Is There a Biological Relationship Between Autism and Suicide?

By Abbie Storan 

This article may be distressing for some readers due to its themes of suicide. If you are feeling suicidal, please visit here for help.

Around 800,000 people lose their lives to suicide each year. The World Health Organisation propose that for every person lost to suicide, there will be 20 more attempting suicide. Autistic people are 7.55 times more likely to die by suicide than the general population. Approximately 1% of the population is Autistic, but many will remain undiagnosed¹. 

When you consider a relationship between Autistic Spectrum Disorder, Mental Illness, and Suicide you will not fall short for evidence relating to the psychological nature of their connection, such as the JAMA network report published this January, which states that Autistic people have a “more than 3-fold higher rate of suicide attempt and suicide than neurotypical individuals, and that over 90% of people with ASD who attempted or died by suicide had another comorbid mental health condition². But what if we want to go deeper? Can we establish a biological explanation for why Autistic people are at such an exaggerated risk of mental illness, suicidal ideation, and death from suicide compared to the Neurotypical population? 

What is Autism? 

Autistic Spectrum Disorder [ASD] is a neurodevelopmental condition which affects how a person experiences the world around them, how they perceive others, and the way in which they communicate. With ASD, everything is different, and everyone is different. Due to the phenotypic heterogeneity as well as the accompanying differences in things like brain connectivity, it has been extremely hard for research to completely describe ASD neurobiology.  However, promising progress is being made with identifying the molecular pathways underpinning ASD³. With the increasing success in neuroimaging data and genetic analysis, it is likely we could see breakthroughs in the diagnosis and treatment of ASD and co-morbidities in the future.  

Before exploring the biology of ASD and Suicide, we should make note of the psychiatric evidence for relationships between ASD and Mental Illness. In 2017 AUTISTICA – the UK’s leading Autism research charity – partnered with the National Suicide Prevention Alliance. They produced a report wherein it was mentioned that depression is present in 30-50% of adults with Autism⁴. Meanwhile in a meta-analysis of 21,797 Autistic participants, 11.8% of were also diagnosed with Schizophrenia Spectrum Disorders⁵. Another large-scale meta-analysis of 26,070 people with ASD reported that the prevalence of co-morbid Anxiety Disorders was 42%. This same study also reported the lifetime prevalence of OCD within participants was 22%⁶.  

In the UK there are approximately 500,000 adults with Autistic Spectrum Disorder (ASD). Eight in ten of these adults will also suffer from mental illness⁷. From a study of 374 adults with ASD researchers found that 66% had experienced suicidal thoughts, and 35% had attempted suicide¹. 

Genetic links between Mental illness and Autism 

Thanks to a fascinating review of genetic associations with psychiatric disorders, from Andrade et al, we can now outline a direct biological relationship between ASD, Depression and Anxiety. This connection is facilitated by the dysfunction of genes encoding voltage-gated calcium channels (CaVs). CaV1.2 and CaV1.3 encourage neuronal firing and also couple excitation to gene expression; studies show this activity is linked to a number of psychiatric disorders. In particular CaV1.3 is encoded by CACNA1D genes, which have been associated with conditions such as ASD, Major Depressive Disorder, Schizophrenia, ADHD, and Bipolar Disorder. Andrade et al report that, “The non-coding SNP rs893363, located in the 3’ UTR of CACNA1D and the putative promoter region of the choline dehydrogenase gene was found in a genome-wide analysis of these five major psychiatric disorders”⁸. 

We can go on to consider the roles of Cortisol and the Hypothalamus-Pituitary-Adrenal axis (HPA) in relation to Autism and Suicide. Cortisol is colloquially referred to as the ‘stress hormone’, stress is a known biological and psychological response to experiencing threatening stimuli. The effect of acute stress is the Fight or Flight response, wherein the Hypothalamus stimulates the adrenal medulla to secrete adrenaline – which decreases activity of the parasympathetic nervous system while increasing activity of the sympathetic nervous system. Meanwhile chronic stress is regulated by the HPA axis⁹. Secretion of cortisol is controlled by actions of the paraventricular nuclei in the hypothalamus. Those nuclei secrete Corticotrophin-Releasing Factor to the pituitary, leading to the release of Adrenocorticotropic hormone into the bloodstream which stimulates cortisol synthesis and release from the adrenal glands. The HPA axis is under direct circadian regulation by the hypothalamic body clock, leading to diurnal rhythms in all components including cortisol¹⁰.  

Many studies on post-mortem brain samples from neurotypical people who died by suicide, and those who died by other means have highlighted higher concentrations  of corticotropin-releasing hormone¹²; suggesting that people who commit suicide biologically possess higher levels of cortisol, thus higher levels of stress. This has been supported by a particularly interesting study by McGowan et al in 2009, outlining the direct role of the HPA axis in suicide. From observations of the hypothalamus  in people who died from suicide they found evidence of hypermyelination as well as reduced expression of the NR3C1 gene – a glucocorticoid receptor responsible for weakening cortisol signalling – compared to their control group of people who had died by other means. Their work also revealed that early-life adversity can have lifelong detrimental effects on function of the HPA axis¹³. Autistic children are 63% more likely to suffer from bullying than neurotypical children; wider research confirms that 16.6-18% of Autistic children are physically or sexually abused¹⁴, and that autistic children are over 2.5 times more likely to be reported to child protection services for abuse¹⁵. So how is this relevant to ASD? The Diurnal Fluctuation of the HPA axis leads to a maximum concentration of salivary cortisol during the first half hour of waking, which decreases throughout the day¹⁰. We know that an increase in cortisol synthesis can dysregulate the HPA axis, and research states that children with ASD have elevated plasma and salivary cortisol concentrations, which we know to be associated with suicide. 

The Role of Serotonin 

We can now consider how serotonin plays a part in Autism and suicide. Hyperserotonaemia – elevated levels of whole blood serotonin – was the first biomarker identified from ASD in 1961, and it is present in more than 25% of autistic people. We can also note that elevated whole blood serotonin has been attributed to OCD too. Although we still do not completely understand how the serotonergic system contributes to ASD pathophysiology, neuroimaging and genetic research has concluded that the following clinical findings are related to both ASD and the serotonergic system: 

• Reduced platelet 5-HT binding, and reduced brain 5-HT binding. Since 5-HT is degraded by aromatic acid decarboxylase into 5-hydroxyindoleacetic acid (5-HIAA), this means reduced 5-HIAA levels are characteristic too.  
• Intensified by tryptophan depletion 
• A genetic linkage to chromosome 17q in males 
• Rare SLC6A4 amino acid variants leading to low expressions of the Serotonin Transport (SERT) receptor – associated with increase in cerebral cortex grey matter volume¹⁶ 

Post-mortem studies of people who died by suicide have revealed low levels of 5-HIAA in the brainstem, as well as in the prefrontal cortex. These low levels are also observed in suicide victims known to have depression and schizophrenia. Dysregulation of the serotonergic system predisposes individuals to suicidal and other self-injurious acts – The amount of 5-HIAA metabolite in the cerebrospinal fluid (CSF) is strongly correlated to current and future suicidal behaviour. So, we know that not only do low levels of CSF 5-HIAA predict a higher rate of suicidal acts, but also indicate more lethal suicide attempts. Most serotonin receptor studies focus on SERT, with results showing reduced amounts of SERT binding sites in suicide victims¹⁷. This information highlights more neurochemical evidence for the biological relationship between Autism and Suicide.  

Hope For The Future 

There is a lot of work to be done to further our understandings of both Autism biology and the biological basis of suicide respectively. Therefore, primary research into the direct biological relationship of suicide and Autism is understandably lacking. From past investigations discussed here, we can be positive this work is underway, and remain hopeful that in the future we may have answers that could keep more autistic people alive. Unfortunately, Autistic people are more prone to experience discrimination throughout their lives from other individuals and even from services expected to keep people safe – undoubtedly having a severe impact on their mental health. There is also still not even enough resources or support specifically for Autistic individuals with mental health issues, which tells us that equally as much progress is desperately needed on a societal basis to reduce Autistic suicides.  

 

References 

1.  Cassidy S, Bradley P, Robinson J, Allison C, McHugh M, Baron-Cohen S. Suicidal ideation and suicide plans or attempts in adults with Asperger’s syndrome attending a specialist diagnostic clinic: a clinical cohort study. The Lancet Psychiatry. 2014;1(2):142-147. doi:10.1016/S2215-0366(14)70248-2 
2.  Kõlves K, Fitzgerald C, Nordentoft M, Wood SJ, Erlangsen A. Assessment of Suicidal Behaviors Among Individuals With Autism Spectrum Disorder in Denmark. JAMA Netw Open. 2021;4(1):e2033565. doi:10.1001/jamanetworkopen.2020.33565 
3.  Ecker C. The neuroanatomy of autism spectrum disorder: An overview of structural neuroimaging findings and their translatability to the clinical setting. Autism. 2017;21(1):18-28. doi:10.1177/1362361315627136 
4.  Cusack J, Cassidy S, Spiers J. Suicide and autism. Published online 2017. Accessed March 23, 2021. http://www.nspa.org.uk/wp-content/uploads/2017/02/1b.-Suicide-in-autism.pdf 
5.  Lugo-Marín J, Magán-Maganto M, Rivero-Santana A, et al. Prevalence of psychiatric disorders in adults with autism spectrum disorder: A systematic review and meta-analysis. Res Autism Spectr Disord. 2019;59:22-33. doi:10.1016/j.rasd.2018.12.004 
6.  Hollocks MJ, Lerh JW, Magiati I, Meiser-Stedman R, Brugha TS. Anxiety and depression in adults with autism spectrum disorder: a systematic review and meta-analysis. Psychol Med. 2019;49(4):559-572. doi:10.1017/S0033291718002283 
7.  Baron-Cohen S. Vulnerability – Autism. Autistica. Published 2020. Accessed March 23, 2021. https://www.autistica.org.uk/our-research/research-projects/why-are-autistic-people-more-vulnerable 
8.  Andrade A, Brennecke A, Mallat S, et al. Genetic Associations between Voltage-Gated Calcium Channels and Psychiatric Disorders. Int J Mol Sci. 2019;20(14):3537. doi:10.3390/ijms20143537 
9.  McLeod S. What is the Stress Response. Simply Psychology. Published 2010. Accessed March 23, 2021. https://www.simplypsychology.org/stress-biology.html 
10.  Sharpley CF, Bitsika V, Andronicos NM, Agnew LL. Further evidence of HPA-axis dysregulation and its correlation with depression in Autism Spectrum Disorders: Data from girls. Physiol Behav. 2016;167:110-117. doi:10.1016/j.physbeh.2016.09.003 
11.  Knapp S. HPA Axis – The Definitive Guide. Biology Dictionary. Published 2020. Accessed March 23, 2021. https://biologydictionary.net/hpa-axis/ 
12.  Offord C. What Neurobiology Can Tell Us About Suicide. Sci Mag. Published online 2020. Accessed March 23, 2021. https://www.the-scientist.com/features/what-neurobiology-can-tellus-about-suicide-66922 
13.  McGowan PO, Sasaki A, D’Alessio AC, et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci. 2009;12(3):342-348. doi:10.1038/nn.2270 
14.  Mandell DS, Walrath CM, Manteuffel B, Sgro G, Pinto-Martin JA. The prevalence and correlates of abuse among children with autism served in comprehensive community-based mental health settings. Child Abuse Negl. 2005;29(12):1359-1372. doi:10.1016/j.chiabu.2005.06.006 
15.  ScienceDaily. Children with autism more likely to face maltreatment, study finds. Published 2019. Accessed March 23, 2021. https://www.sciencedaily.com/releases/2019/02/190215135837.htm 
16.  Muller CL, Anacker AMJ, Veenstra-VanderWeele J. The serotonin system in autism spectrum disorder: From biomarker to animal models. Neuroscience. 2016;321:24-41. doi:10.1016/j.neuroscience.2015.11.010 
17.  Wassink TH, Hazlett HC, Epping EA, et al. Cerebral Cortical Gray Matter Overgrowth and Functional Variation of the Serotonin Transporter Gene in Autism. Arch Gen Psychiatry. 2007;64(6):709. doi:10.1001/archpsyc.64.6.709 

Does our gut microbiome affect the way we think?

By Bruce Veloso

Trillions of microorganisms inhabit the human body at any one time, collectively known as the microbiome. The largest proportion of the microbiome (more than 100 million microorganisms) is in the human gut – up to 100 times the number of eukaryotic cells in the body¹.

Dietary content directly affects the composition of the gut microbiome. For example, it was shown that the composition of gut bacteria present in Europeans is significantly different from that of Africans, a phenomenon which may be attributed to the differences in their regular eating habits². It was observed that the gut bacteria present in Europeans was mainly composed of the Bacteroides enterotype. In contrast to this, the African gut microbiome was mainly composed of Prevotella enterotype.

Furthermore, Wu et al. observed from examination of stool samples from 98 people that Bacteroides spp. are mainly associated with a diet high in animal fat, whereas Prevotella spp. are closely associated with a diet high in carbohydrates².

Zhu et al. explain that after many years of co-existence, some gut bacteria – including six predominant phyla of Firmicutes, Bacteroidetes, Proteobacteria, Actinomycetes, Verrucomicrobia, and Fusobacteria – have developed a ‘symbiotic relationship’  with humans by forming a large portion of the gut microbiome and helping us with a multitude of tasks such as digesting food and preventing growth of pathogenic bacteria¹.

However, the influence of the gut microbiome extends far further than previously believed. The gut and the brain form the ‘gut-brain axis’, where changes in either organ directly impact the other. Experimental evidence suggests that the multiform interactions between the gut and brain likely contribute to several neurological and mental illnesses, such as depression, Alzheimer’s disease and schizophrenia¹.

Here are a few examples:

Microorganisms in the gut can affect the brain of the host organism by regulating the brain-derived neurotrophic factor (BDNF, a nerve growth agent which supports and differentiates neurons) and N-methyl-D-aspartate (NMDA, an amino acid that acts as an agonist, copying the action of glutamate, a neurotransmitter) receptors¹. Changes in BDNF expression are associated with cognitive dysfunction of patients suffering from schizophrenia¹. Interestingly, when the expression of NMDA receptors in a host is enhanced, symptoms are relieved and cognitive ability improves¹.

Additionally, studies have shown that the microbiota can influence the central nervous system by altering hippocampal neurogenesis (process in which new nerve growth takes place in the hippocampus)¹. According to Zhu et al, the hippocampus and lateral ventricle areas of the brain have an important function in learning and memory and therefore can influence the pathogenesis of neurological disorders and symptoms in conditions such as epilepsy, depression, Alzheimer’s disease and Parkinson’s disease¹.

Intriguingly, 95% of serotonin, a neurotransmitter mainly associated with mood and emotion, is produced in the gut, and microorganisms present in the gut may be essential for its production: in sterile mice, serotonin production was reduced to 60%¹. Certain compositions of the gut microbiota may promote the development of depressive disorders. It is fascinating to speculate that we may be able to treat depression and related health conditions using specific food types or even by faecal replacement therapy.

References

1.  Zhu X, Han Y, Du J, Liu R, Jin K, Yi W. Microbiota-gut-brain axis and the central nervous system. Oncotarget. 2017;8(32):53829-53838. doi:10.18632/oncotarget.17754
2.  Wu GD, Chen J, Hoffmann C, et al. Linking Long-Term Dietary Patterns with Gut Microbial Enterotypes. Science. 2011;334(6052):105-108. doi:10.1126/science.1208344

Parasites: Friend or Foe?

By Muhammed Amla

Accounting for nearly 40% of all species on Earth¹, parasites are organisms which survive and reproduce by forming symbiotic relationships with other organisms (known as hosts in this relationship) which benefit the parasite and generally harm the host. Many parasites cause death and disease, but they also have helpful roles in health, industry, crime, and agriculture.

While they are not holidaying in your guts or using their host as live cocoons², parasites can actually be greatly beneficial, from improving agriculture to triggering major evolutionary changes.

Farming

With an estimated 20-40% of global agriculture lost to insects, parasites may offer a far more effective solution than damaging farmlands with costly pesticides. Parasitoids are insects behaving like parasites that kill their hosts in the process³, with many naturally preying on crop pests. One example is the Aphidius ervi, a parasitic wasp that lays its eggs in aphids, turning the aphids into a parasitised mummy⁴. Within 2 weeks, the offspring eat their way out of the aphid, searching for more aphids and perpetuating the cycle.

UK rapeseed oil production is hindered by midges. Several wasp parotoids, such as the Platygaster subuliformis attack these midges, killing up to 75% of their larvae⁵. This non-chemical control of pests not only reduces damage to farmland, but also to health of the farmers. Indeed, it is widely accepted that long-term pesticide exposure is linked to Parkinson’s disease, asthma, depression, ADHD, anxiety, and cancers⁶.

Boosting the Immune System

Being infected is not always a terrible thing. In some cases, it can supply more benefits, such as increased protection in hosts from infection by pathogens. Enterococcus faecali, a mildly pathogenic bacteria living in worms, can evolve rapidly to protect their hosts from more lethal infections⁷. This blurs the line between parasitic relationships, where the parasite feeds from the host while causing harm, and mutualistic relationships, where the parasite and host both provide benefits to each other.

There are two forms of protection a parasite can provide to its hosts: resistance, and tolerance⁸. Parasites that provide resistance reduce the likelihood of other species infecting. For example, bacteria in the gut resist the invasion of non-native species. This specific example is also known as colonisation resistance⁹. Meanwhile, parasites providing tolerance reduce the harm of another invading species. For example, when Monarch Butterfly Larvae are inoculated with Ophryocystis elektroscirrha, a virulent protozoan parasite, they have a higher chance of survival when attacked by the lethal parasitoid fly, Lespesia archippivora, than if exposed to the parasitoid alone (fig. 1)¹⁰.

Figure 1: Monarch survival to adulthood when exposed to the protozoan parasite, fly alone, and the protozoan and fly combined¹⁰

Research has shown that when infected with an intestinal worm, the number of lymphoid follicles (microscopic compartments storing B cells, which produce antibodies against pathogens) in mice increased.

The body naturally produces more B cells to increase antibody production in response to an infection, but it does not typically increase the number of lymphoid follicles. However, upon infection with intestinal worms, a cytokine molecule (IL-4) is produced which stimulates B cells to produce lymphotoxin. This then interacts with stromal cells, which produce another cytokine (CXCL13) stimulating follicle production in the lymph nodes¹¹.

B cell follicle formation was previously thought to only occur during the post-natal period (immediately after birth), but this research showed that this process can also occur in adult mammals in the event of a worm infection¹². While it is not recommended to use intestinal worms directly to boost the immune system, it is important to note that they do strengthen the immune system uniquely and this may shape novel research and ultimately treatment strategies in the future.

Another study involving amphibian hosts and trematode parasites displayed how parasite richness not only dampens pathogen transmission, but also inhibits the spread of Ribeiroia ondatrae, a deadly parasite which causes limb malformations in amphibians¹³.

Driving Evolutionary Change

While there are a wide variety of other factors that influence evolutionary change and diversity, it can be said that parasitic organisms could also have played a key role. It is important to note that the following are mainly theories, with many other factors contributing towards evolutionary change, as opposed to exclusively or mainly parasites.

It is hypothesised that parasites drive organisms to become more diverse and complex. The constant evolutionary arms race between the two promote increased defences by the host against the parasite, meanwhile the parasite increases its effectiveness to infect its host. Using computer programs and parasitic programs in a simulation, it demonstrated how diverse lineages arise from the coevolution of hosts and parasites, encouraging then to form complex traits¹⁴. Similar demonstrations with bacteria¹⁵ also indicate the importance of parasites, showing a noticeable effect on population dynamics and evolution.

Parasites and Sex

Another hypothesis is parasites could have influenced the existence of sexual reproduction. One advantage gained, from shuffling genes and producing genetically diverse offspring, is surviving parasites more effectively. The presence of parasites can encourage the constant genetic turnover and force hosts to keep evolving¹⁶.

An experiment conducted with worms and parasites displayed how selfing populations were wiped out within 20 generations, as opposed to outcrossing populations which persisted throughout the experiment¹⁷. Male snails also start to disappear from the population in areas where parasites are rare, favouring asexual reproduction over sexual, due to the substantial costs of sexual reproduction¹⁸.

Parasites and the Brain

Certain parasites have been known to manipulate host behaviour, for example Toxoplasma gondii, which diminishes a rodent’s predator evasion around cats, turning it into an easy meal. Other examples include rabies, and some sexually transmitted pathogens have been known to influence sexual behaviour. It can be suggested that the human central nervous system has evolved to be incredibly complex as a protective countermeasure against parasites that influence behaviour.

The blood brain barrier is a first line defence from pathogens and toxins present within the bloodstream¹⁹. In the constant arms race, there are other parasites that have evolved to pass the barrier using white blood cells and monocytes as a mode of transport²⁰. Some parasites can cleverly manipulate behaviour externally, for example Toxoplasma gondii increases dopamine, a behaviour altering substance²¹. Others can secrete different hormones and activate specific immune responses to manipulate their host to complete their life cycle or leach resources.

Another countermeasure to protect the brain against behavioural changes by parasites is an increase in the amount of neurochemicals required to induce responses. Some parasites release neurochemicals to alter behaviour, the more required to create a response, the greater metabolic cost on the parasite. Due to the generally large size difference between host and parasite, it renders the attack ineffective. The relentless pressure from the increasing brain size through the course of human evolution could have led to parasites adopting alternative strategies²².

Rather than the parasites directly attaching and physically affecting the brain, some parasites like Ophiocordyceps unilateralis almost never touch the brain, yet precisely control insect behaviour²³.

Another advantage of increasing brain size is developing higher levels of protective complexity, meaning they can take more damage while maintaining normal functionality and behaviour. For this reason, mind controlling parasites are more commonly seen in insects. Increasing neuro-signalling complexity, with the use of a range of receptors, neurochemicals, and timed pulses, closes off a parasite’s attacking options. While more complex signals have an increased metabolic cost, it is disproportionately more expensive for parasites, forcing other means of manipulation²².

References

1.  Dobson A, Lafferty KD, Kuris AM, Hechinger RF, Jetz W. Homage to linnaeus: How many parasites? How many hosts? In: In the Light of Evolution. Vol 2. National Academies Press (US); 2008:63-82. doi:10.17226/12501
2.  Gabbatiss J. Prehistoric parasitic wasps found frozen inside fossilised victims named “Xenomorphia” after terrifying creature in Alien films. The Independent. https://www.independent.co.uk/news/science/wasp-parasite-fossil-discovery-insects-x-rays-a8511316.html. Published 2018. Accessed February 25, 2021.
3.  Natural History Museum. Positive parasites. Published 2016. Accessed February 25, 2021. https://www.nhm.ac.uk/discover/positive-parasites.html
4.  Dragonfli. Aphid Parasite Wasp – Aphidius colemani. Published 2018. Accessed February 25, 2021. https://www.dragonfli.co.uk/products/aphid-parasite-wasp-aphidius-colemani
5.  AHDB. Encyclopaedia of pests and natural enemies in field crops. Published online 2016. Accessed February 25, 2021. https://cereals.ahdb.org.uk/media/524972/g62-encyclopaedia-of-pests-and-natural-enemies-in-field-crops.pdf
6.  PAN. Impacts of pesticides on our health. Published 2021. Accessed February 25, 2021. https://www.pan-uk.org/health-effects-of-pesticides/
7.  King KC, Brockhurst MA, Vasieva O, et al. Rapid evolution of microbe-mediated protection against pathogens in a worm host. ISME J. 2016;10(8):1915-1924. doi:10.1038/ismej.2015.259
8.  Ashby B. Parasites inside your body could be protecting you from disease. The Conversation. Published 2017. Accessed February 25, 2021. https://theconversation.com/parasites-inside-your-body-could-be-protecting-you-from-disease-83068
9.  Pickard JM, Zeng MY, Caruso R, Núñez G. Gut microbiota: Role in pathogen colonization, immune responses, and inflammatory disease. Immunol Rev. 2017;279(1):70-89. doi:10.1111/imr.12567
10.  Sternberg ED, Lefèvre T, Rawstern AH, de Roode JC. A virulent parasite can provide protection against a lethal parasitoid. Infect Genet Evol. 2011;11(2):399-406. doi:10.1016/j.meegid.2010.11.017
11.  Dubey LK, Lebon L, Mosconi I, et al. Lymphotoxin-Dependent B Cell-FRC Crosstalk Promotes De Novo Follicle Formation and Antibody Production following Intestinal Helminth Infection. Cell Rep. 2016;15(7):1527-1541. doi:10.1016/j.celrep.2016.04.023
12.  ScienceDaily. Intestinal worms boost immune system in a surprising way. Published 2016. Accessed January 1, 2021. https://www.sciencedaily.com/releases/2016/05/160505135032.htm
13.  Johnson PTJ, Preston DL, Hoverman JT, LaFonte BE. Host and parasite diversity jointly control disease risk in complex communities. Proc Natl Acad Sci. 2013;110(42):16916-16921. doi:10.1073/pnas.1310557110
14.  Zaman L, Meyer JR, Devangam S, Bryson DM, Lenski RE, Ofria C. Coevolution Drives the Emergence of Complex Traits and Promotes Evolvability. Keller L, ed. PLoS Biol. 2014;12(12):e1002023. doi:10.1371/journal.pbio.1002023
15.  Betts A, Gifford DR, MacLean RC, King KC. Parasite diversity drives rapid host dynamics and evolution of resistance in a bacteria-phage system. Evolution. 2016;70(5):969-978. doi:10.1111/evo.12909
16.  Jones L. What would happen if all the parasites disappeared? BBC. Published 2015. Accessed January 1, 2021. http://www.bbc.co.uk/earth/story/20150127-what-if-all-the-pests-vanished
17.  Morran LT, Schmidt OG, Gelarden IA, Parrish RC, Lively CM. Running with the Red Queen: Host-Parasite Coevolution Selects for Biparental Sex. Science. 2011;333(6039):216-218. doi:10.1126/science.1206360
18.  Lively CM. Trematode infection and the distribution and dynamics of parthenogenetic snail populations. Parasitology. 2001;123(SUPPL.):S19-26. doi:10.1017/s0031182001008113
19.  Götz J. Explainer: what is the blood-brain barrier and how can we overcome it? The Conversation. Published 2017. Accessed January 1, 2021. https://theconversation.com/explainer-what-is-the-blood-brain-barrier-and-how-can-we-overcome-it-75454
20.  Masocha W, Kristensson K. Passage of parasites across the blood-brain barrier. Virulence. 2012;3(2):202-212. doi:10.4161/viru.19178
21.  Prandovszky E, Gaskell E, Martin H, Dubey JP, Webster JP, McConkey GA. The Neurotropic Parasite Toxoplasma Gondii Increases Dopamine Metabolism. PLoS One. 2011;6(9):e23866. doi:10.1371/journal.pone.0023866
22.  Packham C. Did parasite manipulation influence human neurological evolution? Phys.org. Published 2019. Accessed January 1, 2021. https://phys.org/news/2019-08-parasite-human-neurological-evolution.html
23.  Yong E. How the Zombie Fungus Takes Over Ants’ Bodies to Control Their Minds. The Atlantic. Published 2017. Accessed January 1, 2021. https://www.theatlantic.com/science/archive/2017/11/how-the-zombie-fungus-takes-over-ants-bodies-to-control-their-minds/545864/

Giving new life: Stem cells can be used to regenerate beating heart cells

By Muhammed Din

Heart disease, linked with a sedentary lifestyle, consuming junk food and smoking, is a leading cause of death accounting for 31% of global mortality. With so many people suffering with heart disease and current therapeutics being inadequate in replacing damaged myocardium, advances in regenerative medicine may offer a means to improve clinical practice. What if we could regenerate heart cells to replace those damaged in heart disease patients?

The human heart is 70-80% cardiomyocytes (heart muscle cells). These contain myofibrils, which house the fundamental contractile units responsible for muscle contraction, called sarcomeres. Loss of cardiomyocytes contributes to disease progression in heart failure¹.

Cardiomyocyte damage correlates with socioeconomic factors which inevitably cause morbidity and mortality¹-². The role of social factors contributing to congenital heart disease (CHD) in developed countries in not well documented, but a large population-based study conducted in Sweden has shown that the incidence of CHD increases in deprived neighbourhoods³.

There may also be genetic factors. An example of an inherited cardiac disease is long QT syndrome (LQTS), an autosomal dominant disorder affecting 1:1000 live births, associated with 500 different mutations in 15 different genes. Patients show prolonged repolarisation phases (the period of time where heart muscle is regaining electrical potential after contraction) which may predispose them to potentially life-threatening Torsade’s de pointe, otherwise known as ventricular arrhythmias. Mutations commonly arise in KCNQ1 and KCNH2 gene causing LQTS1 and LQTS2, respectively⁴.

Induced pluripotent stem cells (iPSC) are generated from somatic cells  harvested from a patient and converted to stem cells, allowing for autologous transplantation, thereby reducing the need for immunosuppressants.

From their induced stem cell state, iPSCs can  be converted into any type of cell present in the adult human body (pluripotency).  When appropriately stimulated in vitro, iPSCs undergo differentiation, becoming cardiomyocytes appropriate for tissue engineering or 3D bioprinting for transplantation purposes¹. This scientific discovery has generated a new practice of converting iPSCs to  heart cells which can be placed into a damaged heart.

In recent times, widespread use of 3D culture models in scientific research has enabled the experimental modelling of beating heart cells. These cultures give a physiological environment for cells to thrive in, thus allowing the generation of cardiomyocytes from iPSCs. These generated cells are morphologically and functionally like the real thing!

A hydrogel-based cardiac patch was developed with self-morphing properties. This gave a stretchable patch with fibre-like arrangements and mechanical features of a human heart. From here, regenerative medicine and stem cell therapy could expand even further¹.

Many methods  have been adopted in regenerative medicine to generate functional sheets appropriate for use in transplantation, an advancement which may eventually remove the need for organ donors. Organ transplantation carries a risk of organ rejection as the immune system discerns the new organ as not being of self-origin, triggering autoimmunity.

Studies have demonstrated the role of innate cells in transplant rejection: they have  been shown to contribute to both graft rejection and acceptance. Transplant rejection takes place in a number of steps involving the rejection response: allograft rejection leading to recruitment of innate cells and cytokines stimulating immune cells. Thereafter graft destruction is initiated by T cells and non-T cells⁵.

3D bioprinting has brought forth new potential for the use of bioengineering in providing new and enhanced technologies for the regeneration of cardiomyocytes, thus allowing the addition of cells and biomaterials to a well organised structure. Using this cutting-edge approach, iPSC derived cardiomyocytes have been bio-printed into vascularized cardiac tissue and transplanted into a defective heart. As well as this, 3D bioprinting was used to embed supporting cells into a defective heart, for instance, fibroblasts and vascular cells leading to improved therapeutic outcomes in mice.

As a result of this, a fully functional patch was created with expected action potential and electrical conduction as observed in a fully functional heart¹.

The ending of the decade came-forth with a breakthrough in stem cell therapy where we witnessed two Chinese men becoming the first to receive iPSCs therapy for heart disease⁶. This laid down the foundation for innovation and breakthrough in regenerative medicine for decades to come shaping medicine for future generations.

References

1.  Wang K-L, Xue Q, Xu X-H, Hu F, Shao H. Recent progress in induced pluripotent stem cell-derived 3D cultures for cardiac regeneration. Cell Tissue Res. Published online February 5, 2021. doi:10.1007/s00441-021-03414-x
2.  Psaltopoulou T, Hatzis G, Papageorgiou N, Androulakis E, Briasoulis A, Tousoulis D. Socioeconomic status and risk factors for cardiovascular disease: Impact of dietary mediators. Hell J Cardiol. 2017;58(1):32-42. doi:10.1016/j.hjc.2017.01.022
3.  Peyvandi S, Baer RJ, Chambers CD, et al. Environmental and Socioeconomic Factors Influence the Live‐Born Incidence of Congenital Heart Disease: A Population‐Based Study in California. J Am Heart Assoc. 2020;9(8). doi:10.1161/JAHA.119.015255
4.  van Mil A, Balk GM, Neef K, et al. Modelling inherited cardiac disease using human induced pluripotent stem cell-derived cardiomyocytes: progress, pitfalls, and potential. Cardiovasc Res. 2018;114(14):1828-1842. doi:10.1093/cvr/cvy208
5.  Liu W, Li XC. An overview on non-T cell pathways in transplant rejection and tolerance. Curr Opin Organ Transplant. 2010;15(4):422-426. doi:10.1097/MOT.0b013e32833b7903
6.  Mallapaty S. Revealed: two men in China were first to receive pioneering stem-cell treatment for heart disease. Nature. 2020;581(7808):249-250. doi:10.1038/d41586-020-01285-w

Is animal agriculture increasing the risk of disease and pandemics?

By Caitlin Owen

Zoonoses are diseases transmitted between humans and vertebrates. These are relatively rare but potentially devastating events. About 60% of human infections are estimated to have originated from animals¹, and this phenomenon is becoming more frequent². 75% of new and emerging diseases are zoonotic³, and most pandemics are caused by zoonoses⁴.

Zoonotic diseases can emerge when a genetic change happens which allows pathogens to ‘jump’ from animals to humans. Some pathogens may even combine genetic material with each other, allowing them to transfer advantageous mutations and the ability to infect animals and humans. This is thought to have occurred for the 2006 ‘swine flu’ pandemic, caused by an H1N1 virus which features a mix of genetic sequences from various human, avian and swine influenza viruses⁵.

Increasing demand for animal agriculture may be increasing the risk of new zoonoses forming.

Tens of billions of animals are killed every year for human consumption⁶. How does this industry meet our excessive demand for animal products and profits? How do its practices impact on global disease spread?

Disease becomes more likely when large numbers of genetically similar animals of the same species are kept extremely close together⁴.
Even “free-range” hens may  be kept with ~13 birds per square metre in the UK⁷. In the US, they simply have to be outside⁸. Livestock are prevented from moving around to prevent wasting of energy that could be spent on growth. Animals have also been selectively bred with genes that make them better products, causing much of livestock to be genetically similar in favour of bigger chicken breasts, or increased milk production⁴. Low genetic diversity in any population increases its overall susceptibility to certain diseases⁹, and when animals are kept close together¹⁰, especially in poor welfare conditions where they cannot escape the waste of other animals¹¹, or are frequently injured, an ideal breeding ground is presented for pathogens to spread and mutate quickly.

One way that the industry has compensated for this is through mixing antibiotics into animal feed and water supplies, leading to overuse^4;12.
Antibiotics are antimicrobial agents produced naturally by bacteria to reduce the competition presented by other bacteria and it is natural for bacteria to develop resistance through genetic changes for this reason⁴. However, our use of antibiotics in modern medicine presents the need to prevent this from happening too often. We are now accustomed to the various campaigns to reduce antibiotic abuse in human healthcare, yet animal agriculture accounted for a third of UK antibiotic use in 2016¹³. Fortunately, many measures are now being taken to reduce the overuse of antibiotics in animals, but while global demand for animal products continues to rise⁴, the demand for antibiotics will too.

_{SARS-SoV-2, the viral cause of COVID-19, the zoonotic origin of which is yet to be confirmed. Source: CDC}

Domesticated animals now account for 60% of the land vertebrate biomass of the planet, while wild animals only make up 4%¹⁴.  
Humans are the other 36%. This loss of bio-diversity is thought to increase the risk of new zoonoses in a few ways, though this concept is not yet fully understood⁴. One such example is in the spread of zoonotic viruses by mosquitos and ticks – where native vertebrate diversity is high, they feed from a greater variety of hosts, of which only a few are good reservoirs for the virus, leading to fewer infections¹⁵.
 
Paradoxically, the Increasing demand for land for resource-intensive livestock is in turn increasing wild animal-human interface, which also increases the risk of zoonoses jumping species to humans⁴.
Our growing demand for land and resources forces us to further encroach on wild habitats. Cattle in particular require vast amounts of land and crops, which is driving deforestation in places like the Amazon¹⁶. While habitats decline, wild animals are forced closer to human and livestock populations. This increases contact between livestock, wild animals, and humans.

Many zoonoses are already found in animal agriculture as foodborne diseases, such as salmonella, listeria and campylobacter.
Animals are a major source of foodborne pathogens, even in plants after contamination with animal waste⁴. Animal-sourced foods formed 35% of the global burden of foodborne disease in 2010¹⁷, and 2018-19 saw the largest-ever outbreak of listeriosis after 1000 laboratory-confirmed cases in South Africa and over 200 deaths as a consequence.

The number of outbreaks caused by zoonoses is rising, including relative to outbreaks caused by human-specific pathogens.
The total height of the bars represents the total number of outbreaks of disease; red area show the proportion of outbreaks that were caused by zoonoses as opposed to pathogens limited to humans (blue area). Adapted from Smith et al., 2014¹⁸ .

So is animal agriculture increasing the risk of disease and pandemics? The UN seems to think so⁴. In their 2020 report, ‘preventing the next pandemic’, increasing human demand for animal protein was listed as the first of 7 drivers of pandemics and as a contributing factor to other drivers listed,  such as unsustainable agricultural intensification and climate change.

It should be noted that in in lesser-economically developed regions with poor food security, animal products serve as an important source of nutrition that goes some way towards maintaining a healthy immune system and thus reducing the burden of disease⁴. Therefore, the answer is not as simple as everyone simply dropping animal products from the diet right now.

However we are now well aware, diseases do not respect borders and pandemics are worldwide. If we hope to prevent them in future, it will take global change in practices, and when both farming livestock and interacting with wild animals appears to increase the risk of disease, it seems ever-more likely that this will have to involve reducing our consumption of animal products.

References

1. Host range and emerging and reemerging pathogens. Woolhouse, MEJ and Gowtage-Sequeria, S. 2005, Emerging Infectious Diseases, Vol. 11, pp. 1842–1847. Doi: 10.3201/eid1112.050997.
2. Emerging diseases go global. Woolhouse, Mark E. J. 2008, Nature, Vol. 451, pp. 898–899. Doi.org/10.1038/451898a.
3. Risk factors for human disease emergence. Taylor, LH, Latham, SM and Woolhouse, MEJ. 1411, s.l. : 2001, Philosophical Transactions of the Royal Society B: Biological Sciences, Vol. 356, pp. 983–989. Doi: 10.1098/ rstb.2001.0888.
4. United Nations Environment Programme and International Livestock Research Institute. Preventing the Next Pandemic: Zoonotic diseases and how to break the chain of transmission. Nairobi, Kenya. : United Nations Environment Programme, 2020. ISBN No: 978-92-807-3792-9.
5. Origins of the 2009 H1N1 influenza pandemic in swine in Mexico. Mena, Ignacio, et al. 2016, eLife, Vol. 5, p. e16777. Doi: 10.7554/eLife.16777.
6. Food and Agriculture Organization of the United Nations. FAOSTAT: Data. [Online] http://www.fao.org/faostat/en/#data.
7. Department for Environment, Food and Rural Affairs. Code of practice for the welfare of meat chickens and meat breeding chickens. [Online] 2018. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/694013/meat-chicken-code-march2018.pdf.
8. United States Department of Agriculture. Meat and Poultry Labeling Terms. [Online] 2015. https://www.fsis.usda.gov/wps/portal/fsis/topics/food-safety-education/get-answers/food-safety-fact-sheets/food-labeling/meat-and-poultry-labeling-terms/meat-and-poultry-labeling-terms/!ut/p/a1/jZFRb4IwEMc_DY-lx3AG90ZIFmUTZsxm5WUpehSS0pK2jrhPP9wyExed9p569.
9. Does genetic diversity limit disease spread in natural host populations? King, K. C. and Lively, C. M. 4, 2012, Heredity, Vol. 109, pp. 199–203. Doi: 10.1038/hdy.2012.33.
10. Investigation of risk factors for Salmonella on commercial egg-laying farms in Great Britain, 2004-2005. Snow, L C, et al. 19, 2010, British Veterinary Association, Vol. 166, pp. 579-86. Doi: 10.1136/vr.b4801.
11. The animal-human interface and infectious disease in industrial food animal production: rethinking biosecurity and biocontainment. Graham, J. P., et al. 3, 2008, Public Health Reports, Vol. 123, pp. 282–299. Doi: 10.1177/003335490812300309
12. Antibiotic Abuse in Animal Agriculture: Exacerbating Drug Resistance in Human Pathogens. Goldman, Emanuel. 1, 2004, Human and Ecological Risk Assessment: An International Journal, Vol. 10, pp. 121-134. Doi: 10.1080/10807030490281016.
13. The Parliamentary Office of Science and Technology. Reducing UK Antibiotic Use in Animals. [Online] 2018. researchbriefings.files.parliament.uk%2Fdocuments%2FPOST-PN-0588%2FPOST-PN-0588.pdf&usg=AOvVaw2I1wEWBrrsqTAVI2.
14. The biomass distribution on Earth. Bar-On, Yinon M., Phillips, Rob and Milo, Ron. 25, 2018, PNAS, Vol. 115, pp. 6506-6511. Doi: 10.1073/pnas.1711842115.
15. Biodiversity loss and the rise of zoonotic pathogens. Ostfeld, RS. Suppl 1, 2009, Clinical microbiology and infection, Vol. 15, pp. 40-43. Doi: 10.1111/j.1469-0691.2008.02691.x.
16. Persistence of cattle ranching in the Brazilian Amazon: A spatial analysis of the rationale for beef production. Bowman, Maria S., et al. 3, 2012, Land Use Policy, Vol. 29, pp. 558-568. Doi: 10.1016/j.landusepol.2011.09.009.
17. Global disease burden of pathogens in animal source foods, 2010. Li, Min, et al. 6, 2019, Plos One, Vol. 14, p. e0216545. Doi: 10.1371/journal.pone.0216545.
18. Global rise in human infectious disease outbreaks. Smith, Katherine F., et al. 2014, Journal of the Royal Society, Vol. 11, p. 20140950. Doi: 10.1098/rsif.2014.0950.19.