https://www.metaculus.com/notebooks/8701/the-path-to-controlling-cancer/ Treating cancer is a battle against exponential growth of mutating cells, so even breakthrough drugs may offer only incremental increases in survival time before residual tumors rebound. But as we learn more about the fundamental mechanisms of cancer, we can target those processes more directly. When will people diagnosed with the most lethal cancers more often than not survive for years? I will examine progress in cancer treatment and speculate on the path toward managing intractable cancer types. Cancer’s complexity Why are several-year survival rates the currency of progress in fighting cancer? It is easy to wonder, especially if you have a personal connection to cancer, why we keep seeing breakthroughs that result in a small bump in survival times rather than cures. In short, cancer cells are human cells and they evolve. It is easy to kill cancer cells, but difficult to kill them without destroying the patient’s body. And it is extremely difficult to kill every one of them before they evolve again. Most mutations either have no effect or they kill the cell and therefore self-correct. Even when mutations self-perpetuate against all odds, the body has many defenses against them. The chances of a combination of mutations evading all this is vanishingly small, but there are trillions of opportunities for it to happen in the body. By the time it is diagnosed, a tumor has already bested a solid wall of defenses. That means there is no easy fix for cancer, and a variety of treatments are used—primarily different types of surgery, radiotherapy, and chemotherapy. The relative importance of each of these will continue to evolve. Predicting survival rates

https://www.metaculus.com/notebooks/8702/the-promise-and-impact-of-the-next-generation-of-weight-loss-drugs/ Obesity is a burden on individuals and on society, but it has historically been hard to treat. Until recently, weight loss approaches based on diet/lifestyle and drugs struggled to produce safe and sustainable weight loss of greater than 5% of body weight on average. That is changing with the development of highly effective, and apparently safe, new weight loss drugs. Which drugs will make it to patients, when will they arrive, who will have access to them, and how will they impact public health? Obesity is common and has historically been hard to treat Forty-three percent of US adults have obesity, and this number has continued to increase over the last four decades, despite the fact that two-thirds of this group attempts weight loss each year. Although US obesity rates are higher than most other countries, obesity is common in the majority of wealthy countries and its prevalence is increasing nearly everywhere.

https://www.metaculus.com/notebooks/9191/methods-for-solving-protein-structures/ Proteins are complex molecules that comprise the bulk of functional parts of living things. They are encoded in DNA and RNA as genes. By sequencing DNA, or sometimes even the proteins themselves, we can learn the amino acid sequence that makes up a protein. But the way chemical strands fold into the correct 3D shape to form a functional protein is hard to predict. And it’s also often difficult to observe the structure of a protein directly, as they are small enough that the important details involve the positions of individual atoms. Nevertheless, there has been much effort to understand the structures of proteins in humans and other organisms. The structures can explain why a gene and the protein it encodes is essential, why a particular mutation causes cancer, or which drug molecules can fit in a protein pocket to alter the protein’s activity. In short, we can learn how living things work (or don't work) and how we can intervene. There has been an impressive diversity of approaches for predicting protein structures. For example, over the last decade I’ve been intrigued by Foldit, a computer game used to crowdsource human problem solving to find protein structures that best satisfy realistic chemical constraints. Of course, many techniques beyond human intuition are used for prediction too.

https://www.metaculus.com/notebooks/8739/population-crashes-the-deadliest-events-in-history/ Throughout history, for most of the time, world population has been growing, with the rate of that growth also increasing along with the transitions between the foraging era, the farming era, and the industrial era. While declines in the population of specific regions or countries have been more commonplace, declines in the overall world population have been quite rare and haven't lasted very long. The two main causes of such occasional reversals in the overall trend of growth have been pandemics and wars, in that order. While both the data about historical world population and the death tolls of various pandemics and wars are uncertain, what we do know is sufficient to at least give us a sense of the order of magnitude of the worst population crashes in history. Shifting focus from the past to the future, many of the concerns about existential risk have a natural weaker counterpart in the form of concerns about population crashes which are not large enough to tip the species over the precipice of extinction. Since humans have never actually gone extinct or come anywhere close to it during or after the agricultural era, the only base rate information we have comes from the history of global population declines. It's therefore worth looking over the biggest cases to understand their causes along with their magnitudes.

https://www.metaculus.com/notebooks/8807/reducing-nuclear-risk-through-improved-us-china-relations/ Heightened geopolitical tensions can increase the risk of war, and when tensions between nuclear powers deteriorate the risk of nuclear war can increase. One such relationship facing heightened tensions is between the United States and China. This is particularly concerning as China has recently increased its nuclear stockpile and shown increased aggression toward neighboring states. This essay examines the risk of nuclear war between the US and China and offers possible means of lowering that risk. Background China's nuclear stockpile growth has been notable, increasing by 60 warheads from 2019 to 2020, the largest recent increase of any nuclear capable state (see the figure below from the Federation of American Scientists (FAS), US and Russia not shown).

https://www.metaculus.com/notebooks/10685/malaria-and-the-historic-rtss-vaccine/ The following essay was contributed by public health researcher Jon Servello.   This essay makes extensive use of abbreviations. The list can be found here. Malaria caused 627,000 deaths in 2020, largely among children under five years of age in sub-Saharan Africa. Interventions aimed at preventative treatment could save a considerable number of lives, bring about long-term economic benefits to countries with endemic malaria, and yield substantial benefits to humanity as a whole.  After decades of varied success in vaccine development, a four-dose regimen of RTS,S/AS01 (brand name Mosquirix) showed promising initial results in preventing clinical disease from Plasmodium falciparum at 11 trial sites across west and central Africa, though this quickly declined to an average of 25.9% efficacy in the 6 to 12 week old age range, and 36.3% in the 5 to 17 month range. The European Medicines Agency licensed the vaccine in 2015, and RTS,S/AS01 is being rolled out via the Malaria Vaccine Implementation Program (MVIP) by the World Health Organization in Ghana, Malawi, and Kenya.

https://www.metaculus.com/notebooks/8938/solar-power-current-challenges-encouraging-progress/ The world is hugely reliant on fossil fuels. Despite impressive progress in the development of renewable energy, still about 85% of the world’s energy comes from oil, gas, and coal. The progress in recent years has meant that the worst-case climate outcomes are now unlikely. But we are still on course for around 3°C of warming above pre-industrial levels, according to climate models, unless our direction changes further. Climate policy has a huge part to play in improving that situation, and agreements made at COP26 and other international forums can alter our course. But much of the most important change has been down to improvements in technology.

https://www.metaculus.com/notebooks/9247/polygenic-selection-of-embryos/ In vitro fertilization (IVF) is a fertilization procedure in which ova are removed from a woman and combined with sperm in a laboratory culture, with the resulting embryo then implanted in the woman’s or a surrogate mother's uterus. This assistive reproductive technology has been used successfully since 1978, and its use has increased over time, owing in part to women choosing to bear children later in their lives.  Often, combining sperm with extracted ova results in multiple viable embryos. For many years, doctors have been able to perform diagnostic screening tests to check the embryos for chromosomal abnormalities like Down syndrome and gene defects like Tay-Sachs, allowing them to select and implant the healthiest embryo.

https://www.metaculus.com/notebooks/10188/biosecurity-vulnerabilities-of-american-food-supply/ In the early summer of 1968, farmers in Louisiana noticed small, elongated brown lesions running down green leaves of corn. These plants quickly died or experienced extensive rot that rendered the vegetable inedible. By 1970, these symptoms could be seen on acre after acre of corn from Florida to North Dakota. The disease soon had a name: southern corn leaf blight (SCLB). The fungal pathogen that caused SCLB, although virulent, could only infect a specific hybrid of corn. This hybrid, which was bred to develop a more efficient ear, was one of the most planted seeds in the country at the time. Once the cause of the vulnerability was discovered, seed companies simply switched hybrids. By 1972, the American corn market rebounded—although not before suffering major economic losses. The world is now more cognizant of catastrophic biological risk. However, the focus is mainly on direct impacts to human health. The 1970 SCLB epidemic (technically termed epiphytotic) is a prime example of a fast moving plant disease that can inflict sudden and outsized damage to the agricultural industry. Is there significant biorisk to America’s food production and supply? In light of increasing food demand for a growing population and the easy conveyance of biological threats via global trade/travel, let’s explore potential biosecurity vulnerabilities in America’s agricultural industry and discuss possible solutions to mitigate these vulnerabilities.

https://www.metaculus.com/notebooks/11200/war-of-attrition-updated-endgame-forecasts-for-the-ukraine-russia-conflict/ Robert de Neufville is a superforecaster and former Director of Communications of the Global Catastrophic Risk Institute. He writes and forecasts at Telling the Future. Russia appears to have counted on a quick, decisive victory in Ukraine. Its goal was to quickly take Kyiv and other key targets, kill or capture Zelensky, and install a new regime friendly to Russia. If Russia could achieve its objectives within the first few days of the war—so that the conflict was resolved almost as soon as it began—the US and Europe would be unable to unify behind severe sanctions.