2021 may not have been the abrupt shock to the system that was 2020, but it still hasn’t been easy. Many hoped that vaccines against COVID-19 might return the world to a state of normality, but unfortunately that has not happened and the threat of new variants continues to loom. Nevertheless, science continues onward. This year we have witnessed the progression of the technologies we covered last year, as well as the emergence of some exciting new ideas.
Gene therapy has been brought to the forefront of our minds thanks to the ground-breaking vaccines which over half of the planet has now received, and researchers continue to find innovative ways of applying this technology to treat disease. Machine learning is becoming increasingly integrated into medicine and continues to help solve highly complex problems like predicting the three-dimensional structure of proteins. Now, thanks to the increasing availability of wearable health monitors and online health-tracking services, it’s easier than ever for people to take their health into their own hands.
Last year we listed broad categories of innovations (like machine learning as a whole), but we thought we’d try to get a little more specific this time around. What follows is a summary of the top 10 innovations and companies tackling ageing that caught our eye this year.
Technology: Biological Age Tracking
Company: The Dog Ageing Project
We don’t just want to live longer ourselves – we want our animal companions to live longer as well. While dogs might age much faster than humans, they share many of the same age-related diseases, they’re genetically diverse, and they live in the same environments as us. This means there’s a lot to be gained from studying how genes, lifestyle and environment influence canine ageing. What’s more, there are about 90 million pet dogs to recruit from in the United States alone, each with their own personal human caregiver.
The dog ageing project allows owners to nominate their dog and become a citizen scientist. Through surveys, genetic samples that the owners will collect, and through reports of the dogs’ performance on special tasks, the project aims to collect a wealth of data that will help accelerate medical breakthroughs benefitting both dogs and humans.
Technology: Thermogenic compounds
Company: Equator Therapuetics
Clinical trials/research article links: https://doi.org/10.1038/s41586-019-1400-3
We all know that in order to lose weight, we have to eat less and exercise more so that we reach an energy deficit (utilising more calories than we consume). Yet for many people – especially those who are already overweight – this strategy just doesn’t seem to work. That’s because there’s a third factor that influences someone’s net calorie consumption each day: their metabolism. The rate at which a person’s body consumes calories to sustain essential cellular process and to produce heat can vary depending on what they eat, and may be disrupted in metabolic disorders.
Equator Therapuetics are seeking to treat metabolic disorders by harnessing the body’s natural heat production, or thermogenesis. Mitochondria, the tiny power plants within our cells, consume food calories in order to generate electrical charge. This charge can be used to power the production of ATP, the cell’s universal fuel, or it can be released as an electrical current that allows a mitochondrion to generate heat instead of ATP. Equator Therapuetics have been working to identify and study the proteins within the mitochondria that are responsible for this electrical current. This has lead them to identify ‘an unprecedented number of thermogenic compounds’ which could one day be used to help people lose weight, reverse metabolic disease and perhaps even slow ageing by keeping mitochondria healthy. They are now in the process of recording the electrical currents produced by each of these compounds to identify the safest and most selective candidates.
Company: Excision Biotherapeutics
Clinical trials/research article links: https://doi.org/10.1038/s41467-020-19821-7
CRISPR Cas9 technology has brought about a gene editing revolution, allowing scientists to cut, delete and replace desired segments of genetic code at will. This technology continues to be built upon and improved, and every year researchers are developing new and innovative ways to utilise it. CRISPR has the potential to treat genetic diseases by deleting or repairing the causative DNA sequences in diseased cells. Excision Biotherapeutics is exploring a different application of CRISPR – to attack the DNA of deadly viruses like HIV in order to prevent them from replicating.
When an HIV virus infects a human CD4 T cell, it copies its RNA genome into a DNA strand, which is then integrated into the host cell’s own DNA. This viral DNA can remain dormant for years, which makes HIV impossible to fully eliminate through conventional antiviral strategies. However, CRISPR technology has the ability to recognise these viral sequences and cut out essential segments, meaning that it cannot be used to produce new viruses. Excision’s approach uses two guide RNAs (the sequences that tell the genetic scissors where to cut) to recognise and remove large sections of viral DNA, which minimises the chance of the virus mutating to escape the attack.
This year, the first ever clinical trial for CRISPR gene editing as a treatment for HIV was approved following promising animal studies. Excision’s treatment, EBT-101, delivers CRISPR technology via an adeno-associated virus in a one time dose that could potentially become the first functional cure for chronic HIV infection. HIV is not the only target in sight: Excision is also developing similar CRISPR-based therapies for herpes simplex virus, hepatitis B and JC virus.
Technology: Psychedelic drugs
50 years ago, the classical psychedelics psilocybin, mescaline and d-lysergic acid diethylamide (LSD) were being used in psychiatry for forms of depression, anxiety and addictions that were particularly resistant to treatment. Research at the time suggested that these psychedelics were helpful for some people when used in a controlled manner. Unfortunately, this research was of poor quality when compared to what is required today, and changing social and legal stances on these drugs resulted in the cessation of research without a clear answer as to whether or not psychedelic therapy was truly safe and effective.
Since the year 2000, scientific interest in the possible ability of psychedelics to improve mental health has been steadily growing. Psychedelics work by stimulating the serotonin system (involved in regulating mood and anxiety) in an unusual way that shares similarities with established treatments for depression. Many people report beneficial effects after taking psychedelics in a controlled medical environment after all conventional therapies have failed, and a renaissance in psychedelic therapy research is now taking place. For psilocybin alone, the active compound within magic mushrooms, there are nearly 50 recruiting or active NIH trials for conditions ranging from anxiety and depression to Parkinsons Disease and anorexia nervosa.
Mosquirix (also called RTS,S) is far from the most effective malaria vaccine we could hope for. It prevents only around 30% of cases in children under 5, requires up to 4 doses, and its protection fades after a few months. Despite this, its approval was still one of the most ground-breaking developments this year. Malaria is the world’s third deadliest infectious disease, killing upwards of 400 000 people a year, most of them children under 5 in sub-Saharan Africa. Malaria is also the only parasite against which a vaccine has been approved – parasites are much more complex than viruses or bacteria and pose unique challenges for vaccine development.
Mosquirix has been in development for nearly 40 years. It is made from part of a protein from the parasite bound to part of a second protein from the hepatitis B virus, which helps the immune system recognise the malaria protein. Modelling suggests that the lives of 23 000 children could be saved every year if all children received the vaccine in the highest-incidence countries.
Technology: mRNA, epigenetic reprogramming
From the Greek Epi, meaning ‘near’ or ‘upon’, the epigenome is the information that your cells have in addition to your DNA code. The epigenome consists of chemical compounds that do not change the DNA sequence but still affect gene activity. These chemical modifications are known as epigenetic alterations and are important in determining which genes are switched on or off. Throughout life, the distribution of these modifications can change, which can lead to important genes being turned off or rendered overactive. This is called epigenetic ageing, and is a problem for the correct functioning of our cells.
Reversing epigenetic ageing in the lab is actually quite easy: by delivering mRNA molecules that encode transcription factors (molecules that control gene expression), a cell can be reprogrammed into a pluripotent stem cell – an unspecialised cell that is capable of giving rise to several different cell types. This reprogramming results in most epigenetic changes being erased, effectively resetting the cell to a youthful state. It is thanks to this ability of cells to reset themselves that two 30 year-olds won’t produce a baby with a biological age of 30. Unfortunately, we can’t use this kind of reprogramming to reverse epigenetic ageing in humans, as this would cause our cells to lose their identity. For example, the specialised cells in our muscles that allow them to contract would go back to being muscle stem cells and would no longer be able to function.
Turn Biotechnologies’ ERA platform is an ambitious project to reverse epigenetic ageing by applying epigenetic reprogramming in a limited and carefully controlled way. mRNA is used to carefully pulse cells with transcription factors to gradually move the epigenome towards a more youthful state. Different transcription factors can be swapped in and out to tailor the treatment to the targeted tissue. Turn is currently using EPA to develop treatments aimed at rejuvenating skin, muscle, cartilage and ocular tissue, and most of these treatments are now at the animal research stage.
Technology: Oncolytic virus therapy
Cancer is a ‘smart’ disease – it’s made up of the patient’s own cells, and cancer cells mutate very rapidly. This means that tumours can evolve ways of aiding their own survival, such as by supressing immune cells or causing nearby healthy cells to release growth-promoting molecules. To combat such a disease, we need ‘smart’ treatments – treatments that are able to recognise, target and destroy the diseased cells while harming healthy cells as little as possible. Nature may already have given us a solution to this problem in the form of oncolytic viruses. Oncolytic viruses are able to target and attack tumour cells, and can be engineered to reduce their ability to infect healthy cells. Cancers often have weakened antiviral defences, and viruses can also cause infected cancer cells to explode, releasing antigens that stimulate the immune system. Viruses can even be modified to include genes coding for desired molecules, such as immune-boosting signalling molecules or antibodies, which will then be produced by infected cells.
Theolytics is a company seeking to propel the oncolytic viral therapy field forward using its ‘advanced bioselection and screening systems’ to rapidly identify promising viruses from an extensive library. This means they can rapidly identify clinic-ready and therapeutically effective oncolytic viruses that can be produced at scale.
So far, only three oncolytic virus therapies have been approved globally, and only one of those is approved in Europe, the United States and Australia – a modified herpes simplex virus called T-VEC which can help certain patients with melanoma. But Theolytics believe that oncolytic viruses have the potential to produce literally millions of transformative therapies. Their lead programme is to produce an oncolytic virus against ovarian cancer, a complex disease in which the tumour heavily suppresses attacks by the immune system. They aim to develop a virus that will not only kill ovarian cancer cells, but also boost the immune system’s ability to detect and destroy them, as well as killing the non-cancer cells that support the tumour.
Technology: Machine learning
Clinical trials/research article links: https://doi.org/10.1038/s41586-021-03819-2
When one of your cells needs to build a new protein, the genetic sequence of the relevant gene is translated into a sequence of molecules called amino acids, which are joined together to form a new protein molecule. The sequence of amino acids from which a protein is made ultimately decides how it will fold into a three dimensional shape, which in turn determines its function and its interactions with other molecules. However, predicting protein shape based solely on its amino acid sequence has been a massive challenge due to the immense number of possible ways a protein could fold. While there are other ways of determining the structure of a protein experimentally, this requires enormous amounts of time and effort. So far around 100 000 unique protein structures have been worked out, but there are billions of proteins for which the amino acid sequence is known.
Machine learning has just provided us with the tool we need to solve this 50 year-old problem. This year, DeepMind’s Alphafold was used by researchers to predict the structures of 350,000 proteins, including all 20 000 proteins encoded in the human genome, as well as proteins produced by organisms commonly used in scientific research like yeast, fruit flies and mice. What’s more, Alphafold’s predictions were highly accurate, competing with those of current methods for determining protein structure.
Why is this so important? Knowing the shape of a protein not only helps us to understand what it does, but also enables us to design new molecules to interact with the protein to fulfil a desired therapeutic function. The genomics revolution has granted us a vast library of genetic information – so much information, in fact, that scientists don’t really know what to do with it all. Machine learning technologies will now hopefully allow us to translate this genetic information into structural information, keeping pace with genetic sequencing technologies and allowing us to more effectively benefit from existing sequencing data.
Technology: Disease agent-binding drug, cholesterol-degrading proteins
Clinical trials/research article links: https://doi.org/10.1016/j.ijpharm.2021.120522
Atherosclerosis is the world’s leading cause of death. It occurs when ‘bad cholesterol’ (low density lipoprotein (LDL)) builds up within the walls of arteries and becomes oxidised. White blood cells attempt to clean up the oxidised LDL, they are unable to do so, and instead cause an inflammatory reaction that oxidises more LDL. This results in a vicious cycle leading to the growth of ‘fatty plaques’ that progressively narrow the artery and can lead to different cardiovascular events depending on where the plaque is and whether or not it breaks apart.
In most cases, treatments for atherosclerosis are aimed at stopping further plaque growth and preventing cardiovascular events, not at reversing the underlying disease. Shrinking an existing plaque would require us to remove oxidised LDL from the artery wall, and that’s what Underdog Pharmaceuticals is trying to do with a class of compounds called cyclodextrins.
Cylcodextrins are a group of compounds with both industrial and pharmaceutical applications. A cyclodextrin called beta cyclodextrin is good at binding to oxidised cholesterol, making it more soluble and facilitating its removal from the plaque by white cells. However, beta cyclodextrin is also relatively toxic to cells. There are other less toxic cyclodextrins, but these unfortunately don’t bind to cholesterol with high enough affinity. Underdog Pharmaceuticals have custom-engineered cyclodextrins that retain a high affinity for oxidised cholesterol, while remaining non-toxic. This could lead to treatments that can regress atherosclerotic plaques, although we’ll still be waiting a while before we get any indication of how effective they are. Even if all goes well, clinical trials won’t begin until 2023.
Repair Biotechnologies is another company looking to achieve plaque regression using a slightly different approach with their Cholesterol-Degrading Platform (CDP). CDP is a system of engineered proteins which provide cells with a new pathway for breaking down cholesterol into water-soluble products, which are then excreted from the cells and removed by the kidneys. The company announced very promising results in animal trials in March this year, with a 48% regression of plaques in the aortic blood vessels of atherosclerotic mice after just a single treatment, though as in the case of Underdog, we still have a while to wait before human clinical trials can start. Repair Biotechnologies is also looking to use its platform to treat liver diseases in which cholesterol accumulation plays an important role.
Company: Rubedo Life Sciences
Clinical trials/research article links: https://doi.org/10.21203/rs.3.rs-92962/v1
When our cells become badly damaged or undergo too much telomere shortening, an increasing number of them enter a state called senescence. These ‘zombie cells’ stop dividing and wait to be destroyed by the immune system. Unfortunately, that doesn’t always happen, and senescent cells accumulate within our tissues as we age. An increasing body of evidence suggests that these senescent cells are important contributors to the ageing process and that their presence promotes deadly age related diseases such as cancer. If we were able to eliminate these cells using a drug, we might be able to slow some aspects of the ageing process. The problem? We need molecules that only target senescent cells, not healthy ones, in order to avoid toxic side effects.
Rubedo Life Sciences looks to be on track to develop such molecules, which would result in new senolytic treatments that are better tolerated in the frail and the elderly. They took advantage of the fact that senescent cells overproduce an enzyme called beta-galactosidase. Researchers were able to develop a proof of concept drug precursor that, when cut by the beta-galactosidase enzyme, is converted into an active drug which kills the cell. Though it has not yet been peer-reviewed, their initial study suggests that this compound can kill senescent cells in elderly mice without being toxic to healthy cells, and can reduce mortality, cognitive decline and signs of frailty.
Rubedo is currently developing similar compounds aimed at treating respiratory conditions, musculoskeletal disorders, fibrotic diseases and cancer.
So there you have it: our picks for the top ten health and longevity innovations this year. Finding a consensus on the order of the entries was tougher than last year, when the pick for first place (mRNA vaccines) was fairly obvious. This year, we put together a list of nominees and asked our research team to vote on which ones excited them the most. The majority of the entries are for innovations that are still at the preclinical or early clinical trial stages of testing, but that’s OK – we have many promising therapies in the pipeline, and if we are to give ourselves the best chance of curing ageing, we will need to approach it from as many different angles and with as many new technologies as possible.
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