness were evaluated in 26 subjects. Pancreatic Endoderm Cells (PECs) were generated from Human Pluripotent Stem Cells. The study was published in Cell Stem Cell and Cell Reports Medicine on December 2nd. This latest research on using the PSC in diabetic patients did not show a significant change in the effect of diabetes, however, this work will be remembered as a watershed moment in the area of human PSC-derived cell replacement treatments since it was one of the first to demonstrate cell survival and functioning one year after transplantation.
Type-1 Diabetes is defined by the loss of Islets of Langerhans which are the insulin-secreting cells of the body. This ultimately results in excessive levels of glucose in the body. It continues to be one of the most life-altering and oftentimes life-threatening diseases despite the discovery of insulin hormone 100 years ago. Treatment with the insulin hormone reduces but doesn’t completely normalise glucose concentrations. Furthermore, current insulin delivery systems can be cumbersome to wear for extended periods of time, occasionally fail, and frequently result in long-term complications. Islet Replacement Therapy could be a solution since it brings back the production of insulin in the body. However, given the scarcity of donor organs, this solution is not extensively used. All these difficulties highlight the importance of having an alternate supply of insulin-producing cells that could secrete insulin abundantly.
The use of human Pluripotent Stem Cells has become one of the most feasible therapeutic alternatives for the generation of insulin-producing cells. In 2006, researchers at Novocell (now ViaCyte) differentiated human embryonic stem cells into immature pancreatic endoderm cells. This step-by-step protocol for altering the critical signaling pathways was inspired by pancreatic embryonic development. Studies following this showed that when these immature endoderm cells were transplanted in animal models, they were able to mature further and become fully functional. Clinical studies were then started based on these results.
Two different groups report the findings from Phase I/II clinical trials. In both these trials “Pancreatic Endoderm Cells (PECs) were implanted in non-immunoprotective microencapsulation devices” in patients diagnosed with type-I Diabetes Mellitus. The study led by Timothy Kiefer, published in Cell Stem Cell showed that the implants were “very well tolerated” and showed no teratoma formation. There also weren’t any graft-related side effects. Pancreatic Endoderm Cells (PECs) from ViaCyte developed into mature cells that responded to glucose and also secreted insulin in 26 weeks after implantation. The patients were followed-up for over an year and they found that “patients had 20% reduced insulin requirements, and spent 13% more time in the target blood glucose range”.
The study led by Howard Foyt, published in Cell Reports Medicine showed that “engraftment and insulin expression in 63% of devices explanted from trial subjects aroun3 3 to 13 months after implantation”. It took 6 to 9 months from the time of implantation for insulin secreting cells to gradually increase.
Both these studies showed that there was high vasculature in the grafts and the cells in the device may live up to 59 weeks following implantation. When the grafts were analysed, they showed that the main islet cells were present. The study also showed that the implants were safe and the only side effects observed in the subjects were due to the immunosuppressive agents. This underlines that the long-term use of these drugs is a key barrier for the broader adoption of these types of cell replacement therapies. However, there are many questions that are yet to be answered. Some of these include the site of transplantation and the stage of development at which these cells are most suitable for implantation. The safety and efficacy of these implants should also be determined for a longer period of time. Another question is to understand if we can do away with the immunosuppressive treatment. The groups are currently working on these questions and we will hopefully have some positive answers in the near future.
The road to the widespread use of stem-cell derived islet replacement treatment is going to be long and torturous. However, with studies like these finally being initiated at the clinical trial stage, a new age for stem-cell based clinical therapies for diabetes has finally begun.