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Micropipette – The scientist’s paintbrush

Just as painters would struggle to practise their craft without a paintbrush, scientists and technicians alike would be disorientated without a trusted pipette. Pipettes, especially micropipettes, allow scientists to accurately transfer and measure hazardous or harmful substances which are often less than a millilitre in volume.

A lab, and a scientist for that fact, is simply redundant without one.However, before the invention of the micropipette, measuring small quantities wasn’t so simple, or even safe to do so. So how did the micropipette, a tool used by every calibre of scientist, come to its renowned use?

French pipetting: Pasteur Pipette

The term “pipette” was first coined by the French scientist Joseph-Louis Gay-Lussac in the 1820s. However, Louis Pasteur constructed a version of the pipette still utilised in labs today1. Pasteur, a microbiologist by nature, created a pipette to ensure that foreign contaminants were not introduced into his experiments. This provided a sterile environment where decisive conclusions could be made.

The Pasteur pipette, made from either glass or plastic, is similar to an eyedropper and can even be used to dispense cosmetics. However, within the lab, this pipette is not recommended when accurate volume measurements are required. It is generally utilised to add liquids in a drop-wise manner.

Spit, Not swallow: Carlsberg Pipette

Figure 1 Rebel in a lab-coat: Dr.Adah Elizabeth Verder mouth pipetting an unspecified solution, she studied gastrointestinal flora at the National Institute of Health.

The Carlsberg pipette was constructed from a long, thin graduated piece of glass which allowed air flow but, limited the movement of liquid during pipetting. This was an improvement over the Pasteur pipette as it provided accurate volumetric measurements for scientists to utilise. The Carlsberg pipette required suction to measure and transfer liquids, which only 60 years or so ago, was done by creating a vacuum with the user’s mouth (Figure 1)2.

This type of pipetting was aptly named “mouth-pipetting” as the substance was drawn up by an action similar to sipping a Pepsi by straw. This type of pipetting was not for the faint of heart, as one wrong move could have the user inadvertently swallowing toxic or infectious reagents. Successful pipetting by-mouth required adequate experience by the user and depended on the construction of the Carlsberg pipette.

Unsurprisingly, accidents were so widespread that a review of 57 laboratory accidents which caused 47 infections in staff, found that 40% of those infections were attributed to mouth pipetting3. Such hazards and accidents relating to mouth-pipetting were well known to US Army Biological Labs in 1964 during the introduction of the Carlsberg pipette3. This prompted the use of suction devices. Much like a rebellious teenager who refuses to listen, after the introduction of suction devices, mouth-pipetting was still a widely “acceptable” practise in many labs.

Sick of sucking: Marburg Pipette

Figure 2: Ingenious mind: Heinrich Schnitger revolutionised the pipette into one which is safely and heavily used today

Heinrich Schnitger (Figure 2)4, a son of an inventor, joined the Institute of Physiological Chemistry at the University of Marburg as a postdoctoral student in 1957. There he would go onto to create, using the institutes workshop, the micropipette scientists recognise and utilise today.

His post-doctoral studies involved exchange chromatography experiments that separated substances based on their charges. However, during his experiments he found the chromatography methods produced samples that were less than a millimetre in volume. A close witness to Schnitgers work at the time, Martin Klingenberg, outlined that when collecting the fractions, Schintiger “viewed micro-pipetting by mouth with great contempt4.”

His annoyance towards mouth-pipetting grew to such a level, like a modern-day messiah, he disappeared from the lab for a couple of days. Upon divine reappearance, he returned with a tool to pipette microlitre volumes

Astonishingly, his prototype of the micropipette had many features of what a modern micropipette looks like today (Figure 3)5,6 which consists of a spring-loaded piston and a removable plastic tip7. The plastic tip is thrown away after every use to ensure no cross-contamination takes place between reagents.

Figure 3 : Relic of the past, modernised: (left) shows the initial micropipette developed by Schnitger and (right) shows a modern micropipette produced by Eppendorf which has many common features of the original design.

Understanding the importance of the breakthrough, copies of the pipette were made throughout the institute for use. Feedback from scientists using the pipettes were taken into account to improve and alter the initial design. In the same year, the prototype was created, Schiniger applied for a patent in Germany, which was swiftly accepted in 1961.

World-Market domination

Figure 4: Commercialised success : Shows the patent application submitted by Schnitger which was shortly bought by Eppendorf for widespread commercial production.

The real test of the usefulness of his invention, was whether it came to widespread use to avoid the hazards associated with mouth-pipetting. To appeal to the general and wider scale market, Wilhelm Bergman used different shapes and materials to further optimise the micropipette. Shortly afterwards, Eppendorf, a supplier of lab equipment, bought the intellectual rights to manufacturing and marketing the micropipette (Figure 4)4. The initial launch of the pipette, dubbed the Marburg pipette, was widely accepted and used throughout Europe and Germany.

According to one source4, the use of the micropipette didn’t quite catch on in the US as Eppendorf was focusing more on optimisation rather than advertisement. An American company, Gilson, marketed the same pipette, with the addition of an adjustable volume capacity, through the exploitation of various loopholes in patent law. The marketing of the Marburg pipette was a success, and mouth pipetting fell out of fashion and mostly became the subject of edgy jokes between many scientists today.

Sadly, Schnitger died before the global spread of his invention due to a swimming accident in 1964. To an extent, he knew the importance of his work, but there is a difference between knowing and seeing your inventions used, even decades later, throughout the world by scientists and students alike.

Innovation,the cornerstone of science

The Pasteur, Carlsberg and finally the Marburg pipette present the innovative and collaborative nature of science. Each iteration of the pipette has somewhat built upon the previous version. However, there is an astounding feat of difference between the Carlsberg and Marburg pipette that Schnitger achieved which deserves honourable mention.

Modifications and improvements of the Marburg pipette are taking place even today, to produce more ergonomic designs, presenting the never-ending quest to optimise tools for research and teaching uses.

References:

1.         Joseph-Louis Gay-Lussac | French scientist. Encyclopedia Britannica https://www.britannica.com/biography/Joseph-Louis-Gay-Lussac.

2.         Dr. Adah Elizabeth Verder mouth pipetting. (2017).

3.         Phillips, G. B. & Bailey, S. P. HAZARDS OF MOUTH PIPETTING: http://www.dtic.mil/docs/citations/AD0640356 (1964) doi:10.21236/AD0640356.

4.         Klingenberg, M. When a common problem meets an ingenious mind. EMBO Rep. 6, 797–800 (2005).

5.         Martin Klingenberg. The Original Micropipette. The Scientist Magazine® https://www.the-scientist.com/foundations-old/the-original-micropipette-48026.

6.         Pipette.com. Eppendorf Pipettes | Manual/Electronic Pipettes, Repeaters, Dispensers. https://www.pipette.com/Eppendorf-Research-Plus-Fixed-Volume-Pipette.

7.         Vellayutham, B. Who invented pipette? | The Petri Dish. https://thepetridish.my/2019/06/30/who-invented-pipette/.

Photo credits:

Pipette Icons made by Freepik from www.flaticon.com

Micro-pipette photo by Polina Tankilevitch from Pexels

Pasteur-pipette photo by Edward Jenner from Pexels

Lab-bench top photo by Polina Tankilevitch from Pexels

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Molecule of the Month: Auxin

As the bitter, cold winter comes to a slow end in the Northern Hemisphere we are reminded of the warmth and light that spring gladly offers. The icy patches are replaced by the buds and shoots of daffodils, tulips and crocuses that may have planted in the dead of winter.

This re-awakening of Mother Nature is an exuberant affair with plants sensing many factors such as temperature, wind and light allowing these shoots and eventual flowers, to come to establishment. The orchestrated and complicated affair from seed, shoot, to flower is dictated by many signalling molecules that talk and interact with one another.

Auxin plays a large role in the growth and the primary establishment of a plant and even allows the plant to respond to light, an essential source of energy. Within agriculture, synthetic auxin has also been developed as a way of controlling the growth of weeds. However, auxin does not work alone, and other signalling molecules can dictate its production.

Power to Plants

Auxin (Figure 1)1 is a plant hormone that is described to influence nearly every aspect of plant growth and development2. Many biochemical and experimental studies have presented that the amino acid, tryptophan is used by plants to make this fundamental hormone3.

Figure 1:

Most notably, auxin is able grow and elongate cells allowing certain structures of the plant, such as roots and shoots to respond to light4. An effective response to light, known as phototropism, provides multiple developmental and growth cues suggesting evolutionary selection5.

Moving Parts: Roots & Shoots

The power of auxin in guiding the stem can be seen when light is shone onto the plant at an angle. When the light source is at an angle (Figure 2)6 auxin is able to accumulate on the shaded sides of the stem, leaving the lit sides of the stem with little to no auxin. The gradient of auxin leads to the elongation of the cells within the shaded part of the plant, compared to the lit parts. This causes the stem to bends its way towards the light, which is called positive phototropism5.

Figure 2: Auxin is able to guid the stems towards a light source, presenting positive phototropism.

Although, auxin is shown to elongate cells within the shoot, when auxin is present within the root it actually inhibits this process allowing the root to bend away from light7. This is an example of negative phototropism presenting the dual yet opposing effects of auxin within the shoot and root. (Figure 3)8

Figure 3: Shows the dual, opposite effects auxin has on the shoots are roots of the plant.

However, negative phototropism has come into wider questioning as particular studies on garden cress have presented that 50% of the roots show a positive phototropic response, growing towards, instead of away from light9. This may suggest that this response is different between species and that other factors, such as gravity, may play a larger role in the direction of root growth.

More than light?

Aside from auxin guiding the stem or the root of the plant either away or towards light, this hormone is heavily implicated in root development. Root systems are an integral part of the plant as it enables it to invade land, giving it anchorage and also facilitating the uptake of water to survive dry conditions10.

Processes including the initial production of the and normal development of the root are all mediated by auxin11. For example, a study found that a gradient of auxin within cress is crucial for maintaining root stem cell identity presenting its integral role in the establishment of the plant12.  Especially within the root, maintaining stem cell identity is important as plants need to grow roots at a moment’s notice if it becomes damaged.

Stem cells, present in humans and plants alike, are the main source of “immature cells” that are able to form a wide range of specialised cells. However, stem cells in the root require a specialised tissue, the quiescent centre, to maintain them13. Studies on corn and cress have shown that auxin plays a substantial role in the formation, establishment, and maintenance of these quiescent centres within root systems14,15.   

Agricultural auxin

As plant hormones have been found to influence nearly every stage of development, they can be utilised and manipulated towards the use of agriculture to increase yield by destroying unwanted plants.

Compounds that mimic auxin can be utilised as an herbicide that go onto control the growth of unwanted plants, usually killing them. Although, auxin is known to stimulate a variety of growth and development processes, at high concentrations, man-made auxin it is able to disrupt growth and fatally damage the plant16

However, since the widespread and continual use of herbicides worldwide, scientists are worried about various species of weeds that are showing resistance towards synthetic auxin. The first species of weeds resistant to auxin was documented in 1957 but this has since expanded to include a total of 36 species as of 201817. The presence of these resistant weeds remains at relatively low level, when compared to herbicides acting in a different way to auxin. However, they encourage scientists to further understand the biochemical processes that are taking place that lead to resistance.

Cross-talk

Auxin can be seen as they key hormonal regulator of the processes concerning both the root and the stem, but other plant hormones such cytokinin and ethylene can participate in these processes, even crosstalk with one another.

For example, ethylene is an important signal in inhibiting root growth but its eventual effects on the individual cells are mediated by auxin synthesis and transport. Within cress, ethylene increases auxin synthesis that goes to stop the cells of the root from elongating or getting larger18.

Nevertheless, auxin is an integral signalling hormone that influences a wide range of processes from stem cell maintenance to stem and root growth in the response to light. Although, some studies suggest that negative phototropism within roots may have other influences involved, synthetic auxin is widely used within agriculture to destroy weeds.

As the sunshine of spring and summer arrive, the shoots and possibility even the roots of many plants will be influenced under the guide of auxin.

References:

1.         Indole-3-acetic acid. Wikipedia (2021). [Cross-checked with academic material]

2.         Weijers, D., Nemhauser, J. & Yang, Z. Auxin: small molecule, big impact. J. Exp. Bot. 69, 133–136 (2018).

3.         Zhao, Y. Auxin Biosynthesis. Arab. Book Am. Soc. Plant Biol. 12, (2014).

4.         Ma, L. & Li, G. Auxin-Dependent Cell Elongation During the Shade Avoidance Response. Front. Plant Sci. 10, (2019).

5.         Liscum, E. et al. Phototropism: Growing towards an Understanding of Plant Movement[OPEN]. Plant Cell 26, 38–55 (2014).

6.         IGCSE Biology 2017: 2.85: Understand the Role of Auxin in the Phototropic Response of Stems. IGCSE Biology 2017 http://igcse-biology-2017.blogspot.com/2017/06/285-understand-role-of-auxin-in.html (2017).

7.         Eliasson, L., Bertell, G. & Bolander, E. Inhibitory Action of Auxin on Root Elongation Not Mediated by Ethylene. Plant Physiol. 91, 310–314 (1989).

8.         Auxin is a hormone that controls growth in plants cells. https://mammothmemory.net/biology/plants/sexual-reproduction-in-plants/auxin.html.

9.         Kutschera, U. & Briggs, W. R. Root phototropism: from dogma to the mechanism of blue light perception. Planta 235, 443–452 (2012).

10.       Kenrick, P. & Strullu-Derrien, C. The Origin and Early Evolution of Roots1. Plant Physiol. 166, 570–580 (2014).

11.       Overvoorde, P., Fukaki, H. & Beeckman, T. Auxin Control of Root Development. Cold Spring Harb. Perspect. Biol. 2, (2010).

12.       Tian, H., Niu, T., Yu, Q., Quan, T. & Ding, Z. Auxin gradient is crucial for the maintenance of root distal stem cell identity in Arabidopsis. Plant Signal. Behav. 8, (2013).

13.       Scheres, B. Stem Cells: A Plant Biology Perspective. Cell 122, 499–504 (2005).

14.       Kerk, N. & Feldman, L. The quiescent center in roots of maize: initiation, maintenance and role in organization of the root apical meristem. Protoplasma 183, 100–106 (1994).

15.       Della Rovere, F. et al. Auxin and cytokinin control formation of the quiescent centre in the adventitious root apex of arabidopsis. Ann. Bot. 112, 1395–1407 (2013).

16.       Grossmann, K. Auxin Herbicide Action. Plant Signal. Behav. 2, 421–423 (2007).

17.       Busi, R. et al. Weed resistance to synthetic auxin herbicides. Pest Manag. Sci. 74, 2265–2276 (2018).

18.       Xu, P. et al. Integration of Jasmonic Acid and Ethylene Into Auxin Signaling in Root Development. Front. Plant Sci. 11, (2020).

Picture references

Pots on shelf image by Min An from Pexels

Person with plant image by Daria Shevtsova from Pexels

Shoots image by Markus Spiske from Pexels

Roots image by Karolina Grabowska from Pexels

Agriculture image by  freestocks.org from Pexels

Leaf image by  Markus Spiske from Pexels

Split image by Freepik from www.flaticon.com

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Cancer vaccination: Hope or Hype?

As various countries roll out the few COVID-19 vaccines that have been approved, many scientists, world leaders, and citizens hope that this will be a large step towards normalcy. Between report of efficacy data, mutant strains, and vaccine nationalism it is easy to overlook the effect the pandemic has had on cancer patients and their treatment.

More than 1000 patients in London needing urgent cancer surgery do not have a date for their treatment. With the knowledge that a four-week delay in treatment can increase mortality up to 8% it presents a significant risk to these patients1.

Treatment of cancer has centred around three main avenues of approach, including surgery, that have been used for decades. Although these treatment options are effective, some believe that they are outdated. So, what is next for cancer therapy?

Our understanding of the immune system, and how it is manipulated to tolerate cancerous cells, could help researchers to develop immunotherapies, such as cancer vaccines.

Slash, Burn, and Poison: Effective?

The three main treatment options of cancer centre around the destruction of cancer cells within the body. The approaches (Figure 1)2, slash, to represent surgical removal of tumors, burn, to represent the use of radiation to kill cancer cells, and poison, to represent chemotherapy has been utilised to treat, and even cure cancer.

Figure 1: The three main approaches to treat and even cure cancer include slash, burn, and poison which can cause a wide range of side-effects for the patient.

However, some academics and clinicians such as Dr Azra Raza, believe this approach is out-dated given the fact radio and chemotherapy causes a wide range of debilitating side-effects. A study into the side-effects of chemotherapy presented that 86% of patients reported at least one side-effect, that ranged from fatigue all the way to shortness of breath3.

Although, this can be seen as a small price to pay in treating cancer, further studies have gone to show that the approaches of chemotherapy and radiotherapy are able to “profoundly supress” the immune system thereby, causing the patient to become susceptible to other infections and disease4.

Outlining her recently published book, The First Cell, in a Wall Street Journal essay, she argues these approaches have been exhausted to their limit5. She claims that although 68% of currently diagnosed cancers are being cured, those with advanced stages of cancer have the same outcome compared to 50 years ago6.

While her solution to resolve the stagnation is to draw importance to detecting markers that early cancer cells release, such as proteins or genetic material, cancer vaccination remains a huge research interest. 

Prevention

Approximately 10% of the worldwide cases of cancer are caused by viral infection, with upwards of 80% of cases occurring within developing nations7. Viruses that are able to cause cancer, called oncogenic viruses, have the ability to disrupt DNA repair mechanisms or tumour suppressor genes which leads to an unstable genome and uncontrolled growth8.

HPV (Human Papillomavirus) infection is implicated in about 600,000 cases of cancer ranging from the regions of the cervix, anal, vulva, vaginal and penile cancers9.  The association factors between HPV and cervical cancers is higher than the association between smoking and lung cancer presenting a indisputable link between HPV infection and cancer incidence10. Therefore, in this case, vaccination against certain types of HPV provides protection from a wide range of cancers.

There are a range of HPV vaccines currently available for distribution since it was licenced in 200611. Specific vaccines such as Gardasil 9 (Figure 2)12 has been produced to protect against 9-known cancer causing types of HPV and shows excellent efficacy against cervical infection and the presence of cancerous tissues caused by these types of HPV13,14.

Figure 2: Gardasil 9 protects against nine known strains of HPV which is able to cause cancer following infection

A systematic review found that 95,000 participants showed decreased HPV related pre-cancerous cells 4 years after vaccination presenting its power to prevent the formation of more serious types of cancer15.

Despite this success, vaccination of other viruses that cause cancer, such as the Epstein Barr virus (EBV), have been difficult to develop.

Specifically, EBV goes through long periods of dormancy before it goes to cause cancer meaning that patients would need to observed for up to 30 years to evaluate the impact of vaccination16. Not only is this impractical, but it can also incur huge costs. Additionally, the virus preferentially infects humans, making animal models difficult to design which are generally used to test vaccines on.

Destruction

Cancer vaccination in existing patients with malignant tumours, however, is a much more difficult feat to achieve as cancer is highly different between individuals of the same disease type.

Much like regular vaccination, it harnesses the power of the patient’s own immune system. However, it differs in the way that it aims to relieve the suppression placed on the immune system by the cancer, so can identify and eliminate these cancer cells.

Provenge, one of the first personalised cancer vaccines, which is used within patients who have a specific type of prostate cancer underwent a rigorous 13-year clinical trial to become approved17. This vaccine is personalised as it extracts, modifies, and uses the patient’s own dendritic cells so immune cells can go and destroy cancer cells.

Dendritic cells love to show the rest of the immune system all the proteins from viruses or cancer cells that it has picked up allowing the real doers, T-cells, to mount an appropriate response18.

Using this, researchers identified that many prostate cancer cells express and release prostate acid phosphatase presenting a suitable target for the immune system19. When the dendritic cells are extracted from the patient (Figure 3)20, they are loaded with prostate acid phosphatase outside of the body and then re-introduced allowing T-cells to recognise and destroy these cancer cells that express the protein21.

Figure 3: Shows the personalised nature of the cancer vaccine Provenge against prostate cancer.

A systematic review presented that the Provenge treatment course led to a significant improvement in overall survival in prostate cancer patients compared to the control groups. Although, this treatment can give months more survival, it is incredibly expensive at £16,000 at a singular dose causing experts to raise questions about whether the current health care system can handle the personalised cost of cancer immunotherapy22,23.

Horizon

Cancer vaccination provides a powerful avenue of either prevention or destruction and has shown its effects both and inside and out of the clinic. Although, the success of the HPV vaccine presented how cancers caused by viruses can be altogether avoided, developing an EBV vaccine has revealed many practical challenges due to the nature of its life cycle.

On the other side of the coin, using vaccines to destroy existing malignant cells have been used within prostate cancer patients with positive results in relation to overall survival. Again, there is wide questioning of the costs as other cheaper, oral drugs came onto the market not soon after, with similar survival benefits24.

Both these practical and economic challenges aside, the recent approval of mRNA-based vaccines has opened another avenue for cancer vaccination25. If these approaches can be practical, cost-effective, and robust then it is another weapon in the arsenal we have against cancer.

References:

1.         Oncology, T. L. Valuing all lives equally: cancer surgery, COVID-19, and the NHS in crisis. Lancet Oncol. 22, 155 (2021).

2.         Immunotherapy. The John P. Hanson Foundation for Cancer Research http://www.hansoncancerfoundation.org/immunotherapy/.

3.         Pearce, A. et al. Incidence and severity of self-reported chemotherapy side effects in routine care: A prospective cohort study. PLoS ONE 12, (2017).

4.         van Meir, H. et al. Impact of (chemo)radiotherapy on immune cell composition and function in cervical cancer patients. Oncoimmunology 6, (2016).

5.         Raza, A. Cancer Is Still Beating Us—We Need a New Start. Wall Street Journal (2019).

6.         Democracy Now! “The First Cell”: Dr. Azra Raza on Why the “Slash-Poison-Burn Approach” to Cancer Has Failed. “The First Cell”: Dr. Azra Raza on Why the “Slash-Poison-Burn Approach” to Cancer Has Failed.

7.         Schiller, J. T. & Lowy, D. R. Virus infection and human cancer: an overview. Recent Results Cancer Res. Fortschritte Krebsforsch. Progres Dans Rech. Sur Cancer 193, 1–10 (2014).

8.         Luo, G. G. & Ou, J. J. Oncogenic viruses and cancer. Virol. Sin. 30, 83–84 (2015).

9.         Bansal, A., Singh, M. P. & Rai, B. Human papillomavirus-associated cancers: A growing global problem. Int. J. Appl. Basic Med. Res. 6, 84–89 (2016).

10.       Burd, E. M. Human Papillomavirus and Cervical Cancer. Clin. Microbiol. Rev. 16, 1–17 (2003).

11.       QA_HPV_General_EN.pdf.

12.       Ryan, B. Instagram Storytelling May Help Promote HPV Vaccination. Cancer Health https://www.cancerhealth.com/article/instagram-storytelling-may-help-promote-hpv-vaccination (2019).

13.       Cheng, L., Wang, Y. & Du, J. Human Papillomavirus Vaccines: An Updated Review. Vaccines 8, (2020).

14.       Moreira, E. D. et al. Safety profile of the 9-valent human papillomavirus vaccine: assessment in prior quadrivalent HPV vaccine recipients and in men 16 to 26 years of age. Hum. Vaccines Immunother. 14, 396–403 (2017).

15.       Jørgensen, L., Gøtzsche, P. C. & Jefferson, T. Benefits and harms of the human papillomavirus (HPV) vaccines: systematic review with meta-analyses of trial data from clinical study reports. Syst. Rev. 9, 43 (2020).

16.       Cohen, J. I., Mocarski, E. S., Raab-Traub, N., Corey, L. & Nabel, G. J. The need and challenges for development of an Epstein-Barr virus vaccine. Vaccine 31, B194–B196 (2013).

17.       Gardner, T. A., Elzey, B. D. & Hahn, N. M. Sipuleucel-T (Provenge) autologous vaccine approved for treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer. Hum. Vaccines Immunother. 8, 534–539 (2012).

18.       Sallusto, F. & Lanzavecchia, A. The instructive role of dendritic cells on T-cell responses. Arthritis Res. 4, S127–S132 (2002).

19.       Rini, B. I. et al. Combination immunotherapy with prostatic acid phosphatase pulsed antigen-presenting cells (provenge) plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy. Cancer 107, 67–74 (2006).

20.       Provenge is one of the best alternative treatment options for prostate cancer | SayPeople. http://saypeople.com/2012/04/15/provenge-is-the-best-alternative-treatment-option-for-prostate-cancer/ (2012).

21.       Anassi, E. & Ndefo, U. A. Sipuleucel-T (Provenge) Injection. Pharm. Ther. 36, 197–202 (2011).

22.       prostate-cancer-metastatic-hormone-relapsed-sipuleucelt-1st-line-id573-final-appraisal-determination-document2.pdf.

23.       SILVERMAN, E. Can we afford the war on cancer? Biotechnol. Healthc. 9, 13–16 (2012).

24.       Jarosławski, S. & Toumi, M. Sipuleucel-T (Provenge(®))-Autopsy of an Innovative Paradigm Change in Cancer Treatment: Why a Single-Product Biotech Company Failed to Capitalize on its Breakthrough Invention. BioDrugs Clin. Immunother. Biopharm. Gene Ther. 29, 301–307 (2015).

25.       mRNA Therapeutics & Vaccines: Immuno-Oncology – Moderna. https://www.modernatx.com/pipeline/therapeutic-areas/mrna-personalized-cancer-vaccines-and-immuno-oncology.

Image credits:

Syringe photo by Karolina Grabowska from Pexels

Lying on bed photo by Ivan Samkov from Pexels

Vaccine photo by cottonbro from Pexels

Test tube photo by Karolina Grabowska from Pexels

Horizon photo by Johannes Plenio from Pexels

Splitter icon by Freepik from www.flaticon.com

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Molecule of the Month: Oxytocin

Literature, religion and philosophy have sought to understand and rationalise the multifaceted aspects of love through poetry, prose and songs. Shakespeare, Rumi and Ariana Grande have tried to encapsulate the heart wrenching passion of romance and why we humans seem to subject ourselves to devotion.

Recently, science has become interested in the physiological and physical process which underlie the feeling of love. Some researchers go as far as to propose that romantic love, specifically, is a natural addiction which has evolved from our ancesotors1

Away from romance, we know that there are many forms of love we are able to experience over a lifetime. The love between the birth-giver and a child is of especial importance as it is the first impression of pair-bonding which the infant partakes in.

The commonality and universal nature of love doesn’t stop at the feelings surrounding them.  However, there is a widening agreement that oxytocin is able to play apart in the formation of social bonds in both passionate and parental loves.

Heart of the issue

Figure 1: Chemical structure of oxytocin which have increasingly been shown to be implicated in both the parental and romantic forms of love.

Oxytocin (Figure 1)2 is a hormone protein made up of only nine amino acid joined together by peptide bonds and other interactions3. Although, the hormone is stored and released from the pituitary gland (Figure 2)4 it is however, made within the hypothalamus region of the brain5.

Figure 2: Shows the hypothalamus where oxytocin is made and the pituitary gland, where oxytocin is stored and then subsequently released into the rest of the body.

Its primary physical function has been found to promote milk production in people who breast-feed6. However, within people who have a penis it is thought to be one of the most potent chemicals which induce an erection7. However, this hormone is now being recognised as an important regulator of social behaviour including the formation of bonds between both parents and partners8.

Oxytocin is able to illicit its various physical and physiological functions through receptors. Receptors are structures on the surface of cells which oxytocin is able to bind to. Binding of oxytocin to a receptor activates internal signalling pathways of the cell which, in turn, triggers the various functions outlined above9.

Parental Bonds

Oxytocin is one of the main hormones that are present at the miracle of childbirth. Several studies have presented that there is a three-to-four times increase of oxytocin, from baseline, during the course of pregnancy10. Additionally, an increase duration, frequency and amplitude of oxytocin release was demonstrated towards the end of labour, right up until birth. 

Oxytocin is known to part of the mechanism that enables both childbirth and lactation to take place11.During childbirth, oxytocin is released, which causes the contraction of muscles within the uterus. Interestingly, more contraction leads to the release of even more oxytocin thereby increasing the strength and rate of contractions, for the birthing process to come to completion5. Contractions are not only important in birthing, but also, play an essential role to minimise post-birth haemorrhage12.

However, some research has suggested that oxytocin does not appear to be as essential to birth as once thought. This is mainly due to the many instances where labour has happened normally where the pituitary gland is not functioning properly11. Therefore, other signalling pathways through a group of hormones called prostaglandins or even through neuronal networks are thought to compensate or even play a larger role in the birthing process13.

However, oxytocin not only plays a part in the physical process of childbirth, but also is involved in the emotional processing of a child. Oxytocin overall helps the person giving birth to the child to bond with their baby. and it has been shown to decrease the experience of pain involved with birth10. Most studies found a positive correlation between parent-infant contact and oxytocin levels right after childbirth. Unsurprisingly, increased oxytocin in the birth-giver were significantly related to more affectionate contact between them and the child14.

This is of significance as the social and behavioural bonds made between the child and its parents are important for future relationships, whether they be romantic or platonic in nature15,16.

Romantic Bonds

From the first murmurings of a crush, to the exhilarating moments of passion, it has been determined that establishing and maintaining romantic relationships can contribute to our mental and physical health so much so that it underpins parts of our well-being17.

Oxytocin is also associated with the bond between lovers as areas of the brain, which support the formation of romantic attachments, are rich in oxytocin receptors where its effects can be circulated18. Additionally, oxytocin levels between new lovers were substantially higher compared to those in non-attached singles, presenting its large role in the initial, romantic bond formation between people19. These results are additionally consistent within prairie voles which are known to be monogamous20

Older studies have presented that oxytocin plays a role in the emotional aspects of love and companionship which encompasses the feeling of care and trust. Greater partner support was linked to higher blood oxytocin level within couples of binary sexes21. Such findings could give some reasoning to why couples who decided to stay together during a study duration showed higher oxytocin levels at the initial period of romantic attachment, compared to those who broke-up19. This suggests that oxytocin could potentially be an indicator of relationship duration.

Oxytocin not only plays a large part in the emotional aspects of love such as companionship and trust, but it is also deeply tied to the physical aspects of romantic love. Following light touches, there has been a measurable rise in oxytocin levels22. On the more steamy end of the scale, a number of studies have shown that following orgasm, of binary sexes, there are higher levels of oxytocin within the blood than previously measured23,24.

One and only?

However, it is important to note that both within parental and romantic attachments oxytocin is not the only hormone eliciting some of the physical and physiological effects. Other hormones, such as vasopressin, cortisol, and sex hormones such as testosterone and oestrogen can play apart in bond formations25,26,27.

Vasopressin, although very structurally similar to oxytocin, is thought to support behaviours needed for guarding a partner or the more possessive side of attachment, such as jealousy within romantic relationships28,29. Within people who birth, vasopressin of the birth-giver is thought to be implicated in greater new born weight loss, however this requires further study30. Interestingly, vasopressin is assumed to play a larger role within expectant fathers within a singular study further compounding vasopressin as a protective hormone31.

Wired to love

Science has tried its best to encapsulate many of the physical and psychological processes which occur when we are exposed to love, whether that be from a partner or a parent-figure. Surprisingly, both the initial stages of romantic and parental love have some of the same behaviours, mental states and activation of brain regions which can be explained through the actions of oxytocin19.

Various cynics of love may comment that the action of love is simply a neurological and physical scam, given that oxytocin and other hormones play a large part in this process. However, looking to understand that love is so tightly sewn into every molecule of body and cell will surely see us through every heartbreak and disappointment.

References:

1.         Fisher, H. E., Xu, X., Aron, A. & Brown, L. L. Intense, Passionate, Romantic Love: A Natural Addiction? How the Fields That Investigate Romance and Substance Abuse Can Inform Each Other. Front. Psychol. 7, (2016).

2.         Koçyiğit, Ü. The Effects of Oxytocin and Oxytocin Receptor Antagonist Atosiban on the Carbonic Anhydrase and Acetylcholinesterase Enzymes from Lung Tissues of Rats. Cumhur. Sci. J. 38, 450–460 (2017).

3.         Lee, H.-J., Macbeth, A. H., Pagani, J. & Young, W. S. Oxytocin: the Great Facilitator of Life. Prog. Neurobiol. 88, 127–151 (2009).

4.         Mayo Foundation for Medical Education and Research. Pituitary gland and hypothalamus. Mayo Clinic https://www.mayoclinic.org/pituitary-gland-and-hypothalamus/img-20005849.

5.         Osilla, E. V. & Sharma, S. Oxytocin. in StatPearls (StatPearls Publishing, 2020).

6.         Uvnäs­Moberg, K. et al. Maternal plasma levels of oxytocin during breastfeeding—A systematic review. PLOS ONE 15, e0235806 (2020).

7.         Thackare, H., Nicholson, H. D. & Whittington, K. Oxytocin—its role in male reproduction and new potential therapeutic uses. Hum. Reprod. Update 12, 437–448 (2006).

8.         Cochran, D., Fallon, D., Hill, M. & Frazier, J. A. The role of oxytocin in psychiatric disorders: A review of biological and therapeutic research findings. Harv. Rev. Psychiatry 21, 219–247 (2013).

9.         Vrachnis, N., Malamas, F. M., Sifakis, S., Deligeoroglou, E. & Iliodromiti, Z. The Oxytocin-Oxytocin Receptor System and Its Antagonists as Tocolytic Agents. International Journal of Endocrinology vol. 2011 e350546 https://www.hindawi.com/journals/ije/2011/350546/ (2011).

10.       Uvnäs-Moberg, K. et al. Maternal plasma levels of oxytocin during physiological childbirth – a systematic review with implications for uterine contractions and central actions of oxytocin. BMC Pregnancy Childbirth 19, 285 (2019).

11.       Arrowsmith, S. & Wray, S. Oxytocin: its mechanism of action and receptor signalling in the myometrium. J. Neuroendocrinol. 26, 356–369 (2014).

12.       McEvoy, A. & Sabir, S. Physiology, Pregnancy Contractions. in StatPearls (StatPearls Publishing, 2020).

13.       Husslein, P. [The importance of oxytocin and prostaglandins to the mechanism of labor in humans]. Wien. Klin. Wochenschr. Suppl. 155, 1–32 (1984).

14.       Scatliffe, N., Casavant, S., Vittner, D. & Cong, X. Oxytocin and early parent-infant interactions: A systematic review. Int. J. Nurs. Sci. 6, 445–453 (2019).

15.       Feldman, R., Gordon, I., Influs, M., Gutbir, T. & Ebstein, R. P. Parental oxytocin and early caregiving jointly shape children’s oxytocin response and social reciprocity. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 38, 1154–1162 (2013).

16.       Santona, A., De Cesare, P., Tognasso, G., De Franceschi, M. & Sciandra, A. The Mediating Role of Romantic Attachment in the Relationship Between Attachment to Parents and Aggression. Front. Psychol. 10, (2019).

17.       Gómez-López, M., Viejo, C. & Ortega-Ruiz, R. Well-Being and Romantic Relationships: A Systematic Review in Adolescence and Emerging Adulthood. Int. J. Environ. Res. Public. Health 16, (2019).

18.       Acevedo, B. P., Aron, A., Fisher, H. E. & Brown, L. L. Neural correlates of long-term intense romantic love. Soc. Cogn. Affect. Neurosci. 7, 145–159 (2012).

19.       Schneiderman, I., Zagoory-Sharon, O., Leckman, J. F. & Feldman, R. Oxytocin during the initial stages of romantic attachment: Relations to couples’ interactive reciprocity. Psychoneuroendocrinology 37, 1277–1285 (2012).

20.       Cormier, Z. Gene switches make prairie voles fall in love. Nat. News doi:10.1038/nature.2013.13112.

21.       Grewen, K. M., Girdler, S. S., Amico, J. & Light, K. C. Effects of Partner Support on Resting Oxytocin, Cortisol, Norepinephrine, and Blood Pressure Before and After Warm Partner Contact. Psychosom. Med. 67, 531–538 (2005).

22.       Hurlemann, R. & Scheele, D. Dissecting the Role of Oxytocin in the Formation and Loss of Social Relationships. Biol. Psychiatry 79, 185–193 (2016).

23.       Carmichael, M. S. et al. Plasma oxytocin increases in the human sexual response. J. Clin. Endocrinol. Metab. 64, 27–31 (1987).

24.       Carmichael, M. S., Warburton, V. L., Dixen, J. & Davidson, J. M. Relationships among cardiovascular, muscular, and oxytocin responses during human sexual activity. Arch. Sex. Behav. 23, 59–79 (1994).

25.       Carter, C. S. & Keverne, E. B. 4 – The Neurobiology of Social Affiliation and Pair Bonding. in Hormones, Brain and Behavior (Second Edition) (eds. Pfaff, D. W., Arnold, A. P., Etgen, A. M., Fahrbach, S. E. & Rubin, R. T.) 137–166 (Academic Press, 2009). doi:10.1016/B978-008088783-8.00004-8.

26.       Gray, P. B. et al. Human male pair bonding and testosterone. Hum. Nat. 15, 119–131 (2004).

27.       Grøntvedt, T. V., Grebe, N. M., Kennair, L. E. O. & Gangestad, S. W. Estrogenic and progestogenic effects of hormonal contraceptives in relation to sexual behavior: insights into extended sexuality. Evol. Hum. Behav. 38, 283–292 (2017).

28.       Carter, C. S. The Role of Oxytocin and Vasopressin in Attachment. Psychodyn. Psychiatry 45, 499–517 (2017).

29.       Baribeau, D. A. & Anagnostou, E. Oxytocin and vasopressin: linking pituitary neuropeptides and their receptors to social neurocircuits. Front. Neurosci. 9, (2015).

30.       Erickson, E. N., Carter, C. S. & Emeis, C. L. Oxytocin, Vasopressin and Prolactin in New Breastfeeding Mothers: Relationship to Clinical Characteristics and Infant Weight Loss. J. Hum. Lact. Off. J. Int. Lact. Consult. Assoc. 36, 136–145 (2020).

31.       Alyousefi-van Dijk, K. et al. Vasopressin Differentially Affects Handgrip Force of Expectant Fathers in Reaction to Own and Unknown Infant Faces. Front. Behav. Neurosci. 13, (2019).

Photo credits:

Heart Sweets by Anete Lusina from Pexels

Standing Sunset by Lisa Fotios from Pexels

Couple by Ketut Subiyanto from Pexels

Wedding cake by SplitShire from Pexels

Flowers by Ketut Subiyanto from Pexels

Heart Icon by Freepik from www.flaticon.com

Featured

Politicisation Of Science

Science shaping policy and our livelihoods: 2020 has shown us the great extent to which the way science is implemented in policy can affect our environment and health. However, the way in which policy is implemented and which ones are put forward are can be dictated by political ideology and thought.

2020 was an unpresented year for everyone around the globe, our lives have fundamentally changed in measurable and immeasurable ways. Last year was also the time for science to shine, as much of our livelihoods from health to agriculture, depends on scientific and research backed policy to aid our quality of living.

However, policymaking is inherently a political action presenting that science does not exist in a political vacuum, but instead shapes our lives, health, environment and economy in various ways. However, the use and manipulation of science for political purposes has increasingly been pushed to the spotlight, with disastrous consequences to human and environmental health.

Some sociologists comment that the practise of science is political all the way through, but suggests that using science in the scope of gaining political power, damages the checks and balances placed within science to keep it from external bias1.

Science and politics have a fraught history, as it can be manipulated to gain political power and suppress opposing views, as done by the geneticist Trofim Denisovich Lysenko within the Soviet Union. However, to think that the suppression of scientists who disagree with centralised government is simply a symptom of communism, or something of the past, is very misguided as scientists in the US, under Trump, have also been exposed to this.

It is important to note that scientists of the past and present have opposed actions from centralised government to suppress information, in a variety of ways, from becoming whistle-blowers, publishing their findings onto journal articles, and more recently, getting directly involved within politics.

Lysenko’s Science Or Nothing

Figure 1: Statue built of Lysenko and Stalin in Stavropol in 1952 presenting the political power that Lysenko reached was due to the fact his genetical theory fit into the agenda Stalin was presenting at the time.

The Soviet famine of 1932-33 claimed the lives of approximately 6.5 million people due to political interferences such as collectivizing, a practise where small landowners were forced to give up their farms to join a collection of farms, and the seizing of grain by the authorities2,3. As drought and crop failures exasperated this issue, this prompted Joseph Stalin, the ruler at the time, to promise a new variety of crop within a four-to-five-year period, even when experts said this would take at least twelve years.

Political pressure placed on scientific institutions was utilised by Trofim Denisovich Lysenko to claim that crop plants such as wheat, potato and sugar beets could be genetically altered by using the environmental conditions that they are placed in. His theory seemed to allow farmers to sow grain in the spring, instead of the previous autumn season4. More importantly, he promised the Soviet government that productive crop varieties could be produced in only two-and-a-half years, thereby fulfilling political pressure leading Stalin favouring his plan (Figure 1)5 over all others6.

Lysenko’s theories were not backed by science but instead met demand from the government which caused his steady rise to power.

His hypothesis of environmental conditions dictating genes strongly mirrored that of the French academic Jean-Baptiste-Lamarck. However, Lysenko’s methods for improving crops were incredibly ambitious and in reality, he falsified his results, in order to gain support from the communist leaders. He additionally, undermined the basic principle of genes by claiming that they were introduced by “bourgeois geneticists”6. This not only set the stage for a complete ban on the teaching and practices of genetics, but also lead to the imprisonment, deaths and firing of many scientists who disagreed with Lysenko or his theories.

The effect of Lysenko and the Soviet Union’s actions to ban the practise and teaching of genetics not only lead to the incredible decline of soviet genetics, evolutionary and developmental biology but also, exasperated food shortages, and deaths, within the region, as everything grown to his methods died or rotted7. This presents a harrowing story when politics is used to influence science, it has the potential to do irreversible human and institutional damage.

Agenda Trumping Science

Figure 2: Suppression : Dr Rod Schoonover (left) was a prominent analyst who was repeatedly blocked from giving testimony on the effects climate change had on national security efforts as the findings did not adhere to the government’s view on the issue. His story is not an isolated event within Trump’s America.

At the start and the end of Trumps time as president he has at every turn minimised or placed climate change deniers at the heart of his administration. Not only has Donald Trump pulled out of the Paris Agreement, a global effort to combat climate change, but he has recently placed a climate change denier in charge of appointing writers to the National Climate Assessment report8. Therefore, it is very clear to comment that his administration is hostile to the views of human induced climate change even when there is “no doubt left” that the planets climate is changing at an alarming rate9.

Dr Rod Schoonover (Figure 2)10, a prominent analyst was repeatedly blocked from not only testifying, but for submitting a report about various national security implications climate change may pose. The administration stopped the report giving the reason that the findings did not agree with the government’s position on climate change. Although he was able to testify, his written statement was not included in the official record of the hearing. He later stepped down from his position as an intelligence analyst.

Within the US, it is important to note that this is not an isolated case as there have been many other instances where scientists have lost their job for refusing to bury facts either about climate change or even the scale of the COVID-19 pandemic11,12.This presents that scientists who present contrasting information from the states views and agendas are currently vilified but that also, governments of all types can be guilty of such practise.

Since the recent win of the House and Senate by the Democrats, there is hope that climate science and discourse around the pandemic will be dealt with experts and that suppression of science is a thing of the distant past within the US13.

Diverging: Science And Politics

Separate Roads?: Within history and the present day, it has been shown that science and politics have been treated as separate entities as misinformed science has shaped policy or science has been suppressed, as it did not cohere to the views of those in power.

These two cases where science was manipulated for political agenda eerily mirror one another, with anyone who disagrees with centralised government being jailed, as in Soviet Russia or being removed from their roles, as demonstrated in Trumps America.

Both of these cases show instances where science clearly presented a direct conflict with the position the government took when regarding agriculture, climate change or the scale of the pandemic. 

However, it is important to note that there are differences between these instances. In Soviet Russia, Lysenko was a “scientist” himself but used falsified results in order gain political power to silence his opponents. However, many scientists in the US are using honest practises to come to their conclusions, which were being suppressed by the government through firings and refusals to chair experts at meetings. This presents that centralised institutions can manipulate science for their own political gain in order to push their own agenda forward by disregarding or burying conflicting information given by scientists.

Politicians must remember that biology and the environment for that matter do not bow to the whims of their agenda or theory, but instead, follows the dictated rules of nature which we scientists aim to understand as much as possible.

Converging: Science With Politics

Figure 3: Speaking out: The March for Science in 2017, in anticipation to a climate-denying administration aimed to present that scientists would not be silenced on a major issue which millions of Americans face every year,

In anticipation of Trumps administration which widely rejected the principle of human caused climate change, there was already a growing mobilisation of individuals from a STEM background. Shortly after his inauguration, there were wide scale protests (Figure 3)14 and the formation of the  314 Action group, which aids and encourages those with a background of science to run for political office15.

In the House of Representatives 2020 election, candidates endorsed by the 314 Action group won 12 of the 14 contests however, they were defending their place after many of them were elected in 2018. The gains, however, were disappointing, especially as health and science issues played a large factor in this election cycle as only two challenges to a seat, out of eight, were successful16.

Losses aside, if this enables voters and their representatives to take a more evidence-based approach to policy making and debates then it is a step in the right direction. However, this group is not without its critics, with some individuals voicing the 314 Action group should be a bipartisan effort, instead of endorsing solely Democratic nominations17.

More drastically, some even suggest prominent journal editors from Nature should not comment or endorse presidential candidates, as done in the American 2020 election claiming that it adds to the politicisation of science18,19. However, it is important to note that the prominent group bending science to their will, is politicians. There is no group more qualified to scrutinise the handling of the pandemic and the suppression of climate science in America than scientists who study and comment on this phenomenon.

Critics who blame the recent politicisation of journal articles might not know at its inception in 1869, Nature, was calling for science and its principles to be taught at schools in the UK20. This presents the interface of science and its impact on society, is inherently political, and scientists have the ability to drive policy which betters human, environmental and societal health.

The resistance

March for Science slogan which highlights the importance of science in society and in everyones lives.

Politics and science are intimately linked with one another with one shaping the other through history , and the present. However, there is a worry when political agenda shapes science, not the other way round, irreparable damage is done to society and scientific progress.

This is demonstrated through history through Stalin’s rule of the Soviet Union which fired, interrogated or jailed researchers whose work opposed the “acceptable” scientific agenda at the time. Worryingly, similar tactics have been utilised under Trumps America to halt climate and pandemic data from being published as it did not cohere to the views of the administration.

Personally, the politicisation of science is not a symptom of either communist or even democratic institutions, it is, however, a hallmark of fascism21.

To think that however, that scientists are accepting the blatant disregard for the scientific process and their eventual findings are unproven, and if anything has helped researchers to mobilise.

Prominent journal editors have in the past and continue to, provide pressure and critique to governments and institutions which dismiss and minimise the findings of reports commenting on the health of both the environment and society. To silence or discourage scientists, of all calibres, away from talking about governments who plainly suppress or politicise scientific findings is a dangerous practise to the foundations of democracy.

However, there is a wide resistance, to bring science informed policy back into politics, which provides hope that by edging closer to closer to scientific truth that we can improve the health of the people and the environment. Looking forward to 2021, we must continue to provide much needed pressure to institutions that disregard or politicise aspects of science to their agenda.

Note: The phrase communism used throughout the article is used to describe Stalinism but in the interest of simplification have been conflated with one another. My understanding of political theory and different government types are rudimentary at best so if there is any one more versed than me, I would be more than happy to engage in a constructive discussion

Image sources:

Policy collage: Photo by August de Richelieu from Pexels + Photo by Artem Podrez from Pexels

Lysenko: https://www.theatlantic.com/science/archive/2017/12/trofim-lysenko-soviet-union-russia/548786/

Science and Politics sign post: https://medium.com/@priyology/surviving-the-science-politics-interface-8be2b3898252

Science not silence slogan: https://marchforscience.org/science-not-silence-march-for-science/

Spacers: Pipette Icons made by Eucalyp from www.flaticon.com + Politics Icons made by Freepik from www.flaticon.com

References:

1.         Brown, R. H. & Malone, E. L. Reason, Politics, and the Politics of Truth: How Science Is Both Autonomous and Dependent. Sociol. Theory 22, 106–122 (2004).

2.         The Editors of Encyclopaedia Britannica. collectivization | Definition & Facts. Encyclopedia Britannica https://www.britannica.com/topic/collectivization.

3.         R.W. Davies & S.G. Wheatcroft. The Years of Hunger: Soviet Agriculture.

4.         Kolchinsky, E. I., Kutschera, U., Hossfeld, U. & Levit, G. S. Russia’s new Lysenkoism. Curr. Biol. 27, R1042–R1047 (2017).

5.         Borinskaya, S. A., Ermolaev, A. I. & Kolchinsky, E. I. Lysenkoism Against Genetics: The Meeting of the Lenin All-Union Academy of Agricultural Sciences of August 1948, Its Background, Causes, and Aftermath. Genetics 212, 1–12 (2019).

6.         Soyfer, V. N. The consequences of political dictatorship for Russian science. Nat. Rev. Genet. 2, 723–729 (2001).

7.         Kean, S. The Soviet Era’s Deadliest Scientist Is Regaining Popularity in Russia. The Atlantic https://www.theatlantic.com/science/archive/2017/12/trofim-lysenko-soviet-union-russia/548786/ (2017).

8.         Waldmann, S., E, NewsNov. 10, E., 2020 & Am, 11:45. Trump to put climate change denier in charge of key U.S. report. Science | AAAS https://www.sciencemag.org/news/2020/11/trump-put-climate-denier-charge-key-us-report (2020).

9.         Watts, J. ‘No doubt left’ about scientific consensus on global warming, say experts. The Guardian (2019).

10.       Davenport, C. State Dept. Intelligence Analyst Quits to Protest Blocked House Testimony (Published 2019). The New York Times (2019).

11.       Caffrey, M. I’m a scientist. Under Trump I lost my job for refusing to hide climate crisis facts | Maria Caffrey. The Guardian (2019).

12.       Luscombe, R. Florida scientist says she was fired for refusing to change Covid-19 data ‘to support reopen plan’. The Guardian (2020).

13.       Tollefson, J. Scientists relieved as Joe Biden wins tight US presidential election. Nature 587, 183–184 (2020).

14.       Stark, H. The March For Science: Why It Was Really Successful. Forbes https://www.forbes.com/sites/haroldstark/2017/04/23/the-march-for-science-in-dc-and-around-the-world/.

15.       Foley, K. E. Obama’s former science advisor says there are four things scientists should do to fight Trump. Quartz https://qz.com/914280/obamas-former-science-advisor-says-there-are-four-things-scientists-should-do-to-stay-relevant-under-trump/.

16.       Daley, J. New Scientist-Candidates for U.S. Congress Fared Worse Than Expected in 2020. Scientific American https://www.scientificamerican.com/article/new-scientist-candidates-for-u-s-congress-fared-worse-than-expected-in-2020/.

17.       Berezow, A. 314 Action Wants to Elect Scientists, But Only if They’re Democrats. American Council on Science and Health https://www.acsh.org/news/2018/02/22/314-action-wants-elect-scientists-only-if-theyre-democrats-12612 (2018).

18.       Kanter, G. P. Science journal editors shouldn’t contribute to politicizing science. STAT https://www.statnews.com/2020/10/23/science-journal-editors-shouldnt-contribute-to-politicizing-science/ (2020).

19.       Why Nature supports Joe Biden for US president. Nature 586, 335–335 (2020).

20.       Tuckwell, W. Science-Teaching in Schools. Nature 1, 18–20 (1869).

21.       Cliff, J. S. Science Under Fascism and Democracy. Nature 152, 306–307 (1943).

Featured

Anti-vaccine: Past, Present… and future?

Image credit: https://www.pexels.com/photo/flat-lay-of-covid-vaccines-5863278/

Early last week, news broke that the initial findings of Pfizer’s coronavirus vaccine showed a 90% efficacy rate against COVID-191. Although this brings new hope that life may soon resemble the normalcy, we all so crave, the scientific community is treading lightly as the full data is not available and even then, such data will require rigorous cross-examination.

However, after the logistical and manufacturing hurdles with creating millions of doses, the general public need to be willing to accept the vaccine. This has the potential to be somewhat a difficult task given the revival of various anti-vaccination movements. Global studies which aimed to map vaccine confidence are unearthing hotspots of hesitancy, presenting that confidence is remaining low, but improving across Europe, compared to that of other continents2. This poses an additional social and community challenge to improve confidence in vaccines, especially a COVID-19 one.

Confidence and the usage of a vaccine is shown to be intimately linked, as study by the Vaccine Confidence Project, at the London School of Hygiene and Tropical Medicine, found that individuals being confident in the importance and efficacy of a vaccine has the “strongest associations with vaccine uptake” when compared with other factors2.

Coming to terms with the existence of a community which aims to dismantle trust between scientists and society is difficult, but it is important to note that anti-vaccination groups have persisted and existed throughout history. Looking at the motivations, core values and drivers of those who sow distrust in a well-studied avenue of science might be the key to improving confidence and finally, the uptake of any vaccine.

A century old practice

Figure 1: Variola virus is the infectious agent causing smallpox which Edward Jenner popularised a vaccine for in the Western world.

The idea to use vaccines to manage infectious diseases has been around for at least a century and has been documented, as early as 1714, in parts of the Ottoman Empire, Europe and China3. Long before the 18th century, it is thought that these practises were carried out in parts of Africa and India when people were faced with an outbreak of various infectious diseases which include small pox4.

In the eighteenth century, smallpox (Figure 15) accounted for about 10% of all deaths and was especially aggressive within adolescents. Not only was the virus in question, easily spread and contagious, those who survived were left with physical disfigurements and could even go blind6. Since 1664 there were more than 320,000 recorded deaths from smallpox within London presenting the a need for a suitable treatment or preventative measure7.

Edward Jenner, a physician at the time, noticed that individuals which were exposed to infectious material from cowpox also presented immunity to smallpox. After a series of experiments presented that individuals could be protected from smallpox in this way, he showed his findings to the medical establishment who consequently accepted them. Jenner was the first individual to coin the term “vaccination” and to popularise it as a way to prevent disease outbreaks within the Western Hemisphere8.

The Vaccination and the Contagious Disease Acts of 1840-1867 in the UK which followed provided free vaccination of smallpox and later, made the vaccine compulsory to infants and teenagers. Penalties were issued to guardians and parents that did not abide. These laws were met with great resistance as they extended government powers into personal liberties due to the mounting public health crisis caused by small-pox9.

Mirroring: Past and Present Resistance

Resistance of vaccination was widespread in the UK shortly after the introduction of compulsory vaccination. A large number of anti-vaccination books, journals and images of what people perceived vaccination to be (Figure 210) came into circulation8. Interestingly such pictures, which can be perceived as propaganda to encourage anti-vaccination movements, present doctors and even Edward Jenner himself, as feeding this hideous cow-like beast, representing vaccination, young children. However it is important to note that such resistance was not isolated to the UK, but was rampant within other parts of Europe and even the USA at the time8,11.

Figure 2 -Belly of the Beast- A politically motivated print which depicts the act of vaccination as a beast which guzzles and has an appetite for young children. The ant-vaccine troupe is pictured wielding sword and shields probably as defenders of liberty and freedom.

Similarly, opposition to vaccination can be seen even within this century even whilst grappling with a pandemic that a vaccine hopes to provide an exit. Interestingly, a study published in BMJ, presented that the arguments from both present day and 19th century anti-vaccination groups show “uncanny similarities” presenting the “core-beliefs” and attitudes associated with vaccination have not changed8. These attitudes include but are not limited to, that vaccines cause illness, are ineffective and only provide temporary immunity towards disease. 

Interestingly, the language aiming to discourage others to use vaccines have changed significantly. In an article published by Nature, the director of the Vaccine Confidence Project, Heidi Larson, commented that modern anti-vaccination movements are gaining following through the use of “personalised, emotive” language which aims to “appeal to the heart” instead of mainly using fear-based tactics as shown through history12.

In the end, the Vaccination Act of 1898 removed the penalties when guardians did not vaccinate their children against smallpox. Additionally, it included a clause which allowed parents, who believed vaccines were not effective or safe, to obtain an exception certificate.

However, such exception comes at a societal cost

Freedom to refuse, at what cost?

Image showing anti-mandatory vaccine groups at a protest in Hyde Park (Sydney)
Image credit: https://www.abc.net.au/news/2020-05-31/anti-vaxxers-are-exploiting-the-coronavirus-crisis/12302710?nw=0

Many of the arguments which anti-vaccination groups of the past and present have used to refuse mandated vaccines was to demand the freedom to choose whether they wanted to be inoculated or not.

This presents an unique ethical dilemma where bodily autonomy and wide societal benefits are at odds with one another. 

Autonomy of body is an essential liberty which must be respected on every level. However, to achieve herd immunity through the means of vaccination large amounts of the population need to take up said vaccine. For example, for a population to acquire herd immunity through the use of a COVD-19 vaccine more than 60% of a population needs to be inncolutated13. Surpassing the manufacturing and logistics problems of creating millions of doses, the population need to be confident and willing to use this vaccine.

Ultimately, vaccine usage is not only in the interest of personal health, but to that of the community too

Social media and anti-vaxxers: Toxic relations

Image credit: Character vector created by pikisuperstar – www.freepik.com

The tactics of anti-vaccine literature have since evolved in the 20th century due to technological advancement. Such literature has the potential to be distributed in a wide variety of formats over various social media platforms. However, it is important to note that today, such media being circulated can be just as, if not, more damaging as it can reach communities who are undecided on the importance of vaccination.

A paper published in Nature found that although anti-vaccine groups on social media were smaller in size, compared to that of pro-vaccine groups they have the tendency to become “highly entangled” with users who were “undecided about vaccination”14. Worryingly, such groups are entangling themselves with school associations which may still deciding their stance on policy, presenting the influence and power that anti-vaccination groups have on the health of a community.

Therefore, overlooking the importance that the social media presence anti-vaccination communities use will be fatal if we are to dispel the myths and disinformation these groups make15. This presents that social media companies have just as much of a responsibility as the scientific community.

As of October 2020, Facebook has since banned adverts that discourage people from getting the seasonal flu vaccine. However, it has still allowed an anti-vaccine ‘discussion’ to be found, especially within Facebook group pages16. It is unclear how this policy will impact anti-vaccination groups and thinking.

The future?

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Anti-vaccination groups may be smaller in size currently however, extrapolation and modelling studies have suggested that the current rate at which these groups are becoming popularised may cause the size of anti-vaccination groups to exceed pro-vaccine groups within ten years.14

Such findings present there is immeasurable work to done against the rising tide of anti-vaccination groups. Scientists, pharmaceutical companies and finally policy makers have a duty to the wider community to restore the trust eroded by these groups by being transparent with how vaccines are made and what kind of regulatory procedures need to be passed in order for a vaccine to come to market.

Finally, there is hope by better understanding the motivations of past anti-vaccination movements that researchers and communities alike can open a healthy, insightful dialogue on the many benefits of vaccination.  

References:

1.         Thomas, K., Gelles, D. & Zimmer, C. Pfizer’s Early Data Shows Vaccine Is More Than 90% Effective. The New York Times (2020).

2.         Figueiredo, A. de, Simas, C., Karafillakis, E., Paterson, P. & Larson, H. J. Mapping global trends in vaccine confidence and investigating barriers to vaccine uptake: a large-scale retrospective temporal modelling study. The Lancet 396, 898–908 (2020).

3.         Boylston, A. The origins of inoculation. J. R. Soc. Med. 105, 309–313 (2012).

4.         Riedel, S. Edward Jenner and the history of smallpox and vaccination. Proc. Bayl. Univ. Med. Cent. 18, 21–25 (2005).

5.         Kupferschmidt, K. How Canadian researchers reconstituted an extinct poxvirus for $100,000 using mail-order DNA. Science (2017) doi:10.1126/science.aan7069.

6.         Smith, K. A. Edward Jenner and the Small Pox Vaccine. Front. Immunol. 2, (2011).

7.         Krylova, O. & Earn, D. J. D. Patterns of smallpox mortality in London, England, over three centuries. bioRxiv 771220 (2019) doi:10.1101/771220.

8.         Wolfe, R. M. & Sharp, L. K. Anti-vaccinationists past and present. BMJ 325, 430–432 (2002).

9.         Porter, D. & Porter, R. The politics of prevention: anti-vaccinationism and public health in nineteenth-century England. Med. Hist. 32, 231–252 (1988).

10.       Unknown. Vaccination | British Museum.

11.       Siddiqui, M., Salmon, D. A. & Omer, S. B. Epidemiology of vaccine hesitancy in the United States. Hum. Vaccines Immunother. 9, 2643–2648 (2013).

12.       Ball, P. Anti-vaccine movement could undermine efforts to end coronavirus pandemic, researchers warn. Nature 581, 251–251 (2020).

13.       Anderson, R. M., Hollingsworth, T. D., Baggaley, R. F., Maddren, R. & Vegvari, C. COVID-19 spread in the UK: the end of the beginning? The Lancet 396, 587–590 (2020).

14.       Johnson, N. F. et al. The online competition between pro- and anti-vaccination views. Nature 582, 230–233 (2020).

15.       Evrony, A. & Caplan, A. The overlooked dangers of anti-vaccination groups’ social media presence. Hum. Vaccines Immunother. 13, 1475–1476 (2017).

16.       Paul, K. & agencies. Facebook to ban ads discouraging vaccination. The Guardian (2020).

17.       Riedel, S. Edward Jenner and the history of smallpox and vaccination. Proc. Bayl. Univ. Med. Cent. 18, 21–25 (2005).

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Featured

Molecule of the Month: ATP

ATP, or adenosine triphosphate is a molecule which you simply can’t escape if you study science, as so many cellular processes depend on it. The very fibre of our being, our DNA, has aspects of this molecule and allows life to simply flourish.

This wondrous, multi-faceted molecule is the “energy currency” of the cell1, as it provides the “price” which comes along with synthesising and seeing reactions within the body to completion. Every hour, and with every breath, our body is generating this currency so that actions as simple as muscle contraction and essential involuntary processes can take place.

The Wolf of Wall St

When reviewing the overall structure of ATP, the bonds and how they relate to its function, it is not too far off to suggest nature has selected a powerful, chemically harmonious molecule to provide chemical energy. In a helpful sense, the name of ATP can help us construct an idea of what the molecule looks like. Each molecule of ATP is made up of an adenosine nucleotide, a ribose sugar and three phosphate groups. (Figure 1)2

Figure 1- Small, but mighty: The structure of ATP, the three phosphate groups, ribose sugar and the nitrogenous base makes it an ideal molecule for storing chemical energy.

The bonds linking the two phosphate groups to one another are covalent in nature, however they are specifically called phosphoanhydride bonds.3 These bonds are incredibly important as the energy used to fuel biochemical processes and reactions are contained within these bonds. 

Biochemical Battery

In order to release the true power of ATP, the phosphoanhydride bond between the last and adjacent phosphate need to be broken. The chemical process where one of the bonds break, turning ATP into ADP and its associated inorganic phosphate, is mediated by the addition of water. Such reactions, named hydrolysis reactions, are not only limited to ATP, but most biochemicals such as proteins, DNA and carbohydrates.

The difference between ATP and ADP can be thought of like a battery (Figure 2)4 where ATP is the charged molecule, ready to power reactions. After hydrolysis, ADP requires charging via respiration, and the addition of an inorganic phosphate molecule, to return to its charged state.

Figure 2 -Charged for greatness, ATP can undergo hydrolysis reactions to produce ADP which releases a large amount of free energy to link biochemical reactions and processes which would otherwise wouldn’t occur.

Energy is released upon the hydrolysis of ATP for two main reasons. First, there is a great amount of repulsion between the phosphate molecules as they contain a negative charge and are “forced” to be next to one another1. Upon hydrolysis, this repulsion is relieved. Secondly, the products of this reaction, ADP and Pi exist on a lower energy state that the reactants, ATP and water.

Glucose Guardian

ATP is one of the many molecules that makes the process of simply existing, respiration, possible. Respirations is a complex, multi-step process mediated by various organs and the reactions which make this possible is mediated and moreover, possible due to ATP.

However, to really exemplify the purchasing power, as I like to call it, that ATP has we can look at the conversion of a sugar molecule, glucose, into pyruvate.

Just like you cannot make something as complex as cake directly from egg alone, glucose undergoes incremental changes via the use of various “ingredients” to produce pyruvate. The outcome of might not be as tasty as cake however, pyruvate is an important intermediate molecule. Pyruvate has the ability to go into the later stages of respiration and can concentrate itself into fatty acids. Where pyruvate is destined is dependent on the bodies needs and requirements and is adjusted accordingly.

Of the many steps required to produce pyruvate from glucose, the first reaction actually requires the “exchange power” that comes with the hydrolysis of ATP. The first step of this reaction is the conversion of glucose to glucose-6-phosphate (Figure 3)5

Figure 3 – Coupled Up: The breakage of bonds and their reformation, especially for the formation of glucose-6-phosphate, costs energy which the hydrolysis of ATP readily provides.

Although the reaction is mediated by the enzyme hexokinase, the hydrolysis of ATP is an integral part of the process for producing glucose-6-phosphate.

ATP has a twofold purpose in this case, it is a phosphate donor but more importantly, provides the energy required to form glucose-6-phosphate. Without ATP, the conversion of glucose-6-phosphate from glucose would not take place as it deemed “energetically unfavourable” and cannot progress towards completion 6. A process known as reaction coupling, links the hydrolysis of ATP to the formation of glucose-6-phosphate.

The formation of glucose-6-phosphate is an incredibly important biochemical reaction as it both traps glucose, in the form of glucose-6-phosphate, within the cell membrane and the phosphoryl group destabilises glucose, facilitating its further breakdown5.

ATP has been described as approaching “perfection” as the cellular currency the body uses between the energy stored within the bonds and the way in which the hydrolysis reactions are coupled with unfavorable reactions 7. However, there is an emerging consensus and evidence that extracellular (outside of the cell) ATP plays a role in the immune system responses and wider signalling8,9,10.

Nevertheless, the exchange power the ATP utilises has been around since the dawn of biological evolution, right up to the present day presenting the powerful driving force of nature itself 11

Note: “Glucose-6-phosphate” simply means the phosphate molecule is attached to carbon number 6 of the glucose molecule. It is a way in which students and scientists around the world can identify where the modification can take place, and to construct a picture of what the molecule looks like.

References:

1.         Dunn, J. & Grider, M. H. Physiology, Adenosine Triphosphate (ATP). in StatPearls (StatPearls Publishing, 2020).

2.         ATP structure + function. Loreto Sixth Form College A level Biology http://loretocollegebiology.weebly.com/atp-structure–function.html.

3.         Alberts, B. et al. The Chemical Components of a Cell. Mol. Biol. Cell 4th Ed. (2002).

4.         Energy Conversions | BioNinja. https://ib.bioninja.com.au/higher-level/topic-8-metabolism-cell/untitled/energy-conversions.html.

5.         Berg, J. M., Tymoczko, J. L. & Stryer, L. Glycolysis Is an Energy-Conversion Pathway in Many Organisms. Biochem. 5th Ed. (2002).

6.         Cooper, G. M. Metabolic Energy. Cell Mol. Approach 2nd Ed. (2000).

7.         Walsh, C. T., Tu, B. P. & Tang, Y. Eight Kinetically Stable but Thermodynamically Activated Molecules that Power Cell Metabolism. Chem. Rev. 118, 1460–1494 (2018).

8.         Faas, M. M., Sáez, T. & de Vos, P. Extracellular ATP and adenosine: The Yin and Yang in immune responses? Mol. Aspects Med. 55, 9–19 (2017).

9.         Trautmann, A. Extracellular ATP in the Immune System: More Than Just a “Danger Signal”. Sci. Signal. 2, pe6–pe6 (2009).

10.       KHAKH, B. S. & BURNSTOCK, G. The Double Life of ATP. The Scientific American 84–92 (2009).

11.       Plattner, H. & Verkhratsky, A. Inseparable tandem: evolution chooses ATP and Ca2+ to control life, death and cellular signalling. Philos. Trans. R. Soc. B Biol. Sci. 371, 20150419 (2016).

Sex and the immune system

Society would have us believe that men and women are vastly different from one another, that the bridge between these binaries causes confusion, hurt, and pain. Although, the term “Men come from Mars and Women come from Venus” has been critically analysed time and time again, when looking at the workings of the immune system, between the sexes, it couldn’t be more accurate.

The immune system informs the way in which we respond to disease, vaccination, and the susceptibility of autoimmune conditions. Although, people generally contain the same immune workings and cells, there are stark differences between the sexes in how the innate and adaptive immune system work with one another.

Beyond the binary classification, intersex individuals concrete the evidence that these immune differences are caused by differing genetic and hormonal profiles. Worryingly, even though these differences are well researched, there is little to no change in clinical advice when our eventual hope is to personalise medicine for better patient outcomes.

Two sides of the same coin: Adaptive and Innate immune system

The immune system protects us from a wide range of disease-causing agents, and it is split up into adaptive and innate systems (Figure 1)1 which mirrors the different approaches required for different kinds of biological threats.  

Figure 1: Shows the different approaches that the innate and the adaptive arms of the immune system use to clear infections. Although the eventual removal of the infectious agent is the primary outcome of both pathways adaptive responses are more specific and forms the basis of the memory response.

Generally, the innate system is seen as our “first line of defence” and the cells which fall under this classification can successfully control common bacterial infections2. Although, this part of the immune system is very powerful, these cells cannot always clear chronic infections coming from viruses.

This means that a more specific and robust response is required that is provided by the adaptive immune arm of the system. The adaptive immune response is one of the most powerful ways in which the cells of our body aim to overcome and clear infections. Not only does the adaptive response actively kill pathogens, but it also facilitates a memory response which is the underlying principle of vaccination.

Worlds apart

Proteins that are able recognise bacterial molecular structures are known as toll-like-receptors (TLR) and play a large role in informing the innate immune response within humans3. Interestingly, the amount of toll-like-receptor 7 (TLR7) is higher within binary females, when compared to their male counterparts4.

These proteins are integral structures to the immune system as it triggers the clearance of various pathogens, including influenza A and Hepatitis C5. Furthermore, TLR7 can shape and inform the adaptive immune response which is integral to human health and vaccination response.

One of the most important cell types in the adaptive arm of the immune system are T-cells. These cells are ultimately responsible for the establishment, maintenance, and memory functions of the immune system. T-cells form a wide range of subcategories (Figure 2)6 that have distinctive functions from one another.

Figure 2: Shows how immature T-cells come to maturity though various pathways and signals provided by dendritic cells. Once these T-cells reach maturity they can form different subsets which coordinates the response to clear infection.

CD4+ and CD8+ T-cells are of particular importance as CD8+ cells can directly kill infected cells, whereas, CD4+ cells can regulate the immune response7.

Surprisingly, even the type of T-cells between the sexes can differ greatly.

Across nearly every ethnic group, females generally have a higher CD4+ T cell count and higher CD4/CD8 ratio when compared to their similarly aged males4. It is important to note that a higher CD4/CD8 ratio is hallmarked as having a robust immune system.

Cause…and effect

These differences in the adaptive and innate immune systems have a wide range effects on how women and men respond to disease, infection, and vaccination.

Of particular importance, TLRs plays a distinctive role in the way females have a stronger reaction to immune stimulatory molecules within vaccines8. This is thought to be one of the many reasons why females generally have more frequent and adverse reactions to immunisation9. Furthermore, a study found that women receiving a half dose of a flu vaccine generated a higher immune response compared to males who had a full dose, presenting that these sex differences pervade into how disease is managed within society10.

Although, TLR7 is important in controlling the clearance of viruses, it is also a key progressor of systemic lupus erythematosus (SLE) where the immune system attacks its own tissues, causing wide scale inflammation11. As females have a greater amount of TL7R, it is unsurprising to hear that SLE affects women nine times more frequently than men12.

It is a well-documented phenomenon that the outcome of Hepatitis B, HIV and influenza infections differ between the sexes. For example, death from the 2009 influenza outbreak in North America was two times greater within women, even though they have a lower exposure rate compared to men13. Although, it is expected that a robust immune system, marked by the high CD8/CD4 ratio, should clear the infection without difficulty, it is thought that this increases the development of symptoms associated with the disease14.

It’s hormonal and genetic

The biggest genetic difference between men and women are their sex chromosome characterisation which has a wide influence on the immune system.

Binary women have a XX sex chromosome characteristic, whereas binary men have a XY characteristic (Figure 3)14.  During early embryo development, XX females undergo a process called X-inactivation where a random X chromosome becomes silenced15.

Figure 3: Shows the binary XX and XY sex chromosomes which determines an individual’s sex.

The process of X-inactivation is important within XX females as without this process the second X chromosome can “double up” the number of genes16.  

However, this silencing is not perfect as 15 to 23% of X-linked human genes can escape this inactivation meaning the genes are able to be expressed at the same time17. Of particular importance, TLR7 can escape this silencing which is thought to be the reasoning to why TLR7 proteins are so much higher within females compared to males10.

Away from genetic differences, the hormonal profile of biological men and women differ greatly, and they can influence and shape the immune system. The sex hormone predominately within men, testosterone, suppresses the immune system whereas, oestrogen, within females, enhances the effects the immune system18. However, especially within binary women, there is an added layer of complexity as the hormonal states can fluctuate during the menstrual cycle and even menopause19,20.

Breaking away from binary

When making these general observations about how sex, chromosomes, and hormones can affect immunity it is important to note that some individuals break away from binary sex classification. Biological sex can transcend this dualistic organisation of XX or XY sex chromosomes 20.

Individuals with Klinefelter Syndrome have male traits however, due to a random error during fertilisation, they can carry an extra X chromosome meaning their sex chromosome characterisation is XXY21.

People that carry an extra X chromosome respond like binary females as they have a characteristic higher CD4+ T cell number and higher CD4/CD8 T cell ratio when compared to XY males22.  Interestingly, the immunological profile that people with Klinefelter Syndrome have can be reversed by testosterone therapy, further presenting the importance of how sex hormones can influence the immune system22.

Not only do these findings strengthen the argument that these immune differences are due to differing genetic and hormonal profiles, but it also suggests medical interventions, such as hormone therapy, can have large effects on an individual’s immune system.

Widening horizons

Despite the well-researched sex differences in how the immune system works, clinical and vaccination decisions have not addressed these distinctions. This is incredibly concerning as the susceptibility and outcome of infections, diseases and even vaccination has shown sex bias.

This utopia of addressing different treatment courses based on sex requires primary research to funnel resources and funding towards more sex-inclusive studies. Inappropriate dosing recommendations, which put women in danger of various side-effects, may be due to pre-clinical studies not separating their data by sex or even including female specimens within their studies23. Separating sex data is important as further analysis could be made about any differences therefore, going to inform policy change to address these issues24.

Going even further, researchers alongside clinicians, need to include those who transcend our society’s thoughts on sex and gender. Although, there has been more effort to conclude the effects of hormone therapy on bone density within transgender individuals, more effort should be made in how hormone therapy may influence the workings of the immune system25.

While it is important to consider how sex influences the immune system, other factors such as diet, the microbiome, and age also play a part in the responsiveness and robustness of the immune response. This presents great complexity into researching human immune sex differences26,27.

The sooner that sex and gender is considered as a human variables within studies, clinical trials, and healthcare the sooner tailored interventions can produce effective results focusing on the these factors4,20.

Note: In this article when I am referring to “sex” these are biologically defined using sex chromosomes, hormones, and characteristics. This is separate from “gender” which is more societal and mostly refers to behaviours and or roles. This is not a discussion into whether these are separate or even exist and any hateful comments will be deleted.

References:

1.         Akiko Iwasaki. BioRender. https://app.biorender.com/biorender-templates/t-5f176d764f5fad00a77918e1-innate-and-adaptive-immunity.

2.         Charles A Janeway, J., Travers, P., Walport, M. & Shlomchik, M. J. Principles of innate and adaptive immunity. Immunobiol. Immune Syst. Health Dis. 5th Ed. (2001).

3.         Kawasaki, T. & Kawai, T. Toll-Like Receptor Signaling Pathways. Front. Immunol. 5, (2014).

4.         Klein, S. L. & Flanagan, K. L. Sex differences in immune responses. Nat. Rev. Immunol. 16, 626–638 (2016).

5.         Fischinger, S., Boudreau, C. M., Butler, A. L., Streeck, H. & Alter, G. Sex differences in vaccine-induced humoral immunity. Semin. Immunopathol. 41, 239–249 (2019).

6.         Anna Lazaratos. BioRender Templates. https://app.biorender.com/illustrations/edit/608a898ad0a9d300a33da08b.

7.         Robins, H., Emerson, R., Sherwood, A. & Desmarais, C. CD4+ and CD8+ T cell β antigen receptors have different and predictable V and J gene usage and CDR3 lengths (115.10). J. Immunol. 188, 115.10-115.10 (2012).

8.         Fischinger, S., Boudreau, C. M., Butler, A. L., Streeck, H. & Alter, G. Sex differences in vaccine-induced humoral immunity. Semin. Immunopathol. 41, 239–249 (2019).

9.         Klein, S. L., Marriott, I. & Fish, E. N. Sex-based differences in immune function and responses to vaccination. Trans. R. Soc. Trop. Med. Hyg. 109, 9–15 (2015).

10.       Engler, R. J. M. et al. Half- vs full-dose trivalent inactivated influenza vaccine (2004-2005): age, dose, and sex effects on immune responses. Arch. Intern. Med. 168, 2405–2414 (2008).

11.       Souyris, M. et al. TLR7 escapes X chromosome inactivation in immune cells. Sci. Immunol. 3, (2018).

12.       Rider, V. et al. Gender Bias in Human Systemic Lupus Erythematosus: A Problem of Steroid Receptor Action? Front. Immunol. 9, (2018).

13.       Zarychanski, R. et al. Correlates of severe disease in patients with 2009 pandemic influenza (H1N1) virus infection. CMAJ Can. Med. Assoc. J. J. Assoc. Medicale Can. 182, 257–264 (2010).

14.       Klein, S. L. Immune Cells Have Sex and So Should Journal Articles. Endocrinology 153, 2544–2550 (2012).

15.       Graves, J. Sex, genes, the Y chromosome and the future of men. The Conversation http://theconversation.com/sex-genes-the-y-chromosome-and-the-future-of-men-32893.

16.       DISTECHE, C. M. & BERLETCH, J. B. X-chromosome inactivation and escape. J. Genet. 94, 591–599 (2015).

17.       Kalantry, S. Recent Advances in X-Chromosome Inactivation. J. Cell. Physiol. 226, 1714–1718 (2011).

18.       Souyris, M., Mejía, J. E., Chaumeil, J. & Guéry, J.-C. Female predisposition to TLR7-driven autoimmunity: gene dosage and the escape from X chromosome inactivation. Semin. Immunopathol. 41, 153–164 (2019).

19.       Taneja, V. Sex Hormones Determine Immune Response. Front. Immunol. 9, (2018).

20.       Bhatia, A., Sekhon, H. K. & Kaur, G. Sex Hormones and Immune Dimorphism. Sci. World J. 2014, (2014).

21.       Gameiro, C. M., Romão, F. & Castelo-Branco, C. Menopause and aging: changes in the immune system–a review. Maturitas 67, 316–320 (2010).

22.       Differences, I. of M. (US) C. on U. the B. of S. and G., Wizemann, T. M. & Pardue, M.-L. The Future of Research on Biological Sex Differences: Challenges and Opportunities. Exploring the Biological Contributions to Human Health: Does Sex Matter? (National Academies Press (US), 2001).

23.       Los, E. & Ford, G. A. Klinefelter Syndrome. in StatPearls (StatPearls Publishing, 2021).

24.       Koçar, I. H. et al. The effect of testosterone replacement treatment on immunological features of patients with Klinefelter’s syndrome. Clin. Exp. Immunol. 121, 448–452 (2000).

25.       Ravindran, T. S., Teerawattananon, Y., Tannenbaum, C. & Vijayasingham, L. Making pharmaceutical research and regulation work for women. BMJ 371, m3808 (2020).

26.       Vijayasingham, L., Bischof, E. & Wolfe, J. Sex-disaggregated data in COVID-19 vaccine trials. The Lancet 397, 966–967 (2021).

27.       Stevenson, M. O. & Tangpricha, V. Osteoporosis and Bone Health in Transgender Persons. Endocrinol. Metab. Clin. North Am. 48, 421–427 (2019).

28.       Lambring, C. B. et al. Impact of the Microbiome on the Immune System. Crit. Rev. Immunol. 39, 313–328 (2019).

29.       Montecino-Rodriguez, E., Berent-Maoz, B. & Dorshkind, K. Causes, consequences, and reversal of immune system aging. J. Clin. Invest. 123, 958–965 (2013).

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Molecule of the Month: Gluten

Breads, pastries and cakes are foods humans have been making and devouring for centuries. In particular, bread has been a central staple of our diet as scientists in 2018 discovered evidence of bread-making from a 14,000-year-old dig site1.

One central component to breads and other baked goods is gluten. This molecule able to provide unique structure and stability that produces the moreish crumb we are all too familiar with. However, the wonders of gluten do not stop there, as many individuals who avoid meat also use high gluten mixtures as a meat substitute.

Nevertheless, it is important to note that gluten is not well-tolerated within some individuals and can even manifest as celiac disease, a condition where the immune system responds to gluten molecules. Although, gluten free diets are the only means for controlling intolerances, they have become popularised to those not sensitive to gluten. Even though gluten free foods may be perceived by the general public as being healthier to aid weight loss, the scientific evidence is inconsistent presenting great uncertainties with these claims.

Grains to Gluten

Gluten is a protein stored within a wide variety of grains such as wheat, barley and rye to support germination and seedling development2. Grains, especially wheat, are made up of three distinct parts (Figure 1)3 named the embryo, endoplasm, and bran. While the embryo ensures the formation of the next generation, the endosperm stores gluten and starch to support and nourish future development4

Figure 1: The structure of grains include the bran, endosperm and germ which all have a function to ensure the viability of the next generation of plants.

Gluten does not define a singular protein within the wheat, but instead, forms the basis of a complex mixture of related, yet distinct proteins5. Although, there are many sub-categories of gluten, the two main biochemical groups are gliadin and glutenin.

Complex structures

Gluten is widely utilised in baking as it is able to act as a binding agent and is used within processed foods to improve both flavour and texture. However, bread predominantly relies on the tight knit, springy texture that gluten provides through various bonds.

The structure of dough is down to a range of chemical interactions such as hydrogen, ionic and covalent bonds. Hydrogen bonds, an interaction between a hydrogen and another atom, takes place when the gluten is hydrated. Generally, hydrogen bonds are weak in isolation, but with the process of kneading, more bonds are able to form between the gluten (Figure 2)7 and end up contributing significantly to the stability of the dough8.

Figure 2: Shows when gluten (orange) is hydrated and stretched that important interactions, such as hydrogen bonds (black), are able to form giving rise to the tight knit structure of bread.

These unique properties of gluten rests on the ratio of gliadin and glutenin as both are needed to contribute to the desired structure and crumb of baked bread. For example, the hydrated form of gliadin contributes to the viscous and extendable nature of the dough whereas, hydrated glutenin is responsible for both the strength and elasticity of the mixture6. Gluten is also heat resistant, meaning that the dough still retains these properties, upon baking or boiling.

Coeliac Disease

Gluten is able to provide the structure and elasticity sought after in bread and pasta doughs, however, some individuals cannot tolerate gluten and can fall under a whole range of diseases termed gluten related disorders. Although, each of the diseases are related to one another, they are distinct within their manifestation, the most well-known of which is coeliac disease9.

Coeliac disease is classified as an autoimmune disorder where there is chronic inflammation of the intestine10 . An autoimmune disorder is a collection of diseases where the immune system attacks your own cells and classifies harmless molecules as an organism that causes disease11,.

In this case, coeliac disease triggers an immune response towards both gluten molecules and intestinal tissues.12 Just like many other autoimmune disorders, the causes of the disease are multifactorial where genetic and environmental factors interact with one another13.

The inappropriate activation of the immune system towards gluten is marked with the production of antibodies, release of inflammatory chemicals and expansion of immune cells that leads to structural damage (Figure 3)14 of the small intestine15,10. This damage is generally caused by the adaptive arm of the immune system which is known to be highly specific and long-lasting thus, mirroring the aggressive nature of gluten intolerances or allergies16.

Figure 3: Shows the normal (A) small intestine structure and damaged structure (B) resulting from untreated celiac disease.

However, there is also emerging evidence that the innate arm of the immune system may contribute to the progression of the disease17. The innate immune system is made up of a group of specialised cells that are considered as the “first line of defence” when responding to signals of danger from the body18. Gluten peptides are wrongly characterised as “danger” by the body, within Coeliac disease, and studies have shown gluten exposure has resulted shown an increase in eosinophil protein and histamine secretion19.

Gluten free, for all?

For patients with coeliac disease, the only treatment is the avoidance of gluten within the diet entirely. However, gluten free diets have become increasingly popular among the general population who have no reported sensitivities against gluten. This is mainly due to the fact that they are perceived as a healthier choice by the consumer. In 2013, a study found that 65% of Americans think gluten free foods are healthier and 27% of those actually go onto choose these products for the purpose of weight loss20.

A UK study of 40,000 individuals that estimated gluten intake in relation body fat found a decrease of fat percentage in males who had less gluten. However, females who had less gluten showed an increase within fat percentage within presenting a sex difference even after controlling for all other factors21. Although, this may seem significant, the association between gluten and body fat is not clinically relevant. This is mainly because the percentage change of body fat in the sexes are so minute that it is unlikely to provide any benefit to the wider population.

Science in conflict

Many of the studies which measure gluten intake, in relation to metabolic health, present conflicting evidence. A randomised control study presented that low-gluten diets, compared to high gluten ones, resulted in moderate but significant weight loss, over an eight-week period22. Conversely, a related study showed that there was no significant decrease in body weight in the gluten free diet group when compared to a control diet23.

This highlights great uncertainty to whether gluten free diets can provide any weight-loss or health benefit to those who are not sensitive or allergic to gluten. It is particularity important to note, that gluten free foods generally contain lower levels of protein, fibre, iron, vitamins and higher levels of calories, which may stem any nutritional benefit to those who can tolerate gluten24.

Overall, gluten is a wonderous and weird molecules which utilises various chemical bonds to provide the structure within baking. The adaptive arm of the immune system plays a large role in Coeliac disease, however, these is emerging evidence that the innate system may contribute to the progression of the disease. Although there is a big market for gluten free diets in those without sensitivities, the perceived health benefit may be overstated.

References:

1.         Prehistoric bake-off: Scientists discover oldest evidence of bread. BBC News (2018).

2.         Shewry, P. What Is Gluten—Why Is It Special? Front. Nutr. 6, (2019).

3.         The European Food Information Council. Whole Grains. https://www.eufic.org/en/whats-in-food/article/whole-grains-updated-2015.

4.         Tosi, P., Gritsch, C. S., He, J. & Shewry, P. R. Distribution of gluten proteins in bread wheat (Triticum aestivum) grain. Ann. Bot. 108, 23–35 (2011).

5.         Biesiekierski, J. R. What is gluten? J. Gastroenterol. Hepatol. 32, 78–81 (2017).

6.         Wieser, H. Chemistry of gluten proteins. Food Microbiol. 24, 115–119 (2007).

7.         Reuben, B. Bread chemistry on the rise. Chemistry World https://www.chemistryworld.com/features/bread-chemistry-on-the-rise/3004720.article.

8.         Sivam, A. S., Sun-Waterhouse, D., Quek, S. & Perera, C. O. Properties of Bread Dough with Added Fiber Polysaccharides and Phenolic Antioxidants: A Review. J. Food Sci. 75, R163–R174 (2010).

9.         Akhondi, H. & Ross, A. B. Gluten And Associated Medical Problems. in StatPearls (StatPearls Publishing, 2021).

10.       Parzanese, I. et al. Celiac disease: From pathophysiology to treatment. World J. Gastrointest. Pathophysiol. 8, 27–38 (2017).

11.       Smith, D. A. & Germolec, D. R. Introduction to immunology and autoimmunity. Environ. Health Perspect. 107, 661–665 (1999).

12.       López Casado, M. Á., Lorite, P., Ponce de León, C., Palomeque, T. & Torres, M. I. Celiac Disease Autoimmunity. Arch. Immunol. Ther. Exp. (Warsz.) 66, 423–430 (2018).

13.       Ceccarelli, F., Agmon-Levin, N. & Perricone, C. Genetic Factors of Autoimmune Diseases 2017. J. Immunol. Res. 2017, (2017).

14.       NeuroRelief. To Wheat or Not to Wheat: May is Celiac Disease Awareness Month. The NEI Connection https://neuroendoimmune.wordpress.com/2013/05/28/to-wheat-or-not-to-wheat-may-is-celiac-disease-awareness-month/ (2013).

15.       Gianfrani, C., Auricchio, S. & Troncone, R. Adaptive and innate immune responses in celiac disease. Immunol. Lett. 99, 141–145 (2005).

16.       Alberts, B. et al. The Adaptive Immune System. Mol. Biol. Cell 4th Ed. (2002).

17.       Dunne, M. R., Byrne, G., Chirdo, F. G. & Feighery, C. Coeliac Disease Pathogenesis: The Uncertainties of a Well-Known Immune Mediated Disorder. Front. Immunol. 11, (2020).

18.       Hato, T. & Dagher, P. C. How the Innate Immune System Senses Trouble and Causes Trouble. Clin. J. Am. Soc. Nephrol. CJASN 10, 1459–1469 (2015).

19.       Lavö, B. et al. Challenge with gliadin induces eosinophil and mast cell activation in the jejunum of patients with celiac disease. Am. J. Med. 87, 655–660 (1989).

20.       Jones, A. L. The Gluten-Free Diet: Fad or Necessity? Diabetes Spectr. Publ. Am. Diabetes Assoc. 30, 118–123 (2017).

21.       Behrendt, I., Fasshauer, M. & Eichner, G. Gluten intake and metabolic health: conflicting findings from the UK Biobank. Eur. J. Nutr. (2020) doi:10.1007/s00394-020-02351-9.

22.       Hansen, L. B. S. et al. A low-gluten diet induces changes in the intestinal microbiome of healthy Danish adults. Nat. Commun. 9, 4630 (2018).

23.       Ehteshami, M. et al. The Effect of Gluten Free Diet on Components of Metabolic Syndrome: A Randomized Clinical Trial. Asian Pac. J. Cancer Prev. 19, 2979–2984 (2018).

24.       Kutlu, T. Gluten-free diet: is it really always beneficial? Turk. Arch. Pediatr. Pediatri Arş. 54, 73–75 (2019).

Image credit:

Bread and wheat image by Mariana Kurnyk from Pexels

Wheat field image by Pixabay from Pexels

Dough kneading image by ROMAN ODINTSOV from Pexels

Person clutching stomach image by Sora Shimazaki from Pexels

Gluten free image by Henri Mathieu-Saint-Laurent from Pexels

Document discussion image by Alexander Suhorucov from Pexels

Flour split image by monkik from www.flaticon.com

Molecule of the Month: Lawsone

Henna is not only a longstanding part of Bengali culture and other cultures but has been utilized throughout history.

Being of Bengali-British decent, there always have been two distinct parts of my identity. The one where I am to deeply relate to the struggles of a Bollywood protagonist being married off, and the other where I deeply love a morning cuppa. Having the best of the both worlds doesn’t come without its challenges of course, especially when ideological clashes can happen.

However, one aspect of Bengali culture – the use of henna – to either adore the hands of a bride or to dye the hair a range of colours is distinctly part of my ancestry. Just as before a big event of any kind, people tend to paint their nails a myriad of colours, within Islamic cultures, henna is used as part of the beautification process which all genders can partake in.

Henna has been particularly popularised for its use as a “temporary tattoo” within mainstream culture as many high-profile celebrities have been seen to wear it. The orange-red tint that henna leaves behind on its wearers is mainly due to the compound lawsone present. Not only its colour, but other potential medicinal aspects of lawsone have been utilised by various cultures in different timelines too.

Centuries of Use

Longstanding tradition, modernised: Although henna has been used for centuries its modern revival is apparent as many celebrities, such as Queer Eye’s Tan France, are choosing to continue its use into the modern day

The earliest recorded use of henna comes from Ancient Egypt where mummies were found to have henna-dyed hair and finger tints. Further analysis has confirmed the presence of hydroxynaphthoquinone (lawsone), the active ingredient within henna1. However, it is important to note that henna has not only been used for cosmetic purposes in ancient cultures of North Africa and Asia, but has also been utilised for its physiological and medicinal benefits too2.

It is however, important to note that the historical use of henna is not tied to a single religion or culture but instead, spans a wide variety of communities. Henna, however, has seen a modern mainstream use especially within Western circles with celebrities such as Vanessa Hudgens, Beyonce and Tan France choosing to decorate themselves in various designs.

Mother Nature

Figure 1: Naturally henna: Henna which is used on the hair and hands comes from the Lawsonia inermis plant which can be found in various locations around the world and its location is linked to the cultures that it grows within.

Henna, used in dyes and for temporary tattoos come from the leaves of the bushy, flowery henna plant and is known within scientific circles as Lawsonia inermis (Figure 1)3. This plant is commonly found in Australia, Asian and along the coasts of Africa4.

Although there are about 70 compounds which have been isolated from this plant alone, only one, Lawsone (Figure 2)5, has been linked to dyeing and medicinal aspects of the plant2

Figure 2: Chemical structure of hydroxynaphthoquinone, also known as lawsone which is responsible for the dyeing and medicinal purposes of henna.

Lawsone is part of a group of chemicals called naphthoquinones which are aromatic compounds that are present throughout nature and can be found in many plants, fungi, algae and bacteria 6. Aromatic compounds are structures which have the hexagonal shape of bonds as shown in the image.

Naphthoquinones are known to be highly reactive and unsurprisingly, when used as a natural or synthetic dye range from the colours of yellow to red.

Hands & Hair

Duality of henna: Henna can be applied to both the hands and the hair to give its orange-brown hue. The dyeing process is mainly due to a specific chemical reaction between lawsone and the keratin found within the hands and hair.

When applied to the skin, lawsone is able to the stain the area with an orange-red hue which can be used to produce intricate pattens that can last from days to weeks7. However, when applied to the hair, lawsone is able to create a rich colour which can last a couple of months.

The way in which lawsone stains both the hair and the skin are due a specific chemical reaction taking place. Lawsone, the dyeing agent within henna, is able to chemically react with the protein, keratin found in both the hair and skin. This chemical reaction is known as a Michael addition, which is able to form carbon-carbon bonds between compounds, thereby resulting in the strong staining of the skin or hair8.

It is however, important to note that lawsone is thought not to penetrate the hair fibre like box dyes but instead, settles on the top thereby retaining the natural oils and structure of the hair9,10.

More than tattoos and hair-dye?

Healing Mother: Many current drugs have been extracted from nature and investigating the antibacterial effects of lawsone not only serves a purpose to future drug discovery processes, but also, validates the use of henna within traditional medicine

As noted previously, henna has been utilised by ancient civilisations both dye the hair and nails but is has been used for therapeutic purposes. Within traditional medicine, henna has been used to heal spleen diseases, bronchitis and infections of the eyes and intestines11.

Specifically, lawsone is thought to bring about the main therapeutic benefits. Various modern studies have aimed to quantify the antibacterial effects that lawsone has shown against various microorganisms. This is great interest due to the rising tide of antibiotic resistance.

Interestingly, one study found that the growth of E.coli, bacteria that can cause urinary tract infections, was inhibited by increasing the concentration of the herbal powder extracted from henna12. The antibacterial effects observed by lawsone and other naphthoquinones have strong biochemical processes lying at its surface, from its ability to inhibit replication to disturbing the respiration reactions within microbes.

Similar results has been found with other strains of bacteria, confirming the antibacterial activity of henna leaves, which supports its use within traditional circles13.  The use of medicinal plants to ease certain illnesses plays a pivotal role in covering the basic health care needs within developing nations, presenting a requirement to validate and document these medicinal benefits, if any14.

This is an important discovery to note as drug discovery processes have great potential to start within Mother Nature itself. Discovering and isolating ingredients to use in drug design from nature has been utilised in various instances, the most notable of which is the isolation of morphine, from opiate poppies, which is used to treat pain15.

Duality of Henna

A cultural medicine: Henna is part of many cultures and religions however, the medicinal underpinnings of henna are being discovered

Henna, and lawsone for that matter is a multifaceted molecule which is steeped in both deep various cultural roots and its documented pharmacological effects.

From the distinct colour to smell, henna has been utilised over the centuries as a tool to beautify and heal individuals. The use of henna is even woven into scriptures, presenting its longstanding use within various cultures and religions. Although, henna might not be prescribed at the pharmacy today, it is of great interest to researchers studying tropical medicines as it has been used throughout history to ease certain ailments. There is hope by studying and quantifying these effects, if any, that it has the potential to aid future drug discovery processes and validate its use within developing nations.

Note: It is imperative that you DO NOT use henna which contains PPD (known as black henna) , especially within children due to potential allergic reactions. For more information and targeted advice please visit:

https://www.nhs.uk/live-well/healthy-body/black-henna-neutral-henna-ppd-dangers/

Image sources:

Bride with henna design: by TranStudios Photography & Video from Pexels

Tan France with henna: by https://www.refinery29.com/en-us/2018/10/215372/tan-france-gray-hair-house-99-grooming-interview

Hairdressing & hand henna combo: by cottonbro from Pexels and by Jyoti Sweety on Unsplash

Pestle and Mortar with foliage: by PhotoMIX Company from Pexels

Henna on feet: by Butterfly Flower on Unsplash

References:

1.         Chowdhury, A. R., Maddy, A. J. & Egger, A. N. Henna as a Hair Dye: A Current Fashion Trend with Ancient Roots. Dermatology 235, 442–444 (2019).

2.         Badoni Semwal, R., Semwal, D. K., Combrinck, S., Cartwright-Jones, C. & Viljoen, A. Lawsonia inermis L. (henna): ethnobotanical, phytochemical and pharmacological aspects. J. Ethnopharmacol. 155, 80–103 (2014).

3.         Blanco, F. M. Plate from book. (1880).

4.         Pradhan, R. et al. From body art to anticancer activities: perspectives on medicinal properties of henna. Curr. Drug Targets 13, 1777–1798 (2012).

5.         Xavier, M. R. et al. Lawsone, a 2-hydroxy-1,4-naphthoquinone from Lawsonia inermis (henna), produces mitochondrial dysfunctions and triggers mitophagy in Saccharomyces cerevisiae. Mol. Biol. Rep. 47, 1173–1185 (2020).

6.         Lopez, L. et al. NAPHTHOQUINONES: BIOLOGICAL PROPERTIES AND SYNTHESIS OF LAWSONE AND DERIVATIVES — A STRUCTURED REVIEW NAFTOQUINONAS: PROPIEDADES BIOLÓGICAS Y SÍNTESIS DE LAWSONA Y DERIVADOS – UNA REVISIÓN ESTRUCTURADA. Vitae 21, 248 (2014).

7.         El Habr, C. & Mégarbané, H. Temporary henna tattoos and hypertrichosis: a case report and review of the literature. J. Dermatol. Case Rep. 9, 36–38 (2015).

8.         Yang, L. et al. Biodegradation of 2-hydroxyl-1,4 naphthoquinone (lawsone) by Pseudomonas taiwanensis LH-3 isolated from activated sludge. Sci. Rep. 7, (2017).

9.         web-services. Let’s talk about henna: An FAQ. Lush Fresh Handmade Cosmetics UK https://uk.lush.com/article/lets-talk-about-henna-faq (2015).

10.       Saitta, P. et al. Is There a True Concern Regarding the Use of Hair Dye and Malignancy Development? J. Clin. Aesthetic Dermatol. 6, 39–46 (2013).

11.       Rabbani, M., Etemadifar, Z., Karamifard, F. & Borhani, M. S. Assessment of the antimicrobial activity of Melissa officinalis and Lawsonia inermis extracts against some bacterial pathogens. Comp. Clin. Pathol. 25, 59–65 (2016).

12.       Abulyazid, I., Mahdy, E. M. E. & Ahmed, R. M. Biochemical study for the effect of henna (Lawsonia inermis) on Escherichia coli. Arab. J. Chem. 6, 265–273 (2013).

13.       Habbal, O. et al. Antibacterial activity of Lawsonia inermis Linn (Henna) against Pseudomonas aeruginosa. Asian Pac. J. Trop. Biomed. 1, 173–176 (2011).

14.       Rahmoun, N., Boucherit-Otmani, Z., Boucherit, K., Benabdallah, M. & Choukchou-Braham, N. Antifungal activity of the Algerian Lawsonia inermis (henna). Pharm. Biol. 51, 131–135 (2013).

15.       Katiyar, C., Gupta, A., Kanjilal, S. & Katiyar, S. Drug discovery from plant sources: An integrated approach. Ayu 33, 10–19 (2012).

Molecule of the Month: Tryptophan

Good spread: The festive season is generally associated with may foods, of those turkey is very popular choice. One of the components of turkey, tryptophan is thought to cause sleep-inducing effects,.

TW: Article loosely discusses depression and low mood

The holiday season is associated with many things, bright lights, dark nights, lazy Boxing Day mornings, questionably bad Christmas movies and finally, turkey.

Undeniably, one of the best aspects of this season is the food – even coming from a person who doesn’t observe the holiday. Roast potatoes lathered in butter, aromatic rosemary sprinkled all over and juicy, rich mince pies are a few of the delicacies which can be seen during this time of the year

After such indulgence it is common for fatigue to set in. However, one particular festive food, turkey, has been prophesied to cause this food-induced coma. One of the components of turkey, tryptophan, has been of keen interest to the scientific community due to its claims that it can aid sleep. Some studies have even gone further to investigate how tryptophan could aid in the symptoms of depression and low mood.

Could turkey really the culprit of the post-dinner drowsiness?

More importantly, could tryptophan from the diet be used to beat the so-called January blues?

One molecule, four parts

Firstly, it is important to note that tryptophan is regarded as an amino acid, which is one of the essential building blocks, alongside nucleic acids and carbohydrates, that have allowed complex life to thrive on this planet1. Just like joining single Lego pieces together to create a much bigger structure, joining amino acids to one another are produces a larger structure called proteins which include complex enzymes to even the turkey sitting on your plate2.

Figure 1: General Amino Acid: Amino acids are the primary building blocks of proteins and are made up of four key groups. The variability between each of the amino acids comes from the differing ‘R’ group side chains

Generally, amino acids follow the same structure pattern (Figure 1)3 which are made of a basic amino group, an acidic carboxyl group, a hydrogen atom and an organic R side chain4. The variability found within amino acids arises from different R groups which can alter in size, shape and molecular make-up to one another5.

For example, the R group for the amino acid glycine is simply a hydrogen whereas, the one present in tryptophan has what is called an aromatic side chain(Figure 2)6 .

Figure 2: Side piece: Shows the side chains of glycine and tryptophan and how they chemically differ from one another. This chemical difference in bonds is related to the biological differences in function within the overall structure of the protein. (Image is adapted from source)

These R groups have differing chemical properties to one another and even a single amino acid change can change the structure and therefore, the functioning of a protein7.

Throughout nature, there are only 20 of these fundamental side chains, presenting that proteins of nearly every living organism is made from this small group of amino acids8.

As each R-chain and therefore, amino acid is distinct from one another they serve a purpose in the final form of a protein. Such R-groups can form complex, interlinking interactions and even bonds giving rise to beautiful three-dimensional structures and finally, proteins that are specific to a biological function2.

Back to essentials

Of these twenty amino acids, nine of these belong to an exclusive club named essential amino acids. Essential amino acids (Figure 3)9 are part of this group as they cannot be produced in the body, like the rest of them, but instead, need to be taken up by the diet4.

Figure 3: Just the essentials, please: Shows the structures and the R groups in red of the nine essential amino acids that human cannot produce, but instead need to obtained through the diet.

A deficiency in these essential amino acids can cause severe problems within humans as we need a variety of proteins to mainly absorb, transport and finally, oxidise other nutrients10. Not only does this present the need for a varied, healthy diet but shows the importance of these key amino acids.

As tryptophan belongs in this group and additionally, is required to synthesise signalling molecules such as serotonin and melatonin (Figure 4)11 which is known to mediate important processes such as sleep and mood it has been of great interest to scientists.

Figure 4: Complex pathway: Shows the various biochemical changes which tryptophan has to go through until it can produce serotonin and melatonin. The far left bar shows the biochemical structure of each intermediate, while the middle text shows the name of these compounds, the far right text shows the associated enzymes used to transform tryptophan and its intermediates.

Such links between tryptophan, sleep and mood are under investigation and might even be the origin story of the well-known “fact” shared around the Christmas table. However, can turkey really the culprit and moreover, could tryptophan be used to beat the post-Christmas slump?

Modern-day Myth

The well-known hypothesis that the tryptophan within turkey is the cause of post-dinner sleepiness is untrue. Although tryptophan is heavily involved in the process of producing melatonin, a molecule which regulates the natural sleep-wake cycle, its synthesis is tightly regulated and is not dependant on the amount of tryptophan in the blood12.

Melatonin is produced in the pineal gland, which is situated in the brain13. The rate at which melatonin is produced here is not dependant on the concentration of tryptophan but instead, the activity of the enzymes responsible for melatonin production14. In particular, the enzyme hydroxyindole-O-methyl-transferase (Figure 4) is thought to be the rate limiting enzyme of melatonin production, especially at night15.

Rate limiting enzymes can be thought as the slowest step in the creation of one compound to the next. Additionally, this rate limiting enzyme determines the rate at which melatonin is produced and not related to the concentration of the previous intermediates but instead, the activity of the enzyme itself 16.This presents the availability and rate of these enzymes, not the amount of tryptophan, determines the amount of melatonin produced.

Even if the melatonin did not rely on rate-limiting enzymatic function, turkey does not contain enough tryptophan in isolation to cause this effect. Other amino acids such as glutamic acid, lysine and arginine exist alongside tryptophan in turkey and is not abundant enough to illicit these sleep-inducing effects17. Additionally, foods such as chicken, milk and tuna have a similar, and sometimes even greater, tryptophan content, compared to turkey further presenting the tryptophan content of turkey is simply not large enough18.

Nevertheless, experimental studies have persisted to see if tryptophan-rich foods can indeed improve sleep quality. One study has found that tryptophan enriched cereal can improve sleep, melatonin and serotonin levels within 35 elderly volunteers11. However, similar studies have shown no difference in sleep. Within scientific circles, the effects of tryptophan, if any, on sleep is mixed and unclear. It is important to note that these studies also have differing methods, brining into question whether they can be directly compared to one another. Nevertheless, this presents a sizeable research gap which further investigation is required19 .

Serotonin & Tryptophan : Mystery to be solved

Serotonin is a molecule widely responsible for regulating mood and perception and there is evidence that impaired serotonin function and levels can be one of the causes of clinical depression20,21 .

Contrastingly to melatonin production, the rate at which serotonin is produced is directly dependent on the availability of tryptophan, especially within the brain22.Since the body cannot produce tryptophan alone, and requires consumption through diet, scientists have since opened studies to determine whether diet can alter tryptophan and serotonin levels to lift and alter mood in healthy and depressed populations.

Large scale studies focusing on changing tryptophan levels through diet alone are few and far between. Nevertheless, a study of 25 healthy young adults found that when participants were on the high-tryptophan diet their mood increased significantly compared to when they were on a low-tryptophan diet23. This evidence has not been found within larger-scale studies, presenting a difficulty to alter tryptophan levels, and therefore serotonin, through diet outside the scope of a research setting24.

Interestingly, a review of scientific literature into manipulating dietary tryptophan levels have found that healthy individuals are “insensitive” to these changes overall. Likewise, those who have a history of depression present inconsistent results presenting no clear correlation of altering tryptophan levels and the symptoms of depression24.

It is important to note however, that the links between diet and depression have been substantiated by the handful of control studies on the subject25. Although a causal relationship can be shown in this case, tryptophan-specific effects require further investigation and insight within all populations.

Essentially complicated

Although tryptophan may not be the cause of the food coma too many of us experience, they are an essential molecule which the body itself cannot make. Whether tryptophan, or associated diet changes can quell the slump in mood after the festivities are unfounded too. However, this is an emerging and not-well studied part of science that requires further exploration in the years to come. Nevertheless, amino acids, including tryptophan have a basic, common structure where their R-chains present opportunities for the body and nature to produce complicated and physiologically relevant protein compounds.

I hope all my readers have a cosy, serotonin-high festive season, whether you are observing Christmas, Hanukkah or the month of December.

Image references: Turkey: Karolina Grabowska, Sleeping: Ketut Subiyanto, Black&White: Umberto Shaw all from Pexels

Separator reference: https://www.flaticon.com/free-icon/turkey_616897?related_item_id=616731&term=turkey

References:

1.         PubChem. Tryptophan. https://pubchem.ncbi.nlm.nih.gov/compound/6305.

2.         Protein Structure | Learn Science at Scitable. https://www-nature-com.ezproxy.sussex.ac.uk/scitable/topicpage/protein-structure-14122136/.

3.         The Astrophysics & Astrochemistry Laboratory: Amino Acids and Their Production during the Photolysis of Astrophysically Relevant Ices. http://www.astrochem.org/sci/Amino_Acids.php.

4.         Lopez, M. J. & Mohiuddin, S. S. Biochemistry, Essential Amino Acids. in StatPearls (StatPearls Publishing, 2020).

5.         Lodish, H. et al. Hierarchical Structure of Proteins. Mol. Cell Biol. 4th Ed. (2000).

6.         lec5-aminoacids.pdf.

7.         Bromberg, Y. & Rost, B. Correlating protein function and stability through the analysis of single amino acid substitutions. BMC Bioinformatics 10, S8 (2009).

8.         Berg, J. M., Tymoczko, J. L. & Stryer, L. Proteins Are Built from a Repertoire of 20 Amino Acids. Biochem. 5th Ed. (2002).

9.         Joseph, M. The Nine Essential Amino Acids: Functions, Requirements, Sources. Nutrition Advance https://www.nutritionadvance.com/essential-amino-acids-functions/ (2019).

10.       Hou, Y. & Wu, G. Nutritionally Essential Amino Acids. Adv. Nutr. 9, 849–851 (2018).

11.       Bravo, R. et al. Assessment of the intake of tryptophan-enriched cereals in the elderly and its influence on the sleep-wake circadian rhythm. Antropol. Port. 29, 113–120 (2012).

12.       Tordjman, S. et al. Melatonin: Pharmacology, Functions and Therapeutic Benefits. Curr. Neuropharmacol. 15, 434–443 (2017).

13.       Aulinas, A. Physiology of the Pineal Gland and Melatonin. in Endotext (eds. Feingold, K. R. et al.) (MDText.com, Inc., 2000).

14.       Peuhkuri, K., Sihvola, N. & Korpela, R. Dietary factors and fluctuating levels of melatonin. Food Nutr. Res. 56, (2012).

15.       Liu, T. & Borjigin, J. N-Acetyltransferase is not the rate limiting enzyme of melatonin synthesis at night. J. Pineal Res. 39, 91–6 (2005).

16.       Zhao, M. & Qu, H. Human liver rate-limiting enzymes influence metabolic flux via branch points and inhibitors. BMC Genomics 10, S31 (2009).

17.       Fisher, C. & Scougall, R. K. A note on the amino acid composition of the Turkey. Br. Poult. Sci. 23, 233–237 (1982).

18.       Richard, D. M. et al. L-Tryptophan: Basic Metabolic Functions, Behavioral Research and Therapeutic Indications. Int. J. Tryptophan Res. IJTR 2, 45–60 (2009).

19.       Lindseth, G. & Murray, A. Dietary Macronutrients and Sleep. West. J. Nurs. Res. 38, 938–958 (2016).

20.       Berger, M., Gray, J. A. & Roth, B. L. The Expanded Biology of Serotonin. Annu. Rev. Med. 60, 355–366 (2009).

21.       Cowen, P. J. & Browning, M. What has serotonin to do with depression? World Psychiatry 14, 158–160 (2015).

22.       Fernstrom, J. D. Large neutral amino acids: dietary effects on brain neurochemistry and function. Amino Acids 45, 419–430 (2013).

23.       Lindseth, G., Helland, B. & Caspers, J. The Effects of Dietary Tryptophan on Affective Disorders. Arch. Psychiatr. Nurs. 29, 102–107 (2015).

24.       Soh, N. L. & Walter, G. Tryptophan and depression: can diet alone be the answer? Acta Neuropsychiatr. 23, 3–11 (2011).

25.       Ljungberg, T., Bondza, E. & Lethin, C. Evidence of the Importance of Dietary Habits Regarding Depressive Symptoms and Depression. Int. J. Environ. Res. Public. Health 17, (2020).