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Biomedical Research Health and Disease

Medicinal Cannabis

Introduction

Cannabis, also known as weed, is a type of marijuana. Cannabis sativa, Cannabis indica, and Cannabis ruderalis are three plants in this category that exhibit mood-altering and hallucinogenic properties (Kayser, 2017). People use cannabis for relaxing purposes; yet, several countries have enacted legislation making cannabis illegal since it is deemed a narcotic. In the United States, however, marijuana is legalised for medical and economic reasons, such as treating chronic diseases and increasing work prospects. The significance of cannabis to current health care will be discussed in this article, as well as whether or not cannabis should be legalised globally

Structure

There are many misconceptions about CBD and THC. They both impact mood, but THC’s effects are more severe than CBD’s since THC gets you high. They share the same chemical formula, as indicated in the image below, therefore they are isomers, but the atom configurations differ. THC is prohibited in many places throughout the world because it generates a high, whereas CBD is utilised by healthcare professionals to treat anxiety, depression, and other conditions.

Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two main psychotropic substances found in cannabis products, as illustrated below:

(Atakan, 2012)

These drugs have a negative impact on the neurological system. As these molecules have a structure that is quite similar to another brain chemical, some receptors in the nervous system may mistake them for other regular brain chemicals. They bind to cannabinoid receptors on neurons, which are part of the endocannabinoid system (“How does marijuana work,” 2020), which employs cannabinoid neurotransmitters to send and receive messages. Overall, they have an effect on the hippocampus of the brain, affecting the person’s ability to build new memories and control their emotions, as well as their ability to learn and accomplish activities. It also affects the cerebellum and basal ganglia, which are parts of the brain that control gesture, balance, and posture (“How does marijuana,” 2020). As a result, cannabis users will appear to have a slower response.

History

Shen Nung, the inventor of Chinese medicine, first recorded cannabis in his pharmacopoeia in around 500 BC. Cannabis was first cultivated in Central Asia or the west of China. Cannabis has also been documented in Indian, Assyrian, Greek, and Roman literature. Cannabis was described in this literature as having the ability to treat depression, asthma, and pain. 

CBD had then been introduced to the western world, offering medical benefits such as mood enhancers and the prevention of convulsions in children. In a 1936 film, it was discovered that CBD is a highly addictive chemical that causes mental disease and violence. Marijuana has recently gained widespread acceptance as a treatment for patients suffering from mental illnesses, and CBD has been approved for medical usage in most parts of the world (“History of cannabis”). While studying in India in the 1930s, an Irish doctor named Sir Willian Brooke O’Shaughnessy discovered that cannabis can help with stomach pain. Then, people started to notice the effects of THC, which is the psychoactive ingredient in cannabis, which led to a lot of debate on CBD. 

Medicinal Uses

As previously mentioned, CBD has pain-relieving and antipsychotic properties. It also has the ability to alleviate cancer symptoms, protect nerve cells, and aid the heart.

In terms of pain relief, CBD inhibits the activation of endocannabinoid receptors, blocking them from accepting endocannabinoids and so preventing the regulation of sleep, appetite, pain, and the immune system. Some of these painkillers operate best when combined with THC, the psychoactive ingredient in marijuana. CBD was studied to see if it could help with the symptoms of fibromyalgia, a disorder that causes widespread discomfort. The study looked at 2701 people with fibromyalgia and found that using CBD helped them feel better (Kubala, 2021).

CBD oil can also aid with anxiety, insomnia, and PTSD in terms of mental health. They assist the body to metabolise serotonin by targeting 5-HT1A, a serotonin receptor, so that serotonin levels rise and a person’s mood is lifted (Leasca, 2019). CBD can lessen anxiety during a test, according to a study involving 57 males who consumed CBD 90 minutes before the test (Leasca, 2019).

CBD oil has been demonstrated in certain studies to shrink cancer tumour size and improve heart failure symptoms, but current trials are not well-designed and the data is insufficient. A woman in the United Kingdom was diagnosed with a 41mm tumour, but she refused chemotherapy and radiotherapy. Regular CT scans every 3-6 months revealed that the tumour was diminishing, and she confessed that she had been taking CBD oil (“Daily usage of Cannabidiol,” 2021). In another study, nine healthy males were given 600mg of CBD oil before participating in a stress test that raised blood pressure. It was discovered that these males had a lower increase in blood pressure, implying that CBD can help to lower blood pressure (Kubala, 2021).

Criticism Around the World

Medicinal cannabis is generally accepted in many nations throughout the world, including the United Kingdom, New Zealand, Poland, and others. Canada, the United States (certain states), and South Africa are among the countries that have legalised recreational marijuana, while others, such as China, Japan, and Indonesia, still consider it illegal. 

Cannabis is regarded as less hazardous than strong amounts of alcohol, and countries that make it legal strengthen control over crime and the cannabis trade while also allowing cannabis to be more widely accessible for medicinal uses. Companies must have a licence to sell cannabis in the United States, and it is also taxed in states that have legalised it, such as Washington, which has a 37 per cent excise tax on those sales.

Cannabis is now classified as a Class C narcotic in nations that have legalised it, such as in the United Kingdom, so that maximum punishments for supply can be reduced and policy can be focused on more serious offences. Medicinal cannabis, on the other hand, has been demonstrated to provide medical benefits, such as pain relief, as previously indicated. As a result, private doctors in the United Kingdom who are registered with the General Medical Council are permitted to prescribe medical cannabis if other treatments have failed.

Some countries have legalised cannabis to make it easier for authorities to assess and control the substance; nonetheless, this could lead to issues such as widespread usage of the drug and harmful repercussions such as violence and mental illness. In general, medicinal cannabis is beneficial in the treatment of patients and the alleviation of pain. If it is carefully handled, it will be helpful to society.

Mary Ho Yan Mak, Youth Medical Journal 2022

References

Healthline. 2020. What Is Cannabis? Facts About Its Components, Effects, and Hazards. [online] Available at: <https://www.healthline.com/health/what-is-cannabis&gt; [Accessed 16 April 2022].

nhs.uk. 2022. Medical cannabis (cannabis oil). [online] Available at: <https://www.nhs.uk/conditions/medical-cannabis/&gt; [Accessed 16 April 2022].

National Institute on Drug Abuse. 2020. How does marijuana produce its effects? | National Institute on Drug Abuse. [online] Available at: <https://nida.nih.gov/publications/research-reports/marijuana/how-does-marijuana-produce-its-effects&gt; [Accessed 16 April 2022].

The University of Sydney. 2022. History of cannabis. [online] Available at: <https://www.sydney.edu.au/lambert/medicinal-cannabis/history-of-cannabis.html#:~:text=The%20use%20of%20cannabis%20originated,father%20of%20Chinese%20medicine)%20pharmacopoeia.> [Accessed 16 April 2022].

Women’s Health, Leasca. 2019. Wait, Can CBD Legit Help With Anxiety?. [online] Available at: <https://www.womenshealthmag.com/health/a26826400/cbd-and-anxiety/&gt; [Accessed 16 April 2022].

Bmj.com. 2021. Daily use of cannabidiol (‘CBD’) oil may be linked to lung cancer regression | BMJ. [online] Available at: <https://www.bmj.com/company/newsroom/daily-use-of-cannabidiol-cbd-oil-may-be-linked-to-lung-cancer-regression/&gt; [Accessed 16 April 2022].

Science Direct, Kayser. 2017. Cannabaceae. [online] Available at: <https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/cannabaceae/&gt; [Accessed 16 April 2022].

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Biomedical Research Commentary

A Man Who Received a Heart Transplant from a Pig

Giving organs to someone who needs them is known as organ transplantation. The concept of organ transplantation was initially proposed in the 1900s, and the first cornea transplant was performed in the Czech Republic, with the patient regaining his sight. Joseph Murray performed the first kidney transplant in the United States in 1954, and the same approach is still used today, benefiting many patients. In 1963, Dr. Thomas Starzl performed the first kidney transplant in the world, but the patient died soon after. Dr. Starzl began a series of studies into drugs in order to help patients who had a transplant live a longer life. In 1965, an organ donated by a deceased individual happened in the United Kingdom. Dr. Christaian Banard of South Africa performed the world’s first heart transplant. Although the patient died as a result of the procedure, it demonstrated that transplantation is possible. The first successful kidney transplant occurred in 1967, following multiple investigations. In the 1980s, countries all over the world began to establish donor cards and organizations to administer transplants in order to ensure the safety and reliability of organs supplied by donors.

Transplant occurs when a collection of cells from one person are removed and transplanted into another person or another area of the same person’s body. When people receive a transplant, the recipient’s immune system may reject it because it recognises it as foreign
tissue. Immunosuppressive medicine may be required after the transplant to prevent rejection. Transplants of hearts, lungs, and livers, to name a few, are now possible thanks to current technology, but standard tests and checkups between the donor and recipient are
required, such as blood groups, tissue kinds, infection, and general health.

Dr Richard Lower’s attempt to transfer blood from animals to humans in 1665 was initially rejected because it resulted in many deaths. However, according to BBC News, “Man gets genetically-modified pig heart in a world-first transplant.” Bartley P Griffith, a surgeon at the
University of Maryland School of Medicine, performed this 7-hour surgery to transplant a genetically modified pig heart into David Bennett, a 57-year-old patient with terminal heart disease. Bennett would die if the surgery was not performed, so this was his last resort.

David Bennett was convicted of the stabbing in 1988. Mr. Bennett was sentenced to ten years in prison for stabbing Edward Shumaker in 1988. The public has argued that Mr. Bennett is unworthy of a heart transplant because of his history and that he does not deserve attention despite being the first man in the world to receive a transplant from other animals. Doctors, on the other hand, believe that a person’s history should not be used to determine the level of care he receives because doctors must adhere to the four pillars of
medical ethics: do no harm, justice, autonomy, and non-maleficence.
On January 31, 2022, medical professionals from the University of Maryland School of Medicine (UMSOM) and the Maryland Medical Centre (UMMC) performed the surgery. Dr. Mohiuddin, the scientific director, and Dr. Griffith, the clinical director, monitored the surgery.

Dr. Mohiuddin is a *xenotransplantation expert, and he co-founded the Cardiac Xenotransplantation Program with Dr. Griffith in 2017. Dr. Mohiuddin spent over 30 years proving that pig hearts can function normally in humans through peer review, and the last 5 years modifying the surgical process used in transplantation surgery. UMSOM received $15.7 million USD in funding for the research. The pig heart has been genetically modified: there are genes in pig hearts that may cause human rejection; these genes have been removed. In addition, six genes that aid in the acceptance of a pig heart by humans were inserted into the genome. Another gene that promotes the growth of pig heart tissues was also removed.

The doctors at the medical school determined that Mr. Bennett is not a candidate for a human transplant; this decision is usually made when the patient’s health is at its worst. This is due to Mr. Bennett’s irregular heartbeat, which resulted in the mechanical heart pump being banned and him receiving a human transplant because he did not follow doctors’ orders. The solution of using a genetically modified pig heart was first approved by the United States Food and Drug Administration (FDA), as genetically modified pig hearts are
only used for medical experiment purposes. Although the FDA rejected Dr. Mohiuddin’s trial experiment a few years ago, they approved this surgery that lasted for 7 hours because it was the last option to save the patient’s life. This surgery was successful, and Mr. Bennett’s heart function is still normal. He did, however, need to be watched. First, consider the heart’s performance, such as irregular heartbeats, swelling, and so on. Second, his immunology response, such as how his immune system reacts to the new genetically modified pig heart, and whether or not rejection occurs. Mr. Bennett will also need to take anti-rejection medication.

The public, on the other hand, has criticised the surgery as unethical and dangerous. Animal rights, religion, and medical implications were some of the ethical issues raised by this performance. For starters, the People for the Ethical Treatment of Animals (PETA) ruled that
genetically modifying an animal’s organ to make it act like a human organ is unethical. Furthermore, the pig heart was removed in the morning on the surgery day, prompting some to argue that animals have the right to life as well. In terms of religion, some people in
certain regions may refuse to accept an animal’s organ being transplanted into a human body; for example, Muslims and Jews do not consume pigs, though there are exceptions if it saves someone’s life. In terms of medical implications, the four pillars of medical ethics
should be considered: beneficence, non-maleficence, autonomy, and justice. Patients should be given adequate information about the procedure, as well as the potential risks and outcomes of the surgery.

According to the Health Resources and Services Administration of the United States (HRSA), 106,671 men, women, and children are currently waiting for an organ transplant, and 17 people die each day while waiting for an organ transplant. If Mr. Bennett recovers
successfully from the surgery, it will demonstrate that transplants from animals can also work in humans, resolving one of the current medical problems of limited organs for transplantation. However, ethical issues should be addressed first by increasing public awareness and education. If the problem is resolved, it will result in a significant
improvement to current healthcare systems around the world, as well as providing a higher quality and more efficient healthcare for its people.

*Xenotransplantation: transporting animal organs to human

Mary Mak, Youth Medical Journal 2022

References

Kidney transplant tests. (n.d.). Organ Transplantation – NHS Blood and Transplant. https://www.nhsbt.nhs.uk/organ-transplantation/kidney/is-a-kidney-transplant-right-for-you/ki
dney-transplant-tests/

What is organ donation and transplantation? (2019). NHS Organ Donation.
https://www.organdonation.nhs.uk/helping-you-to-decide/about-organ-donation/faq/organ-do
nation-and-transplantation/

A history of donation, transfusion and transplantation. (2018). NHS Blood and Transplant.
https://www.nhsbt.nhs.uk/who-we-are/a-history-of-donation-transfusion-and-transplantation/

Man who had a pig heart transplant was guilty of a 1988 stabbing. (2022, January 15). BBC
News.
https://www.bbc.co.uk/news/world-us-canada-60010155#:~:text=The%20man%20who%20re
ceived%20the

Three ethical issues around pig heart transplants. (2022, January 11). BBC News.
https://www.bbc.co.uk/news/world-59951264

University of Maryland School of Medicine Faculty Scientists and Clinicians Perform Historic
First Successful Transplant of Porcine Heart into Adult Human with End-Stage Heart
Disease. (n.d.). Www.umms.org. Retrieved January 22, 2022, from
https://www.umms.org/ummc/news/2022/first-successful-transplant-of-porcine-heart-into-adu
lt-human-heart cf_chl_jschl_tk=d_yQWc529rsUr2zUV6uriZXLm2di70fll9uuXumm9Cc-1
642863048-0-gaNycGzNCJE

Reardon, S. (2022). First pig-to-human heart transplant: what can scientists learn? Nature.
https://doi.org/10.1038/d41586-022-00111-9

HRSA. (2021, May). Organ Donation Statistics | organdonor.gov. Www.organdonor.gov.
https://www.organdonor.gov/learn/organ-donation-statistics

Organ and tissue transplantation. (2012). Vic.gov.au.
https://www.betterhealth.vic.gov.au/health/ConditionsAndTreatments/organ-and-tissue-trans
plantation


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Biomedical Research

Brain Reading Technology

Reading minds is not as far fetched as it seemed to be in the past. With much research and technology, verbalizing a person’s thought process appears possible.

Introduction

Brain reading is a process in which there is indulgence in neural responses evoked by the brain through stimulus followed by a detection through fMRI to decode the original stimulus. This was proposed by neuroscientist Marcel Just and his colleagues at Carnegie Mellon University. Through artificial intelligence technology, they analyzed complex brain activities and deciphered the patterns in equivalence to the brain functioning. This involves construing the way one thinks of a number or an object, reads a sentence, or expresses an emotion in parallel with addition of their futuristic approach to a particular thought. Suicidal tendencies are very common due to emotional disturbances and the tendency to conceal this even from loved ones. This process enables one to detect if the person is having a thought of suicide by just analyzing his brain’s response to words like happiness or death. This could even prove as a life saving method.

Sir Elon Musk’s Recent Discovery

After much research and human trials, the owner of the Tesla, Elon Musk, recently came up with the discovery of a surgically implantable device called Neurolink chip that can read the user’s brain using brain wave technology and decoding speech waves. This will promote easy communication between human brain and machine which might prove to be a boon to cure many medical problems.

Fig: Neurolink

The chipset will be installed in the skull with it’s surgical placement through the artificial intelligence technology. It is said to have thickness in parallels to the brain neurons and thinness as the hair strand with the facility of multiple devices to be fitted in different sections of the brain. Partial anaesthesia might be given during the process.As for how it’s working, is taken into account it’ll be analogous to our brain working action.Our brain sends information to different parts of the body through the neuronal network called neurotransmitters, generating electric fields. The actions are then recorded with placement of electrodes translating them into algorithms in accordance with the understanding for the machines. In this manner Neuralink will be able to read our minds and find a way for communication between humans and machines.

Fig: Elon Musk’s surgical robot for implantation of Neurolink

Neurolink needs quick and precise insertions into the brain cortex, therefore keeping safety measures in mind a surgical robot is designed for this purpose. This robot will ensure perfect insertion of the module into the brain which isn’t visible to the naked eye. The robot is designed in such a manner which will not only ensure quickness,preciseness and perfection but also insertion without contact with any arteries or veins thus avoiding any complications or side effects. This will then be completed by covering the exposed part of the skull with the chipset module.

At the start of it’s usage, it’ll be beneficial for the paraplegic and epileptic patients with operational and interactive sessions with the machines. In others with loss of optic nerve control, a help to bring back their eyesight could be made possible. In paralytic patients restoration of memory, speech and motility could be ensured. If this project proceeds a new technology could come into being where along with human to machine interaction may be possible similarly human to human interaction could also be possible without actually communicating. 

Conclusion

It might prove as a blessing or curse will be perceived in the mere future. On one hand where it can be proved as a boon for improving health conditions similarly on the other hand it might be harmful as one’s private thoughts might be captured and misused by the companies acquainted with this technology,thus violating their neurorights. The technology is almost on the verge of becoming a reality,hence one needs to now figure out how to keep up with the ethical morals and standards. Soon this will no longer be imagining design fiction.

Pratiksha Baliga, Youth Medical Journal 2022

References

[1]Fields, R. D. (2020, March 10). Mind reading and mind control technologies are coming. Scientific American Blog Network. https://blogs.scientificamerican.com/observations/mind-reading-and-mind-control-technologies-are-coming/.

[2]John, C. (2020, July 24). Neuralink explained: How we will talk to machines using our brain. TheQuint. https://www.thequint.com/explainers/what-is-neuralink-and-how-does-it-work-explained.

[3]Ethrington, D. (2020). Elon Musk Neurolink. Google image result for https://techcrunch.com/wp-content/uploads/2020/08/the-prototype-robot-being-tested-in-the-lab.jpg. Retrieved April 23, 2022, from https://images.app.goo.gl/fggzFMLz59ZZzxDr6

[4]Archyde, A. (2020, August 29). Neuralink presents its first functional device to read nervous system activity. Archyde. Retrieved April 23, 2022, from https://www.archyde.com/neuralink-presents-its-first-functional-device-to-read-nervous-system-activity/

Categories
Biomedical Research

Thalidomide: Horrifying Tragedy of the Past, Auspicious Treatment of the Future

Introduction

Thalidomide is a medicinal drug that was developed in the 1950 by the Western German Company Chemie Grünenthal, and was sold and distributed in 46 countries, marketed by 14 pharmaceutical companies1. This medicine created catastrophic impacts on the lives of individuals, and it was only 5 years after thalidomide became widely available over the counter that the connection was made between the drug and its effects on pregnant women and their children, who had birth defects due to thalidomide. Since the ‘thalidomide scandal’, as it became known, led to a series of legal battles and settlement disbursements, as well as huge changes in the way in which drug trials are now conducted and the safety of all drugs.

Intended use

The original intended use of thalidomide was as a sedative or tranquilizer, but then began to be used to treat a variety of other illnesses – such as colds, flu, nausea, and morning sickness in pregnant women1. While thalidomide was being researched and developed into a drug suitable for human use, it did not undergo any clinical trials involving humans. Instead, testing was solely carried out on animals, and it was determined in the early stages of this research the rodents were supposedly able to be unaffected by a dose of thalidomide which was over 600 times the normal human dose2. Unfortunately, it was only after the link between thalidomide and birth defects was made that it was questioned how this drug was even made available for human use, especially as it was readily available from pharmacies without the need for a prescription. These queries led to an investigation in which it was discovered that extensive tests beyond animal testing into thalidomide had not taken place – and thus the drug should not have been declared safe to use. However, thalidomide was deemed to be harmless to humans, and was licensed in Germany in July 19561.

Treatment for morning sickness

Although the most infamous large-scale side effect of thalidomide is the foetal birth defects it caused, this drug additionally caused a multitude of serious health hazards – which were ignored by Chemie Grünenthal from when many reports about these problems began inundating the company from as early as 1959. One such side-effect of thalidomide is peripheral neuritis3, which is a type of nerve injury that can be anywhere in the body. This damage will start with a tingling sensation in the feet and hands, then numbness and following by feeling cold. Severe muscular cramps are often another symptom of peripheral neuritis, and other effects can include limb weakness and loss of coordination. Whereas some of the symptoms can be treated to improve them or remove them completely, it is more common that they are irreversible.

While thalidomide was not intended to be used specifically as a treatment for morning sickness for women in the early stages of their pregnancy, this drug was found to be relatively effective in relieving this problem. When thalidomide started to be produced and sold in the UK from 1958, it was produced by ‘The Distillers Company (Biochemicals) Ltd’. One of the brand names which thalidomide was sold under was Distaval. On the advertisement for this brand, it was stated that: “Distaval can be given with complete safety to pregnant women and nursing mothers without adverse effect on mother or child.”1 Not only was there a lack of evidence to prove this claim, but also pregnant women were taking it under false guidance, and many were even prescribed it.

Chemistry of the drug

The chemical formula of thalidomide is C13H10N2O4 and has the scientific name ‘a-(N-Phthalimido)glutarimide3.

(4)

Thalidomide exists as two isomers, which are mirror-images of each other. The (R)-Enantiomer has sedative effects and explains why thalidomide was so effective when it was used as a medication for sedation and tranquilisation. The (S)-Enantiomer, however, is teratogenic. Teratogenic drugs are agents which can affect an embryo or fetus’ development and can cause congenital malformations5. The thalidomide that is sold as medication is a mixture of these two forms, as these isomers interconvert under biological conditions, rendering the process of separating them before the drug is distributed and used ineffective.

The infamous consequences of thalidomide

Tragically, thalidomide is most well-known for the widespread birth defects it caused – and the first child who was affected by the taking of thalidomide was born on 25th December 1956 to an employee of Chemie Grünenthal. If a pregnant mother took thalidomide, this could culminate in a series of disabilities including, but not limited to: shortened limbs, missing limbs, sensory impairment, facial palsy, damage to the eyes and ears or lacking ears and ears, brain damage, and impacts on the skeletal structure6. As to the location of the birth defect on the body pertained to the day or days which the pregnant mother took thalidomide – and even a single day could be the difference between lacking limbs and brain damage. In a video produced by the Science Museum about what it is like to be affected by thalidomide, Dr Martin Johnson (Chairman of The Thalidomide Trust) speaks about how the days on which thalidomide was taken can cause specific congenital defects7. He discusses that, if thalidomide were taken around day 20 of the pregnancy, this would cause central brain damage in the child. If the drug were taken on day 21, the eyes would be impacted, and if it were taken on days 22 to 23, the ears and face would be affected, and hearing would almost certainly be greatly impaired. Thalidomide was only found to affect the foetus if the mother took the drug between 20 and 37 days after conception – and outside of this window, thalidomide would not have any effect1.

Thalidomide was available as a medication from 1956, though only in Germany, and became obtainable throughout much of Europe and some countries in Asia (like Japan) later in the 1950s. It was on the 26th of November 1961 that thalidomide, under all brand names, was formally withdrawn by its creator Chemie Grünenthal. In less than five years this drug was widely distributed and sold, it is estimated that over 100,000 babies were affected by it globally – approximately half of which died only months after birth1. Currently there are less than 3,000 people who were babies affected by thalidomide.

Individuals affected by thalidomide

The Thalidomide Trust, a charity which supports those born with birth defects as a result of thalidomide, carried out a survey amongst its beneficiaries, in which it showed that over 90% of them experienced severe and/or continuous pain often. Low mental health is, unfortunately, another health problem typically associated with those living with thalidomide-related disabilities, especially depression, anxiety, and loneliness.

Of the babies affected by thalidomide that survived beyond the first few months of infancy, Louise Medus was one. Louise was born on the 23rd of June 1962, to her father David Mason, and her mother Vicki Mason – who had been prescribed thalidomide during her pregnancy only weeks before the drug had been recalled en masse. Louise states in an article by the Guardian8: “Like the other parents of thalidomide parents, I’m sure they [her parents] were expecting a fully formed baby and some of us didn’t have arms, some of us didn’t have legs, some of us didn’t have arms of legs.” Louise published her memoir in 1988, entitled ‘No Hand To Hold & No Legs To Dance On’.

As a result of the fatal and irreversible damage attributed to the drug thalidomide, large settlements were due to those affected. The Distillers Company (Biochemicals) Ltd, which was the company that sold thalidomide as a drug in the UK, agreed to a final settlement in 1973 to pay damages to 429 people in the UK who had been affected by thalidomide from birth. Additionally, the Thalidomide Trust was established, in which thalidomide survivors are able to receive support and annual grants6.

9In New Zealand and Australia, Diageo (the parent company of The Distillers Company (Biochemicals) Ltd) paid AU$89 million to approximately 100 individuals in  compensation. As recently as in 2014, it was ruled by a court that in Spain, the company Grunenthal (another seller of thalidomide) would pay €35 million to 22 people affected there. Yet there are approximately 180 people in Spain still seeking compensation.

(10) In June 1961, an article promoting the taking of thalidomide in the third trimester of pregnancy was published, claiming to be written by a ‘R.O. Nulsen, M.D.’ but was in fact written by the medical director of Chemie Grünenthal. In the early 1960s when birth defects were being noticed and linked to thalidomide, Chemie Grünenthal obscured these findings from public view and refused to take responsibility for creating thalidomide – which was the cause of them. It was around 6 months after the article allegedly written by a Dr Nulsen that this evidence was made public in Germany. 

Horrifyingly, the drug company Chemie Grünenthal did not publicly apologise to those affected by thalidomide until 2012 – approximately 50 years after the drug was first released.

Current research and future treatment prospects

Despite the tragic results that transpired from the use of thalidomide, this drug continues to be researched presently and now presents auspicious results in treating conditions such as types of cancers and leprosy. According to the Mayo Clinic11, it has been determined that thalidomide helps regulate the body’s immune system, control inflammation and slows the processes of creating new blood vessels – which cancers utilise in order to grow and spread throughout the body. The US Food and Drug Administration (FDA), on the basis of research like this, has approved thalidomide in use for treating erythema nodosum leprosum (skin lesions caused by leprosy) and multiple myeloma.

Additionally, in 1964, a doctor in Jerusalem called Dr Jacob Sheskin, administered thalidomide to a patient with leprosy in order to act as a sedative and help the patient to sleep2. Surprisingly, the effects of the thalidomide were remarkable – and the leprosy appeared to have been cured. However, the condition returned once the patient stopped taking thalidomide, and so it was determined that thalidomide was suppressing the disease rather than treating it.

Furthermore, another example of the positive effects of thalidomide is when it was utilised as a treatment method against mantle cell lymphoma11. In 1996, a man named Garry Edling was diagnosed with this condition, but the cancer became progressively worse despite five rounds of chemotherapy and a stem cell transplant. Garry was treated by the consultant Dr Simon Rule, who prescribed him thalidomide based on Dr Sheskin’s plan: to improve symptoms and to prospectively alleviate pain. Garry receives thalidomide as part of a drug trial, as this drug remains unlicensed in the UK and can only be prescribed under severest caution. When he began taking the drug, Garry’s tumours began shrinking, and Dr Rule said, “his response is nothing short of remarkable”. On the other hand, Garry has suffered from side effects such as muscular pain, and numbness in his hands and feet – yet this is the cost of prolonging his life.

Consequential legislation

The thalidomide tragedy also led to the creation of the 1968 Medicines Act in the UK, as the UK government wanted a greater stronghold over the regulation of the drug industry. This act classes medical drugs into three categories12: general sales list medicines, pharmacy medicines, and prescription only medicines. General sales list medicines are able to be sold by any shop, but pharmacy medicines can only be sold in a pharmacy – though a prescription is not necessary. Prescription- only medicines are the category with the highest level of restriction: they can only be sold by a pharmacist if prescribed by a doctor.

In the USA, after thalidomide was prohibited from being distributed and sold, the Kefauver-Harris Amendments were made in 1962 to the 1938 Food, Drug, and Cosmetic Act13. This meant that there were strict guidelines instigated for the process of drug approval in the United States – crucially requiring drugs to be safe as well as effective before being approved for medical use.

Conclusion

To conclude, thalidomide is an infamous drug with a fatal and horrifying history, causing thousands of birth defects and deaths in infants. This drug was not researched and studied thoroughly enough to warrant it being approved, licensed, and widely distributed – and even prescribed – to unknowing individuals. In spite of this horror, the thalidomide tragedy has meant that there has been improved legislation in place to improve the safety of future drugs and prevent the same consequences from occurring again. Furthermore, thalidomide is now being utilised in an effective way to treat conditions like leprosy and is yielding positive results. The consequences of thalidomide are tragically irreversible, but fortunately this drug can now be directed towards improving lives, and with anticipation another tragedy like it will not arise again.

Samara Macrae, Youth Medical Journal 2022

References

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Categories
Biomedical Research

Emerging Treatment Options for Triple-Negative Breast Cancer

Tanya Ghai1,*

1Polygence (advised by Khloe Gordon)

*Corresponding author: tanyaughai@gmail.com

Abstract

Triple-Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer that accounts for 10-20% of all breast cancer diagnoses, yet it has a poor prognosis and few effective therapeutic options [43]. Typically diagnosed at grade 3 or above, TNBC grows relatively quickly compared to other breast cancers, and it has a high recurrence rate. A key characteristic of  TNBC is that it lacks expression of 3 receptors: the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER-2). The 5-year survival rate of this breast cancer is 91 percent; however if this cancer has metastasized, the survival rate drops to about 11 percent [42]. Here we review current standard therapies available, second-line therapies, and other emerging treatments for this disease with an emphasis on risks associated with specific patient attributes.

Introduction

TNBC is a devastating cancer with very high metastatic and recurrence rates. It is a very intricate disease with a variety of different subtypes and molecular breakdowns, making it very difficult to treat. TNBC accounts for approximately 15 percent of breast cancers diagnosed worldwide, amounting to almost 200,000 cases each year [6]. Also, TNBC appears to be more commonly diagnosed among black women compared with Caucasian women [45]. Because TNBC is hormone receptor negative and epidermal growth factor negative, TNBC is insensitive to endocrine therapies and other therapies targeting these receptors. 

TNBC is an aggressive subtype of breast cancer that is so complex, it can be further broken down into its own 6 subtypes: basal-like 1 (BL1), basal-like 2 (BL2), mesenchymal (M), mesenchymal stem-like (MSL), immunomodulatory (IM), and luminal androgen receptor (LAR) [46]. These subtypes are characterized by different gene signatures and cellular characteristics (Figure 1). 

Figure 1. Description of TNBC subtypes and characteristics. Created with BioRender.com. Adapted from “Intrinsic and Molecular Subtypes of Breast Cancer”, by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates 

The basal-like subtypes are characterized by the BRCA mutation. The BRCA mutation, a mutation in the BRCA 1 or 2 genes, is a common cause of TNBC, as it is a tumor suppressor gene that regulates DNA growth and repair [8]. Having this mutation drastically increases the chances of developing breast cancer as 55%–72% of women with the  BRCA1 mutation and 45%–69% of women with the BRCA2 mutation will develop breast cancer by 70–80 years of age [8, 10, 22].  Some treatments for tumors harboring the BRCA mutation include PARP inhibitors because it damages the DNA of the cancer cells containing mutated BRCA (which are already deficient in DNA repair mechanisms due to the BRCA mutation). 

Like many types of cancer, TNBC is also defined by the interaction between the PD-1 and PD-L1 inhibitor pathways, a key modulator of cancer immune surveillance. This interaction is a defining feature in the immunomodulatory subtype of TNBC, but is not limited to this subtype. The PD-1 receptor is expressed on immune cells and acts as an inhibitor of activation and anti-tumor function, while it’s ligand, PD-L1, is expressed by many tissues in the body but is often upregulated in cancer cells, essentially hiding from the tumor cells [18]. Immunotherapies can be used to block this interaction and prevent the inhibition of immune cells (Figure 2). Generally these therapies only work if there is already an immune response present within the tumor. 

Figure 2. Mechanism of action for checkpoint inhibitors targeting PD-1 and PD-L1. Created with BioRender.com. Adapted from “Immune Checkpoint Inhibitor Against Tumor Cell”, by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates 

Standard Treatment of Care for Triple-Negative Breast Cancer

For early stages of localized TNBC, surgery and adjuvant or neoadjuvant chemotherapy are the standard first line treatment. For early stage disease that has not yet metastasized, surgery is used to remove smaller tumors. However, if the tumor is large or present in the lymph nodes, radiation can also follow surgery. For more advanced tumors, chemotherapy is the most common course of action [11]. Chemotherapy drugs that are often used include docetaxel, doxorubicin, anthracyclines, taxanes, capecitabine, gemcitabine, and cyclophosphamide [9]. 

However, for more advanced metastatic TNBC, more aggressive forms of treatment may be required. Platinum-based chemotherapies, specifically cisplatin and carboplatin, are typically used for TNBC that harbor the BRCA mutation. Both are alkylating agents that stop tumor growth by cross-linking guanine bases and adding alkyl groups to cause DNA damage and induce cell death [37, 39, 40].

Carboplatin is often used in combination with paclitaxel, a chemotherapy drug, to get the most effective results [37, 39]. Both cisplatin and carboplatin are most effective as neoadjuvant treatments. Cisplatin displays a slight survival advantage over carboplatin, but they both offer a can serve as a relatively effective treatment for local TNBC [39, 40]. Neoadjuvant treatment with cisplatin and carboplatin resulted in a high pathologic complete response rate for BRCA-1 mutation carriers. They also show a high pathological complete response (pCR) rate, rate of disappearance of all invasive cancer, BRCA mutated, metastatic TNBC [39]. In a very early study in 2015, Carboplatin administration, when given prior to chemotherapy, was shown to increase the 3 year survival rate for non-relapsed patients to 85.5% compared to 76.1% with just chemotherapy [44]. 

Like many chemotherapies, these platinum-based drugs carry a risk of inducing hematological toxicity, including neutropenia, anemia, leukopenia, lymphopenia, and thrombocytopenia [12]. Therefore, platinum-based chemotherapy may not be the right form of treatment for an immunocompromised patient, or a patient who already has a low red blood cell or platelet count due to other causes. Carboplatin is not recommended for patients who are pregnant, and cisplatin is not recommended for patients who are breastfeeding [12, 40].  

Second-line Treatment Options 

As the TNBC becomes more advanced, the treatment options become more intricate as well. Most of these treatments are considered second-line treatments, which can follow standard treatment upon relapse or disease progression. PARP inhibitors are a type of treatment for metastatic TNBC arising from the BRCA-1 mutation. The 2 main PARP inhibitors used for TNBC are Olaparib (Lynparza) and Talazoparib (Talzenna) [21, 31]. Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes — PARP 1, PARP 2, PARP 3 [31]. Since PARP enzymes are involved in normal cell homeostasis, Olaparib is able to obstruct overall tumor growth [31]. It is typically used as a monotherapy, or as follow-up treatment to platinum-based therapies [31]. Talazoparib is also a poly (ADP-ribose) polymerase inhibitor, inhibiting PARP1 and PARP 2  [21]. The efficacy of olaparib was a 56.3% objective response rate in a study done in February 2021 [13]. The FDA approved Talazoparib for treatment of HER negative, advanced breast cancer in October of 2018 [2]. In the FDA study, the primary efficacy outcome was a median progression free survival (PFS) of 8.6 months for treatment with talazoparib compared to 5.6 months for regular treatment, where the control group was receiving a placebo [2]. 

Some common adverse effects of these PARP inhibitors include anemia, neutropenia, leukopenia, thrombocytopenia, nasopharyngitis/upper respiratory tract infection/influenza, respiratory tract infection, stomatitis–a condition that causes painful swelling and soreness inside the mouth, and alopecia–an autoimmune disorder associated with hair loss [16, 23, 25, 26 41]. If the patient has a history of chronic respiratory tract infections or other issues regarding the respiratory tract or low white blood cell, red blood cell, or platelet count, this treatment may not be the right treatment for the patient. Both olaparib and talazoparib are not recommended for pregnant patients [16, 23, 25, 26 41]. 

Immunotherapy is another class of advanced treatment options,and in the treatment of TNBC, has focused on preventing the PD-1 and PD-L1 interaction. The two primary immunotherapies used for TNBC are Atezolizumab (Tecentriq) and Pembrolizumab (Keytruda) [24, 34, 36].  Atezolizumab is often used in combination with paclitaxel. It is a humanized IgG antibody that binds to PD-L1, preventing its interaction with PD-1 and B7-1.2 [34]. Pembrolizumab is a highly selective IgG4-kappa humanized monoclonal antibody against the PD-1 receptor [24, 36]. By inhibiting the interaction of PD-1 and PD-L1, these monoclonal antibodies cause a shift in the activation state of tumor-specific immune cells by alleviating inhibitory signals, thereby increasing anti-tumor immune response. In March of 2019, the FDA approved atezolizumab for PD-L1 positive metastatic TNBC  [3]. The efficacy for atezolizumab and paclitaxel treatment was a median PFS of 7.4 months versus a median of 4.8 months without atezolizumab. Also, the overall response rate was 53% with the immunotherapy treatment versus 33% without it (placebo)[3]. This study done by the FDA shows that atezolizumab has a promising future in TNBC treatment. In July of 2021, the FDA approved pembrolizumab for high-risk, early-stage TNBC [5]. Pembrolizumab with neoadjuvant chemotherapy showed a 63% pCR rate out of 1174 patients compared to a 56% pCR rate for patients who just received chemotherapy, displaying that the treatment is not as promising as atezolizumab [5]. 

The common adverse reactions of immunotherapy treatment of either atezolizumab or pembrolizumab are asthenia, dyspnea—or difficulty breathing, alopecia, peripheral neuropathy—damage to the peripheral nerves that causes muscle weakness and numbness, mucosal inflammation—which causes abdominal pain with a burning or tingling sensation, stomatitis, insomnia, anemia, and neutropenia [14, 15]. For these symptoms, a patient who already suffers from a condition that causes difficulty breathing, has a low white or red blood cell count, or already suffers from conditions regarding the intestines may not consider this treatment as it could worsen health severely. Pembrolizumab should not be used during pregnancy and atezolizumab isn’t recommended during pregnancy [14, 15]. 

Antibody-Drug Conjugate (ADC) therapies are another advanced treatment option that are designed to deliver potent molecules to cancer cells. These ADC’s consist of an antibody that is specific for a tumor-associated antigen linked to a drug that is meant to inhibit growth of the tumor (Figure 3) [29]. This serves as a more targeted treatment as it harms only the tumor cells and not healthy, normal cells. One of the few FDA-approved ADC is sacituzumab govitecan [29]. Some other ADC’s in earlier stages are ladiratuzumab vedotin, trastuzumab deruxtecan, AVID100, U3-1402, CAB-R0R2-ADC, and Anti-CA6-DM4 [29]. These drugs are used with various different kinds of antibodies.  Sacituzumab govitecan works by targeting Trop-2, which is an intracellular calcium signal transducer, and selectively delivering SN-38, an active metabolite of irinotecan [29] According to the FDA, the median PFS was 4.8 months and the median overall survival was 11.8 months for patients receiving sacituzumab govitecan. This was compared to lower PFS and lower overall survival with patients who just received chemotherapy [4]. This is still in its early stages but is showing promising results for patients of all ages and differing numbers of previous treatments. The FDA granted regular approval to sacituzumab govitecan in April 2021 [4]. 

The adverse effects of sacituzumab govitecan are neutropenia, alopecia, anemia, hypophosphatemia—low levels of phosphorus in the blood, and asthenia—or abnormal physical weakness [17]. Thus, patients with very low white blood cell counts or low red blood cell counts prior to treatment should consider not receiving treatment. Also, patients who already have hypophosphatemia due to other causes, or are already suffering from other forms of physical weakness may consider not taking this treatment. Sacituzumab govitecan should not be used if the patient is pregnant [17].

Figure 3. Composition of antibody-drug conjugates targeting cancer cells. Potent, toxic molecules are delivered in a cancer-specific manner via tumor antigen-specific antibodies to induce apoptosis in the cancer cell while sparing healthy tissue. Created with BioRender.com

The harmful molecules are delivered with the antibody that binds to the antigen (specific to the tumor cell). This makes it a targeted therapy as it only targets the tumor cells and doesn’t harm normal cells. The toxins are delivered into the cancer cell, harming or killing (apoptosis) the tumor cell. 

Emerging Treatment Options/ Future of Treatment for TNBC

The mammalian target of rapamycin (mTOR) is a protein from the phosphatidylinositol 3-kinase-related kinase family of protein kinases and is highly active in TNBC as it is involved in tumor regulation, growth, and sensing and integrating multiple signals from growth factors and nutrient signals [20]. It may have a strong involvement in malignant transformation [20]. Inhibiting the PI3K/AKT/mTOR signal pathway is a great mechanism to stop/reduce tumor growth. Currently, such treatments are in early clinical trials and are still developing as a treatment strategy for TNBC. 

There is a specific subtype of TNBC that is associated with overexpression of the epidermal growth factor receptor (EGFR). Targeting this pathway appears to be promising, but not much research seems to be present of the growth factor receptor itself [32].

There is also a new development in the scientific realm of mRNA vaccines, and this may be a future possibility in treating cancer [28].

Discussion

Triple Negative Breast Cancer is a very deadly form of breast cancer that does not express hormone receptors (estrogen and progesterone receptors) nor the human epidermal growth factor (HER 2). Since these receptors cannot be targeted,  the therapeutic options have historically been limited to standard chemotherapy and radiation following surgery, if possible. However, a number of treatments for TNBC have arisen in the last couple of decades and are producing marginal benefits over standard treatments, but they represent promising new avenues for approaching treatment of TNBC. With so many promising treatments under development, this paper attempted to explore their utility and their implications for specific patient cohorts. These emerging treatments are in the early stages of development and, per FDA regulations, are typically only used as second line treatments following standard therapy, or—in dire cases—may be used in compassionate use cases. As the scientific field continues to expand, new aspects of treatment will continue to emerge, leaving the future of TNBC treatment very bright. 

Tanya Ghai, Youth Medical Journal 2022

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44.  Triple-Negative Disease May Have New Treatment Option. (2020, January 21). Breastcancer.Org. https://www.breastcancer.org/research-news/triple-negative-may-have-new-tx-option

45.  Trivers, K. F., Lund, M. J., Porter, P. L., Liff, J. M., Flagg, E. W., Coates, R. J., & Eley, J. W. (2009). The epidemiology of triple-negative breast cancer, including race. Cancer Causes & Control, 20(7), 1071–1082. https://doi.org/10.1007/s10552-009-9331-1

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Categories
Biomedical Research

BRCA2’s Relation with Aldehydes Leads to a Higher Risk of Developing Prostate Cancer Than BRCA1

Abstract

Although two of the most significant breast cancer susceptibility proteins, BRCA1 and BRCA2, interact with each other in the same DNA damage repair (DDR) pathway (BRCA1 works in checkpoint activation and DNA repair, and BRCA2 plays a major role in homologous recombination), they react differently when exposed to aldehydes. Aldehydes, RCHO, have a more significant impact on heterozygous BRCA2  as mutation carriers than heterozygous BRCA1 mutation carriers because they directly interact with the BRCA2 proteins. Workers in the chemical industry, alcohol drinkers, and users of products with aldehydes in them are all at a higher risk of being exposed to aldehydes, specifically formaldehyde. Aldehydes directly interact with BRCA2 because the formaldehyde destabilizes and stalls DNA replication forks, increasing the genomic instability which increases mutational risk. On the other hand, aldehydes do not directly interact with BRCA1, so there is no increase in the risk of prostate cancer for heterozygous BRCA1 carriers. In addition, studies have shown that heterozygous BRCA1 carriers’ primary cells are defective in a stalled replication fork repair function, so aldehydes might not have much of an impact on them. This retrospective analysis research paper discusses why the difference between the responses of aldehyde exposure from patients with a heterozygous germline mutation in BRCA2 and BRCA1 leads to a higher risk of prostate cancer in BRCA2 mutant carriers than BRCA1

Introduction

Faulty BRCA1/2 genes are two of the most common causes of developing breast, prostate, pancreatic, and other types of cancer. They are genes that guide the production of tumor suppressor proteins. Everyone is born with two copies of this gene, one from each parent, and variants in these genes can cause cancer at an early age. Even if you inherit a faulty copy of the gene from one of your parents, you can still possess a good copy because embryos can not develop if both copies happen to be mutated. Overall, BRCA1/2’s primary function is DDR (1). Wildtype BRCA1 and BRCA2 genes both participate in mitophagy, cell cycle checkpoints regulation, transcriptional regulation, and homologous recombination (2). Although BRCA1 and BRCA2 have many similarities, there are also some differences in their functions. Unlike BRCA2, BRCA1 plays a vital role in embryonic development (3) and is a co-regulator of androgen receptors (4). BRCA1 works with RAD50, NBS, MRE1, and RAD51 for DNA repair, BARD1 and BAP5 for the ubiquitination cycle, HDAC and RB for chromatin structure regulation, CHK1, CHK2, TPX2, and NuMA for cell cycle regulation, and c-Myc, ZBRK1, E2F1, and CtlP for transcriptional regulation (5). It controls spindle formation and centromere numbers (6). It is also a pleiotropic DNA damage response protein meaning it has a role in DDR and makes sure the cell does not go through the cell cycle with mistakes in the DNA (7). Early on in homologous recombination, BRCA1 works with nucleases and coordinates DNA end resection to form the single-stranded DNA (8). BRCA1 carriers are also most likely to develop triple-negative breast cancer (9). BRCA2’s role is to regulate RAD51, a key enzyme in homologous recombination, filament formation and activity, and cytokinesis (10) (11). BRCA2 also takes part in telomere homeostasis, cell cycle regulation, chromosome segregation during mitosis, facilitating mitophagy, and many more functions in the cytoplasm (12). This gene plays a vital role in the stabilization of the replication fork as well (2). Mutations in BRCA2 are the most common cause of prostate cancer (13). Prostate cancer is the second most common neoplasm and is the second most common cancer in men. It usually occurs in older men as it is the most common risk factor and forms in the prostate tissue, a gland in the male reproductive system (14). Thirteen out of every one hundred American men develop prostate cancer, and about two to three of them will die from it. African-Americans have the highest chance of developing prostate cancer with two times the rate of mortality of other men. Family history is also associated with a higher risk of developing prostate cancer. Some examples include having more than one first-degree family member with prostate cancer, being diagnosed when you were fifty-five or younger, or being diagnosed while other family members had breast, ovarian, or pancreatic cancer. Doctors have used some methods to treat prostate cancer: a prostatectomy, removing the prostate, and external or internal radiation therapy. (15) Prostate cancer can spread outside of the prostate gland, which can cause it to be very deadly. (16) BRCA1 mutation carriers have a lower risk of developing prostate cancer at about 3.4%. (17). However, together, BRCA1/2 mutation carriers have anywhere from an 11% to 33% increased risk of developing prostate cancer. (18) Aldehydes have been suspected to play a role in a higher risk of prostate cancer when associated with mutated BRCA2 genes versus BRCA1. Aldehydes are reactive and organic compounds that can be used as building blocks to build other chemicals that make products like perfumes, resins, dyes, detergent, soap, and some other organic acids (19). Aldehydes can be cytotoxic, mutagenic, and carcinogenic. Too much aldehyde exposure can lead to lousy aldehyde metabolism, which could potentially cause cancer (20). Too many aldehydes in your body can lead to damaged mucous membranes, scarred tissue, headaches, a hangover-like state, faster heartbeat, and stomach problems. In addition, compared to other tissues, acetaldehydes have the most effect on your brain and can cause memory loss (21). They can also oxidize to form carboxylic acids, making them irritate your skin (22). Aldehydes can be found in the air because of pollution from automobiles, industrial waste, fossil fuels being burnt, paint, and surgical smoke. Aldehydes can also be present in food or drinks and be manufactured (19) (23). Out of everything, aldehydes are most likely found in environmental sources and natural objects like cinnamaldehyde, vanillin, roses, citronella, vanilla, orange rind, and acrolein (23) (19). They can be formed within your system without outside exposure by lipid peroxidation, carbohydrate or metabolism ascorbate autoxidation, amine oxidases, cytochrome P-450s, or myeloperoxidase-catalyzed metabolic activation (24). We need to understand aldehydes’ impact on BRCA1 and BRCA2 because, from this information, we can understand a potential cause for why BRCA2 mutant carriers are more likely to develop prostate cancer. It is important to know why patients with BRCA2 mutants are more likely to develop prostate cancer because understanding the difference could potentially inform treatment approaches and help carriers avoid certain lifestyles. Knowing that BRCA2 mutations play a significant role in prostate cancer will push people to be more cautious, and beyond that, if they know why it is more likely to cause prostate cancer than BRCA1 mutations, they will know what to avoid. 

Background

Aldehydes have a more significant impact on BRCA2 than BRCA1. Formaldehyde exposure causes heterozygous BRCA2 truncations to be sensitive to BRCA2 haploinsufficiency. People who inherit a faulty BRCA2 copy have reduced BRCA2 protein levels. The levels go down below the amount that is required for sufficient DNA repair (25). One way to help fight against the problems caused by formaldehyde is the use of ribonuclease H11. Ribonuclease H11 helps improve the instability in the replication fork and chromosomal aberrations. BRCA2 not functioning correctly causes mutagenesis during DNA replication through R-loops (26). Aldehyde dehydrogenase (ALDH2) is a mitochondrial enzyme that is one of the most strongly associated genes with alcoholism. ALDH2 decreases the risk of alcohol toxicity by increasing acetaldehyde levels for one of two reasons: either the acetaldehyde is oxidized slower, or the ethanol is oxidized faster. When a variant of ALDH is produced, it can cause an imbalance between acetaldehyde and ethanol oxidation, leading to changes in the acetaldehyde concentration (27). ALDH2 metabolizes aldehydes to make them less toxic, and if you are frequently exposed to aldehydes and have a poor aldehyde metabolism, which could happen by inheriting genetic variants of ALDH2, then you have the potential risk of developing cancer. Exposure to aldehydes causes BRCA2 proteins to lose their function and break down our body’s defense mechanism, meaning that they cannot repair DNA. Aldehydes cause BRCA2 proteins to lose their function because of the replicative stress caused by formaldehyde. Aldehydes induce DNA damage that BRCA2 haploinsufficiency cannot repair, which leads to more mutagenesis (and eventual cancer development). Since BRCA2 genes are extra sensitive to aldehydes compared to other proteins, it is common for there to be a disruption in their function. A test has been done in which they used two cell line models, genetically engineered cells and cells from patients with a faulty copy of the BRCA2 gene, to understand the effect of aldehydes on BRCA2 (25). Oxidative metabolism produces replication stress which triggers genetic instability from BRCA1/2 (7). ALDH metabolizes internal and external aldehydes and mitigates oxidative stress. It also helps abrogate oxidative stress and helps it resist against chemotherapeutic agents (28). This shows that although aldehydes can be extremely dangerous, ALDH is actually helping BRCA2 proteins away from oxidative stress. Heterozygous BRCA2 mutations that are also exposed to formaldehyde have more genomic instability because of the replicative stress that the formaldehyde causes. Formaldehyde exposure also induces selective proteasomal degradation of BRCA2, leading to an unstable DNA replication fork that causes stalled DNA (29). One more thing that formaldehyde exposure causes are induced haploinsufficiency. Heterozygous BRCA2 carriers have BRCA2 protein levels that are already down by 50%, and exposure to aldehydes makes it go down by another 20%, causing the induced haploinsufficiency. (8) BRCA1 mutations are also sensitive to acetaldehyde because of defective homologous recombination. However, when BRCA1 has secondary mutations, it allows it to have proficient homologous recombination. (30) Similar to BRCA2 mutation carriers, when BRCA1 is exposed to formaldehyde, DNA damage and stalled DNA replication results. However, the cells of heterozygous BRCA1 carriers are defective in a stalled replication fork repair function. Formaldehyde also causes a defect in the DNA replication fork. (8) This may explain the reason behind aldehydes having a greater impact on BRCA2 mutant carriers. Since BRCA1 carriers already have a defect in the stalled replication fork repair function, formaldehyde does not change anything for them as they are already adapted to compensate for this loss, and therefore will not make it any worse. This is extremely important in understanding the difference between BRCA1/2 when associated with aldehydes. If BRCA1 is unaffected, and BRCA2 is affected, then BRCA2 will be more likely to contribute to prostate cancer (6). The information gathered in turn means that cells with BRCA1 mutations are already able to adapt to the type of replication fork stalling that is induced by aldehydes, so they are better adapted to withstand that kind of effect versus BRCA2 mutant cells that do not have adaptive mechanisms to deal with the addition of stalled replication forks, leading to more mutagenesis and increased risk for cancer.

Method

This research paper is a retrospective analysis meaning the conclusion was discovered based on pre-existing research. BRCA2 mutation carriers have a higher chance of developing prostate cancer than BRCA1 mutation carriers. Why though? Especially since they interact with each other in the same pathway, why does a mutation in one increase the risk of developing prostate cancer over the other? To figure out the answers to these questions, I started by reading about our key players, which are BRCA1, BRCA2, and prostate cancer. After going through many primary literature articles and reviews, I started to understand the similarities and differences between the two types of breast cancer genes. I used PubMed as my search engine. As I continued researching, I came across a review about an experiment conducted by Professor Ashok Venkatraman about aldehydes concerning BRCA2 and prostate cancer. After I looked deeper into this, I realized that there was definitely a connection here, but what about BRCA1 and aldehydes? There is no direct relation between BRCA1 and aldehydes, but they perform a similar function when BRCA1 is mutated, which could explain why aldehydes do not affect them. By the time I was done performing my research, I had been through multiple resources about aldehydes, prostate cancer, BRCA1/2, and all of their connections.

Results

Due to an experiment led by Professor Ashok Venkatraman, it can be concluded that aldehydes cause BRCA2 proteins to lose their function and not be able to repair DNA causing cancer. He and his research group used two cell line models: genetically engineered cells and cells from patients with faulty copies of the BRCA2 gene to understand their connection. He overexpressed BRCA2. (25). Their first attempt was to recapitulate the sensitivity by knocking out BRCA using CRISPR/Cas9. They took a cell line that did not have this mutation and examined its response to aldehydes. From this test, they learned that it was not very sensitive. However, if they were to mutate or knock down the gene, then it sensitized the cells to aldehydes causing them to die. When you have a cell line that does not have a BRCA2 deficiency, the cells are fine even if they are exposed to aldehydes. However, if they do have a BRCA2 deficiency, then they are sensitive to aldehydes. When you want to test the function of a protein, you should consider what happens when you knock it down, or if it is knocked down, and what it becomes sensitive to that it might not have been sensitive to before. They looked at models in which it was not deficient and was deficient (has the mutation), and because they were genetically engineered, they were able to control the expression of both BRCA1 and BRCA2 using a DOX inducible system. Within the DNA, they genetically engineered a section and inserted a gene called a siRNA (short interrupting RNA). They genetically engineered a siRNA that was for BRCA1 and BRCA2 (two different siRNAs). siRNA is under doxycycline inducer, so after you have inserted this gene, treating the cells with doxycycline (an antibiotic) turns on transcription of whatever the gene is under the DOX inducible promoter. This will only be expressed and made into a protein if you use doxycycline. After this, the siRNA is going to bind to the mRNA and form a double-stranded RNA. The siRNA is particular and perfectly matches BRCA1/2. Cells do not like double-stranded RNA, so when it happens, it gets destroyed by a proteasome. This system is how they knocked down BRCA1/2. It is not permanent, and the expression is not entirely stopped. The amount of expression is described by how much DOX you use. First, they knocked down BRCA1 in a dish of cells, and then they treated it with aldehydes. They had a parental cell line (control group) and their treatment groups. They tested just BRCA1 and then just BRCA2 in terms of aldehydes versus no aldehydes. They then compared these results and were able to say that aldehydes impacted the mutants much more significantly than they did the parental line. The vehicle, whatever your treatment is dissolved in (DMSO in this case), and the other is the treatment group (aldehydes). Through the tests, we see that BRCA2‘s viability percentage gets lower and lower as it has higher exposure to aldehydes. BRCA1‘s percentage also goes down, but not as much as BRCA2‘s. (31) They looked at the viability under these two treatment groups and compared the results. The first main conclusion from the studies includes that cells that are homologous recombination deficient are hypersensitive to acetaldehyde. The next one is that an ALDH inhibitor known as disulfiram aims for BRCA1/2 deficient cells. Acetaldehyde and disulfiram induce severe replication stress in BRCA2. The acetaldehyde hypersensitivity of the cells that lack BRCA2 leads to non-effective DNA replication, checkpoint activation, G2/M arrest, and apoptosis. Acetaldehyde treatment invoked homologous repair, potentially explaining the reduced survival rate of cells without BRCA2. The mouse models used for the experiment show us that acetaldehyde treatment prevents growth in tumors deficient in the BRCA1/2 proteins. Upon treatment by acetaldehydes or disulfiram, the replication was significantly reduced with the absence of BRCA2. The use of disulfiram is good because if you treat it with an aldehyde inhibitor, it will not be able to create the breaks in DNA that need to be repaired. They used an alcohol aversive agent because it almost serves as a treatment. It only kills the cancer cells that are deficient (leads to selective killing of BRCA2 deficient cells). They could use this as a potential therapy. Even though people at a higher risk of exposure may develop cancer because it leads to a higher risk of gaining a mutation, you could treat it and cause so much DNA damage that the cells do not just cause mutations, but they have so many breaks that they die. 

(32)

Discussion

The results from this experiment allowed me to hypothesize that although BRCA1 and BRCA2 interact in the same pathway, they do not react the same when exposed to aldehydes. Exposure to aldehydes causes our bodies’ defense mechanisms to stop working, so the damaged DNA cannot be repaired. Although this can happen in any cell, BRCA2 genes are more sensitive to aldehydes, so they are more affected. Aldehydes are more likely to affect BRCA2 because although BRCA1/2 are both affected by aldehydes, acetaldehyde and disulfiram induce severe replication stress in BRCA2. One problem with this experiment is that overexpression is imperfect since you end up having more copies of that gene in the cell than you would in a clinical setting, so you may get some off-target effects. After this experience, some more things that should be looked into are how we can prevent aldehydes from affecting BRCA2 mutation carriers and what we can do to treat people who have been affected. It is also essential to understand how we can prevent people from being exposed to aldehydes in general. Aldehyde exposure can lead to way more problems than prostate cancer, so we must consider all possibilities. In conclusion, aldehyde exposure is hazardous in that it affects BRCA2 mutation carriers even more and leads them to be more likely to develop prostate cancer than BRCA1 mutation carriers. 

Nihitha Reddy, Youth Medical Journal 2022

Reference Page

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Categories
Biomedical Research Health and Disease

Why should we not underestimate the role of epigenetics in treating cancer?

Over the last several hundred years, we have witnessed marvellous breakthroughs in genetics. From the works of Charles Darwin to Mendel, there is no doubt that these theories have moulded our understanding of genetics today. However a recently emerging area of scientific research could add to our understanding of genes. Epigenetics is an emerging area of medical research of how our behaviour and environment can change the way genes work. Epigenetics cannot alter our DNA sequence, however it can affect how the body reads the DNA sequences.

In the 18th century, the French scientist Lamarack argued that acquired genes can be transmitted. However he believed that this was the sole basis of inheritance which we know is not to be the case. Whereas in Darwin’s theory of evolution, he suggested that lifetime experiences could lead to the formation of gemmules which attached themselves to egg and sperm, hence affecting offspring. 

How do epigenetic mechanisms work?

Epigenetic changes affect how genes are expressed. There are various epigenetic mechanisms which can occur in our bodies. DNA methylation and histone modification are examples of these mechanisms. 

DNA methylation is the addition of a methyl group to the 5th carbon of cytosine residues( which are linked by a phosphate to a guanine nucleotide ) catalysed by DNA methyltransferases. Consequently this forms 5-methylcytosine.  The cytosine residue linked to the nucleotide is known as a CPG dinucleotide. The methyl group is obtained from the methyl donor S -adenosine methionine. Levels of this methyl donor(SAM) depend on the intake of vitamin B12, B6 and folic acid. The methylation of these cytosine residues to form 5-methylcytosine significantly influences cell differentiation. The methylation of CPGs in the promoter region is associated with gene repression. Methylation is known to turn genes ‘off’.

Similar to DNA methylation, histone modification does not alter the DNA sequence however it modifies its availability to the transcriptional machinery. Chromatin consists of histones and DNA. An example of a well known histone modification is the histone acetylation of lysine. Acetylation neutralises  the positively charged lysine residue in the histone tail: this reduces the strength of the bond between the DNA and histone tails. This causes it to be more accessible to transcription factors.

Causes behind epigenetic marks

Epigenetic marks can be affected by exposure to various metals. Experimental analyses have shown that there were DNA methylation changes after arsenic exposure.Arsenic can be found in rocks, soil and insecticides. Another metal which is shown to have caused epigenetic alterations is cadmium. Cadmium toxicity mechanisms can cause epigenetic alterations during embryonic development : a set of genes responsible for transcription regulation control have shown changes in DNA methylation associated with concentrations of cadmium in pregnant women. Cadmium can be found in soil, and contaminated water, as well as through diet, for example through cereals, vegetables and smoking.

Furthermore air pollution can affect the epigenome. Exposure to atmospheric pollutants can lead to changes in DNA methylation of immunity and inflammation genes, which has been associated with reduced lung function and thus lung cancer. Benzene is also associated with changes of DNA methylation. Low-level benzene exposure has been linked to blood DNA methylation changes such as a decrease in DNA methylation of the genes LINE-1 and MAGE-1: this could increase the risk of developing acute myelogenous leukaemia.

Diet also can influence epigenetic mechanisms. A reduction in calorie intake might attenuate the epigenetic changes which occur during ageing. Smoking can also result in epigenetic changes. At specific parts of the AHRR gene, smokers typically have less DNA methylation than non-smokers. After a smoker quits, the smoker tends to have increased DNA methylation at this gene.

Epigenetic marks: a cause behind cancer

The first human disease to be linked to epigenetics was cancer. Researchers found the diseased tissue caused by colorectal cancer had less DNA methylation than normal tissue. In normal cells,  CpG clusters(known as CpG islands) are normally free of methylation. However, in cancer cells, these CpG islands are excessively methylated, leading to  genes turning off that should not be silenced . This typically occurs in the early stages of cancer. 

Excess methylation of the promoter of the DNA repair gene MLH1 causes a microsatellite (a repeated sequence of DNA) to become unstable  by shortening or increasing its length. This has been linked to many cancers such as gastric, endometrial and colorectal cancers.

Epigenetic Treatments

At present, two classes of epigenetic drugs have been approved by the FDA, DNA methylation inhibitors and histone deacetylase inhibitors. The first approved drug was 5-azacitidine.

5-azacitidine is an analog of cytidine, with a nitrogen atom in the position of the 5th Carbon. Cytidine can be incorporated into DNA and RNA. Due to 5-azacitidine’s similarity to cytidine, both compounds are recognised by DNA and RNA polymerases, therefore the drug is incorporated into the DNA during replication. The drug is recognised by DNA methyltransferase. The DNA methyltransferase transfers a methyl group as usual. However as the nitrogen is in the fifth position this causes a permanent  bond between the DNA methyltransferase and 5-Azacitidine. This causes DNA methyltransferase to degrade, which leads to the reduction in methylation . The drug had a high level of toxicity when tested on mice. Hence the drug is now given in low but repeated doses so the epigenetic effects can occur without a high level of cytotoxicity.

5-azacitidine

RG-108

RG108 is a non-nucleoside analog which specifically  targets DNA methyltransferases. This interacts with the catalytic domain(the region of an enzyme that interacts with its substrate to cause an enzyme reaction), and then blocks its active site with a low level of cytotoxicity.  Unlike nucleoside analogs like 5-Azacitidine, non-nucleoside analogs do not incorporate themselves into DNA. Therefore they do not induce any toxicity.

RG-108

Conclusion

In conclusion, epigenetics has significantly added to our understanding of how environmental influences can affect whether and how genes are expressed.  Epigenetics drugs have a great potential to be effective against a number of cancers by reversing epigenetic mechanisms. The field of epigenetics will continue to grow, enabling scientists to develop more targeted drugs against cancers.

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·      Lanata, C., Chung, S. and Criswell, L., 2018. DNA methylation 101: what is important to know about DNA methylation and its role in SLE risk and disease heterogeneity. Lupus Science & Medicine, 5(1), p.e000285.

·       Heerboth, S., Lapinska, K., Snyder, N., Leary, M., Rollinson, S. and Sarkar, S., 2014. Use of Epigenetic Drugs in Disease: An Overview. Genetics & Epigenetics, 6, p.GEG.S12270.

·      Ganesan, A., Arimondo, P., Rots, M., Jeronimo, C. and Berdasco, M., 2019. The timeline of epigenetic drug discovery: from reality to dreams. Clinical Epigenetics, 11(1).

·      Science Direct. 2016. N Phthaloyltryptophan. [online] Available at: <https://www.sciencedirect.com/topics/medicine-and-dentistry/n-phthaloyltryptophan&gt; [Accessed 19 February 2022].

·       Zheng, Z., Zeng, S., Liu, C., Li, W., Zhao, L., Cai, C., Nie, G. and He, Y., 2021. The DNA methylation inhibitor RG108 protects against noise-induced hearing loss. Cell Biology and Toxicology, 37(5), pp.751-771.

Picture Credits:

·      n.d. Azacitidine. [image] Available at: <https://en.wikipedia.org/wiki/Azacitidine#/media/File:Azacitidine.svg&gt; [Accessed 27 February 2022].

·      n.d. RG108. [image] Available at: <https://images.app.goo.gl/T4Pybm3arRbWaqH47&gt; [Accessed 27 February 2022].

Categories
Biomedical Research Health and Disease

Influence of Technology in Dentistry

As technology is already seen to be changing in many sectors of society, the development of new devices and systems to benefit the whole healthcare system, including dentistry, is definitely inevitable. New systems to benefit patients and dentists will overall lead to better patient-centred care. Some of these new technologies will be explored here and how this will impact the field in general.

One form of technology, which has been introduced within society for a while but only just begun to be utilized in dentistry, is Augmented Reality (AR) and Virtual Reality (VR). Augmented Reality uses visual elements to create an enhanced version of the real physical world by analysing the world in front of the viewer and adding filters. This has excellent uses in dentistry such as dental students using AR to practice procedures. Rather than using mannequin heads which cannot be used at all times, dental students can improve and develop their manual dexterity skills anywhere. In the dental practice, dental professionals can create accurate representations of patients’ teeth on a model and present them what their teeth should look like after treatment and procedures. This automatically creates a greater satisfaction and comfort for the patient about how their teeth can be improved, which can give them confidence and be less fearful of the whole process. It gives the patient a greater awareness of their problem and makes them more likely to undergo treatment without being skeptical. Furthermore, multiple AR models can be created with different aesthetics to present to a patient clearly what treatment they would like. This would overall lead to greater patient satisfaction. Similarly, these benefits can be seen for both the dentist and patient with Virtual Reality. VR involves a person wearing a headset to immerse themselves in a completely different environment to what they are actually in. This contrasts AR where a person can visualise something through a screen but would not experience the same immersion. For this reason, VR can be used by training dentists and dental students to observe a real procedure and learn how to carry it out from an experienced dentist’s perspective. Learning from a third person perspective would not be as engaging. Using VR would mean students would learn much more effectively and even practice these skills with greater understanding. Similarly, for patients needing specialist care or patients who are fearful of procedures, VR headsets can be used to make the environment more comforting for them, which also makes the procedure easier for the dentist to complete.

Furthermore, the use of Artificial Intelligence (AI) has been utilized to analyse data throughout many aspects of society and has excellent opportunities in the field of dentistry too. AI algorithms have already been set up to analyse huge amounts of data to find the best treatment options for patients. Health data, research and treatment techniques can be analysed as a whole to offer diagnostic recommendations for individual patients. Further collection of data and analysis, such as with genomic data would offer a deeper understanding into each person, providing a better personal care. With AI having access to such information, better treatment options are available. However, one drawback of this is that the handling of such huge amounts of data has to be done with care as practices may be susceptible to data hacks and leaks which would ruin patient privacy and confidentiality. However, with such large-scale data processing, much better security systems would be in place too. Another implementation of AI on a larger scale could involve the use of smart toothbrushes. With our homes being filled with smart devices, the use of a smart toothbrush would improve our lives further. Used in conjunction with an app, a variety of sensors in the toothbrush analyse the method with which the user is brushing their teeth and while scanning the area of the mouth, the user can be notified on how to improve their brushing. With real time feedback on whether too much pressure is applied, which areas have been missed and which technique should be used, over time the user’s oral health would improve greatly. At the expense of these benefits, there are some negatives which include the extent to which data is being collected while these systems are used, which would put off some consumers.

In addition to all of these, multiple technological advancements, including in robotics, allow for a better treatment for the patient and follows the philosophy of patient-centred care to a greater extent. For example, intra-oral cameras have begun to be utilized by dentists to view harder-to-see areas of the mouth in greater detail. When complex procedures occur, the site has to be inspected clearly and intra-oral cameras ensure no abnormalities are missed. Similarly, as such a huge number of patients receive dentures every year all over the world, intra-oral scanners play an amazing role in the production of dentures. Normally, when an impression of the teeth has to be made, a thick liquid material, usually alginate or polyvinyl siloxane, is set in the patient’s mouth before a set of dentures can be made. This has to be sent to a lab to make a set of dentures for a patient. However, using intra-oral scanners means that a quick digital impression of the teeth can be formed with just one tool and this digital scan of the patient’s mouth can be sent to the lab. The process of creating an impression is much faster and is much easier for the patient. The resulting denture will be more accurate too which results in better patient satisfaction too. Furthermore, as dental practices regularly send impressions to dental labs, some dental implants could be made by the dentist itself with the help of 3D printing. Using the same digital scanning technique but instead creating an implant quickly for a patient makes the whole process faster. Rather than running a whole dental laboratory, dentists can 3D print certain implants and money can be saved, which results in patient expenditure falling too and costs reduced. The greater accuracy too leads to better results. Furthermore, the actual procedure of setting implants within the patient can be assisted with technology too, such as with the use of the YOMI robotic system which increases accuracy of procedures whilst ensuring safety.

The technologies utilized in dentistry allow for an excellent improvement to patient care as procedures become more accurate and patients are satisfied with their results which mirrors the dentists aim of providing patient centred care.

Arya Bhatt, Youth Medical Journal 2022

References

The Medical Futurist. 2020. 9 Technologies That Will Shape The Future Of Dentistry – The Medical Futurist. (online) Available at: https://medicalfuturist.com/the-amazing-future-of-dentistry-and-oral-health/

Evanson, A., n.d. How 3D Printing Is Revolutionizing Dentistry. (online) Evanson DDS. Available at: https://www.evansondds.com/how-3d-printing-is-revolutionizing-dentistry/

n.d. Professional 3D Printing Materials. (online) Available at: https://dental.formlabs.com/uk/materials/

https://itero.com/en-gb

Categories
Biomedical Research Health and Disease

The Human Respiratory System: A Marvelous Bodily Circuit or a Fragile Interconnected Network?

Introduction

Breathing is an automatic action controlled by our medulla while asleep, unconscious, or awake. The fact that our bodies take this simple action of inhaling the air that ubiquitously surrounds us as an autonomic action suggests a significant importance to the body’s function. This is only the start of humans’ detailed, intricate, and adapted respiratory system- an undoubtedly marvellous feat of human evolution. In this article, we will explore deep into this system and question the failsafe’s- since, without oxygen in our bodies, we become ineffective, weak, and fruitless: often leading to death.

Why Do We Need Oxygen?

As multicellular organisms, humans contain an abundance of cells. These cells must carry out their specialized functions within tissues- most of which are active processes (requiring energy). This introduces the process of cellular respiration, an enzyme-controlled reaction that releases energy in the form of an activated nucleotide known as ATP (Adenine Tri-Phosphate). This enables cells to carry out DNA replication, active transport, synthetic pathways, and muscle contraction via actin-myosin interactions in muscle fibres. As a result, oxygen is necessary for cells to respire and carry out basic essential functions. Therefore the process of breathing to obtain oxygen is critical for humans.

In a fatal context- the lack of oxygen to the brain due to no inhalation of air(and hence oxygen) will lead to a deadly condition known as Cerebral Hypoxia. This is because the cells of the brain require a constant supply of oxygen to respire. Therefore a lack of oxygen means glucose is not metabolized quickly enough within brain cells, and hence there is not enough ATP being released. The lack of energy causes brain cells to die and neurons to shut down. Therefore in Cerebral Hypoxia- the brain cells can die out in 5 minutes without oxygen, leading to death.

The Mechanism and Adaptations

It is vital to understand how our cells receive oxygen via the respiratory system- but as we explore this, we shall also come across numerous organs that host multiple functions, making what seems easy, effortless. Everyday actions turn into a precise mechanical process. The respiratory system starts by a simple inhaling activity conducted manually or automatically. This first step is crucial for the function of the respiratory system. Hence it is assigned as an autonomic action by the body- controlled by the Medulla oblongata of the brain.

The air then travels through our mouths and down to the first main structural feature- The Larynx (seen in figure 1).

Figure 1. A detailed view of the larynx, including examples of Cartilage, explored further in the paragraph below. Image sourced from WFSA – Airway Masterclass 3 : The Larynx

The Larynx (also referred to as the voice box) is located just behind the tongue. It is a complex organ with nine pieces of Cartilage within it, namely: the epiglottis, thyroid, arytenoid, cuneiform, corniculate and cricoid cartilage. Cartilage is a connective tissue that has major structural significance. Referring back to the Larynx, Cartilage’s abundance ensures it is held in place without collapsing and allows it for some flexibility to change shape. The Larynx connects the throat and the trachea with four main functions: Protecting the top part of the trachea, directing food and drink away from the trachea, enabling speech, and finally allowing for unrestricted flow of air towards the trachea. We can primarily focus on the last two functions as these are the ones most concerned with the respiratory system. When we inhale air, the muscles hold the Cartilage firmly in place so that the air from the mouth or nasal passages (if inhaled through the nose) may flow through the Larynx smoothly. 

The Larynx is also adapted in numerous ways to fulfill its functions as the voice box. The Larynx has a thin lining of mucous membranes and hence has several secretory and squamous epithelial cells lined on its surface. This ensures that the Larynx remains moist, so vibrations of the vocal folds are more smooth. The vocal folds are formed by narrow ligaments: the false vocal folds and true vocal folds. The false vocal folds do not make sound at all but serve to protect the true vocal folds located beneath them. Sound is produced by the muscles of the Larynx (cricothyroid and thyroarytenoid), moving the vocal folds into the stream of passing air. Pitch depends on how tight the folds have been stretched across the creek. This links back to the abundance of cartilage in the Larynx- connecting the muscles to the vocal folds and indirectly changing vocal fold length.

Figure 2. A view of the respiratory system, from Larynx to Lungs. Image sourced from Pharmacy180-Trachea

Once the air passes through the larynx, it enters the Trachea- our next prominent structural feature of the Respiratory system. The Trachea is a cylindrical tube that carries air down from the bottom of the larynx to the bronchial tubes. The Trachea is adapted to ensure that it does not restrict the mobility of the neck, enables the unrestricted flow of air, and is strong enough to prevent collapse during low internal air pressure as inspiration occurs.

The Trachea achieves this by containing alternating bands of cartilage and muscle to hold open the Trachea and allow air to flow easily. This also provides sufficient structural support to ensure the Trachea has some resistant properties to external forces, such as being crushed and not collapsing during low internal pressures due to inhalation(inspiration). Additionally, the inside and outside of the tracheal walls are lined with membranes of solid elastic fibres to provide flexibility which ensures the Trachea does not limit movement of the neck. The neck moves by a pivot joint and is vital for seeing in different directions; hence, these elastin fibres in the tracheal lining are crucial.

Figure 3. A cross section of the trachea with detail on the surface lining. Labels point to the glands on trachea surface, explored further below. Image from Yale Histology

 The trachea is also lined with ciliated epithelial cells and goblet cells. The goblet cells release mucus via the Glands, seen above in Figure 3, and trap any dust or bacteria that have been inhaled before they can reach the lungs and cause infection. The cilia, hair-like projections formed from microtubules, are present on the surface of the epithelial cells lining the tracheal wall and waft the mucus up the trachea for the mucus to be expelled via coughing. The process of removing the mucus occurs by simple cilia action and coughing or sneezing (if particles/bacteria are caught in nasal passages). In the first case, the cilia move the mucus by creating a rhythmic beat and hence a current. This causes the slime to move up the trachea, through the larynx, and into the pharynx, where it shall mix with saliva from the mouth. From here, it may be swallowed back and travel down the esophagus for it to be broken down by the stomach acid. In a cough, the central airways narrow, and the phlegm/mucus globs are propelled up the trachea by a column of high-velocity air. The noticeable coughing sound is formed by the air moving past the larynx at such high speeds. The phlegm/mucus is transferred directly to the pharynx, where it may be swallowed back down into the esophagus or expectorated. The process of sneezing is a mechanism to clear the nose following the detection of foreign bodies in the nose, such as pollen, dirt, or bacteria. When we sneeze- our chest muscles contract and cause the lungs to become slightly compressed while our throat muscles relax. Then a column of air is sent through the nose at approximately 100mph to clear out the built-up phlegm.

The trachea, therefore, carries air down into the bronchi. The bronchi are transport tubes that further carry the air into the lungs. The lungs can hold about 5 liters of air, and since we have two lungs, the Bronchi must transport the air into both lungs. As a result, we see a split of the main bronchial tube into the left and right bronchus. However, this is not the end of the bronchi’s branching as the right and left bronchus now rapidly subdivide into numerous small tubes. The smallest of these are the bronchioles, with about ½ mm diameters. The bronchial tubes are attached to thousands of tiny air sacs called alveoli. Cumulatively, the millions of alveoli can create a surface of about 100 square meters. The alveolar walls are also surrounded by a network of one cell thick capillaries. As a result, the high surface area means that diffusion, where oxygen moves from the air sacs to the veins, can occur more quickly. Alveolus and Capillaries are also one cell thick- reducing the diffusion pathway significantly and allowing the gaseous exchange of CO2 and O2 to happen effortlessly. Moreover, the fact that we continuously inhale and exhale maintains a crucial diffusion gradient between the contents of O2 in the blood capillaries and the alveoli. 

Once oxygen diffuses into the blood by the gaseous exchange at the alveoli, it must be transported to the cells to allow for the vital process of cellular respiration to occur. A specific protein facilitates the transportation of oxygen within the blood called hemoglobin. This quaternary globular protein contains four prosthetic Haem groups (Fe 2+). These bind with oxygen to form an Oxyhaemoglobin complex. This reaction is reversible, as when the oxyhemoglobin reaches the bodily cells requiring oxygen- it must release the oxygen. 

As a result, the cells now obtain oxygen and, assuming it also receives sufficient glucose, can carry out the process of respiration to metabolize the glucose, release ATP and hence have enough energy to conduct basic, essential, and active functions.

Failsafe

Upon exploring the respiratory system, we can appreciate that it is highly detailed and relies on multiple structures to carry out their functions for oxygen to be transported to the cells. This naturally raises a few questions: has the body prepared for the case where one of these structures fail to carry out their function? What if the trachea unexpectedly closes due to the wearing of cartilage? What if the lack of cilia prevents unrestricted airflow through the trachea?

These would significantly impact the delivery of oxygen to cells and disrupt cells’ conduction of necessary actions. Therefore there must be failsafe’s in place to account for these unexpected malfunctions because this meticulous, interconnected, and adapted system is essential to sustaining life.

Focusing primarily on the lungs, the site where CO2 is removed from the bloodstream and O2 is taken up, we can see an example of a protective measure. The pleura, wall of the lungs, is composed of very soft material with two layers. The visceral pleura covers the lungs while the parietal pleura lines the diaphragm and ribs. By attaching to the inside of the rib cage- there is a prevention of collapse and damage from external pressure. This ensures that the lungs’ shape, structure, and function are maintained. However, this is only a preventative measure rather than a direct failsafe. What if a broken middle rib punctured the lungs? Are there any measures to ensure the rest of the respiratory system can continue its operations? The answer is frankly no.

Conclusion

In the prolonged absence of oxygen, the human body cannot function and shuts down and dies. The respiratory system ensures that we continuously provide our numerous cells with sufficient oxygen, enabling them to carry out essential, active bodily processes as part of tissues or organs. It’s a marvellous, meticulous and adapted bodily circuit, but it is fruitless if one part of the circuit malfunctions. The lack of failsafe makes our beautiful respiratory system a fragile network of interconnected structures on thin ice.

Aryan Bhadra, Youth Medical Journal 2022

References

  1. http://www.sciencedirect.com. (n.d.). Tracheal Tube – an overview | ScienceDirect Topics. [online] Available at: 

https://www.sciencedirect.com/topics/medicine-and-dentistry/tracheal-tube

[Accessed 21 Nov. 2021].

2. DEZUBE.REBECCA (2019). Overview of the Respiratory System. [online] MSD Manual Consumer Version. Available at: 

https://www.msdmanuals.com/en-gb/home/lung-and-airway-disorders/biology-of-the-lungs-and-airways/overview-of-the-respiratory-system

3. Cleveland Clinic (2020). Respiratory System: Functions, Facts, Organs & Anatomy. [online] Cleveland Clinic. Available at: 

https://my.clevelandclinic.org/health/articles/21205-respiratory-system.

4. Healthline. (2017). Why Do We Sneeze? Everything You Need to Know. [online] Available at: 

https://my.clevelandclinic.org/health/articles/21205-respiratory-system.

5. Dickey, B.F. (2018). What it takes for a cough to expel mucus from the airway. Proceedings of the National Academy of Sciences, 115(49), pp.12340–12342.

Categories
Biomedical Research

Life with no Limits: The Immortal Jellyfish

Introduction

From time immemorial, humans have been obsessed with the concept of longevity and immortality. Most civilizations, from the Spanish Conquistadors to the Ancient Greek and Roman empires, have tales of an ancient fruit or fountain that gave them the key to eternal life. While this seemed like a plausible idea then, we certainly now know that there is no such mystical item. However, one organism does have such a gift: a gift that gives them the trait of immortality.

The Immortal Jellyfish

Turritopsis dohrnii, also known as T.Dohrnii, is a hydrozoan species of jellyfish that was first discovered in the Mediterranean sea and has since spread to many research facilities and laboratories worldwide. Like its counterpart jellyfish, T.Dohrnii starts its life as a planula, a special type of larva. The planulae settle at the bottom of the sea, where they split into multiple genetically identical medusae. These medusae fully mature into grown, adult jellyfish in a matter of weeks. However, unlike the other species of jellyfish, T.Dohrnii possesses a special defense mechanism known as ‘Transdifferentiation.’ This cellular mechanism allows T.Dohrnii to revert back into its polyp or juvenile stage when in physical danger. This process looks remarkably similar to what we define as “immortality” and has many promising medical applications as well.

Potential Medical Applications of Transdifferentiation

Unlike dedifferentiation, a process where cells can differentiate or revert back to a less-differentiated stage within its own lineage, transdifferentiation allows cells to differentiate back to a stage where cells can switch lineages. The pioneering work by Takashi and Yamanaka showed that the overexpression of four transcription factors (Oct4, Sox2, KLF4, and cMyc) could induce somatic cells to form pluripotent stem cells. These induced pluripotent stem cells (iPSCs) are capable of infinite regeneration and can differentiate into any somatic cell type while still retaining the same genetic background. This groundbreaking discovery was instrumental in opening multiple doors in regenerative medicine, disease modeling, and drug discovery, especially in cardiology and neurology.

It is common knowledge that neurons are by far the most difficult cells to regrow and produce. However, through the use of transdifferentiation, we may be able to re-populate thousands of lost neuronal cells caused by neurodegenerative disorders such as Alzheimer’s and Parkinson’s. Using transdifferentiation, phenotypes of cells can be altered and changed. Cells found commonly throughout the body, such as skin fibroblasts and peripheral blood mononuclear cells, can be reverted into a stage where the cell can proliferate into glial and neuronal cells. This proves especially effective in the critical stages of late-onset diseases. In a study done on rats, it was found that the skin fibroblasts injected into mouse brains were able to survive up to 6 months and had very minimal risk of tumorigenesis. These cells can also be used to model neurodegenerative disorders such as ALS and have been shown as a potential therapy for spinal cord trauma.

Cardiovascular diseases such as ischemic heart disease, heart failure, stroke, and peripheral arterial disease are the leading causes of death in the United States. The reversal of these heart diseases requires an orthopedic heart transplant. However, this requires the mass use of immunosuppressants in the body, leading to side effects such as dyslipidemia and hypertension, which continue to exacerbate the progression of heart disease. These flaws lead to the need for more advanced forms of treatment such as regenerative medicine. However, there is one major problem with the development of regenerative medicine therapies: the lack of “suitable cell sources.” An ideal cell source would be an autologous somatic stem cell to avoid the possibility of immune rejection. Mesenchymal Stroma cells are suitable cell sources; however, there are very minute amounts of these cells in the body. Advances in the study of transdifferentiation in somatic cells may help alleviate the issue. Through the use of specific transcription factors, transdifferentiation can be used to differentiate resident somatic cells into the desired cell type. For example, with ischemic trauma in the myocardium, transdifferentiation proves to be an effective therapeutic treatment. Cardiac Fibroblasts can be differentiated into cardiomyocytes that the body can use to repair the injury, reduce scar formation, and improve the overall ventricular function.

Conclusion

Since its inception by Yamanaka, the technology surrounding the study of transdifferentiation of iPCS cells has advanced tenfold and has found use in disease modeling, drug discovery, and regenerative medicine. Transdifferentiation has given us the ability to model disease in a petri dish, screen various drugs without ever giving them to patients, and regenerate cells on a large scale in vivo without the fear of activating inflammatory pathways. This concept is very promising and holds great potential, but it is still complicated, time-consuming, and needs more standardization. The study of T.Dohrnii may help in advancing it. Maybe one day, we would see the first human being past the age of 150.

Shreyas Gupta, Youth Medical Journal 2022

References

  1. A.M.N.H. (2015, May 4). The “Immortal” Jellyfish That Resets When Damaged | AMNH. American Museum of Natural History. https://www.amnh.org/explore/news-blogs/on-exhibit-posts/the-immortal-jellyfish
  2. Chun Liu, C. L., Farhan Himmati, F. H., & Nazish Sayed, N. S. (2017, August 31). Paying the Toll in Nuclear Reprogramming. PubMed Central (PMC). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562677/
  3. Jennifer P. Connell, J. P. C., Santhisri Kodali, S. K., & John P. Cooke, J. P. C. (2015, September 11). THERAPEUTIC TRANSDIFFERENTIATION: A NOVEL APPROACH FOR ISCHEMIC SYNDROMES. PubMed Central. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666425/
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