Categories
Health and Disease

Mendelian Laws: How Does a Better Understanding of These Principles Help With the Diagnosis and Treatment of Complex Diseases?

From an obscure 1866 paper titled “Experiments on Plant Hybridization” published in the “Proceedings of the Natural History Society of Brünn” an Augustinian friar named Gregor Mendel is synonymous today as being the Father of modern genetics. His genius was to combine his talents for the biological sciences as well as his love of mathematics during his study of biological inheritance with garden pea plants. He devised a methodical process of developing statistical expectations about inheritance data through monohybrid and dihybrid crosses that is still studied today [1]. By doing so he moved the study of inheritance from being an observational art form like Darwin’s pangenesis and the blended inheritance theorems into a modern scientific process that was not only quantifiable and reproducible, but which also be applied in the understanding of a wide number of genetic conditions such as thalassemia and Duchenne muscular dystrophy [2].

His three principles of inheritance have continued to be widely used in scientific research today to explain the basic characteristics of inheritance.

“Mendelian diseases” are single-gene diseases that are caused by mutant genes that interfere with the specific function and phenotype shown in a genome [3]. These single-gene conditions can be readily modelled using Mendelian laws of inheritance and our understanding of these conditions is generally more complete. However, these diseases are extremely infrequent, accounting for less than 1-7% of all registered single-gene and complex diseases worldwide [8].

A solid understanding of Mendel’s discoveries and principles potentially offers us the ability to track diseases through family pedigrees. Mendelian diseases also tend to be less influenced by external factors and observational studies as well as genome research has expanded our knowledge as to which alleles are the dominant and recessive forms. This knowledge allows us to fairly accurately predict the statistical probability of specific genetic conditions occurring in future generations. In families with these Mendelian conditions, this understanding can be put to good use in helping individuals or families from a clinical point of view [4][5][6].

An example of the use of this knowledge of Mendel’s laws within medicine is in those suffering from thalassemia. In a situation where both parents are carriers for the thalassemia gene, the offspring would have a 25% chance of having severe thalassemia/ thalassemia major [7]. These unfortunate babies would have blood cells that undergo constant rapid breakdown, requiring regular blood transfusions leading to suffering and a reduced lifespan. Amniocentesis to confirm the foetus’s thalassemia status could be performed to help the parents make an informed choice as to whether to continue with the pregnancy.

However, not all diseases are based on the simple Mendelian single-gene model of inheritance. Complex diseases are those conditions that are caused by a combination of genetic, environmental, and lifestyle factors, some, or most of which have not yet been identified. In real life, complex diseases are far more common than Mendelian disorders and include conditions such as Alzheimer’s disease, Type 2 diabetes, heart disease, and multiple sclerosis [9]. These diseases may involve a number of different genes which are influenced by a multitude of external factors leading to a complex of different disease phenotypes. In this situation, the individual is said to have a genetic predisposition to having that disease, where despite carrying the genes, they are not necessarily destined to have the condition.

These conditions do not conform to standard Mendelian Laws of inheritance and reaching a full understanding of the disease is complicated and requires detailed comprehension of the external factors at play, if indeed they can be full identified [10]. Furthermore, interactions of these external factors with the genes as well as between themselves make this challenge even more complex.

However, whilst they may not fully conform to standard Mendelian Laws, the fundamental principles of Dominance, Uniformity and Segregation can still be applied to some extent in helping to understand the dynamics at play within these diseases. Increasing research and understanding of the external factors may help us to create better mathematical models in which we can apply these Mendelian Laws. Conversely knowing the way in which these laws govern genetic inheritance, may in fact help us to identify external influences which were previously unidentified furthering our understanding of the disease as a whole [11].

Given his love for biology and mathematics, I am certain that Gregor Mendel would very much approve of such an approach as well as be amazed at how far his little garden experiment has taken us and the field of genetics over the past 150 years.

Natalie Ho, Youth Medical Journal 2022

References

1. Admin. (2021, March 5). Mendel’s laws of inheritance-mendel’s laws and experiments. BYJUS. Retrieved February 28, 2022, from https://byjus.com/biology/mendel-laws-of-inheritance/

2. Admin. (2021, February 9). Mendelian disorders -different types of mendelian disorders. BYJUS. Retrieved March 1, 2022, from https://byjus.com/biology/mendelian-disorders/

3. Nature Publishing Group. (n.d.). Nature news. Retrieved March 1, 2022, from https://www.nature.com/scitable/topicpage/mendelian-genetics-patterns-of-inheritance-and-single-966

4. Fullick, A. (2015). Edexcel A level biology B. Pearson.

5. U.S. National Library of Medicine. (n.d.). Sex-linked recessive: Medlineplus Medical Encyclopedia. MedlinePlus. Retrieved March 1, 2022, from https://medlineplus.gov/ency/article/002051.htm#:~:text=Sex%2Dlinked%20diseases%20are%20passed,the%20other%20parent%20is%20normal.

6. Alliance, G. (2009, July 8). Inheritance patterns. Understanding Genetics: A New York, Mid-Atlantic Guide forPatients and Health Professionals. Retrieved March 1, 2022, from https://www.ncbi.nlm.nih.gov/books/NBK115561/

7. NHS. (n.d.). NHS choices. Retrieved March 1, 2022, from https://www.nhs.uk/conditions/thalassaemia/causes/

8. Rahit, K. M. T. H., & Tarailo-Graovac, M. (2020, February 25). Genetic modifiers and rare mendelian disease. Genes. Retrieved March 1, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140819/

9. U.S. National Library of Medicine. (2021, May 14). What are complex or multifactorial disorders?: Medlineplus Genetics. MedlinePlus. Retrieved March 1, 2022, from https://medlineplus.gov/genetics/understanding/mutationsanddisorders/complexdisorders/

10. Nature Publishing Group. (n.d.). Nature news. Retrieved March 1, 2022, from https://www.nature.com/scitable/topicpage/complex-diseases-research-and-applications-748/

11. Alliance, G. (2010, February 17). Classic mendelian genetics (patterns of inheritance). Understanding Genetics: A District of Columbia Guide for Patients and Health Professionals. Retrieved March 1, 2022, from https://www.ncbi.nlm.nih.gov/books/NBK132145/

Categories
Biomedical Research Commentary

CRISPR Gene Editing: From novel treatment to reality

Originally released in the year 2000, the Marvel blockbuster film series features a team of six genetically enhanced beings called the X-Men. It appears that every time a new X-Men movie is released on the big screens, the world looks to science to answer the age-old question: “Is the creation of such mutants a possibility?”. 

With the endless developments in genetic engineering and the discovery of CRISPR-Cas9 gene editing in 2020, it is difficult not to wonder if the creation of such mutants in our reality is possible. Yet, much sooner than we expected, these so-called “superhumans” are already walking amongst us, with a range of unbelievable powers including super-strength, super-speed, and mind-blowingly high brain power that increasingly mirror superhuman powers seen on the big movie screens.

To understand the science behind these superhumans, we must first understand the basis of gene editing, which forms the foundation and function of CRISPR-Cas9.

What is CRISPR-Cas9?

CRISPR-Cas9 is a new and unique form of gene editing that allows medical scientists to edit parts of the genome by removing, adding, or altering sections of the DNA sequence [1]. Discovered back in 2021, it has been one of the frontiers of genomic research and a common hot topic within the medical community due to its simplicity, versatility, and precise method of genetic manipulation. The cheap price associated with CRISPR has ultimately made it more desirable than previous methods of DNA editing available on the market including transcription activator-like effector nucleases (TALENs) and zinc-finger nucleases (ZFNs), which are much less cost-effective and accessible [2].

So why is CRISPR-Cas9 gene editing relevant to us right now?

The answer lies in the enormous potential of CRISPR gene editing for treating a wide range of life-threatening medical conditions that have a genetic basis and foundation such as cancer, hepatitis B, and high cholesterol. For example, the excess fatty deposits in major blood vessels causing high cholesterol can be resolved through genetic engineering techniques that “turn off” the genes that regulate cholesterol levels in our body [6]. A new study conducted by Nature 2021 revealed that knocking out the protein PCSK9 with CRISPR significantly reduced LDL cholesterol in monkeys by around 60% for at least 8 months [3]. Although it is likely to be many years before any testing for CRISPR technology can be carried out on humans, this kind of breakthrough within our own genus is impressive. As much current research is focused specifically on ex-vivo or animal models, the intention is to use the technology to routinely treat diseases in humans that can’t be addressed through routine drugs and medications.

How does this form of gene editing work?

The foundation of CRISPR-Cas9 is formed from two key molecules that introduce a mutation into the targeted DNA: the Cas9 enzyme and guide RNA (gRNA). The guide RNA has RNA bases that are complementary to the target DNA sequence in the original genome, and this helps the gRNA bind to the correct region within DNA. The Cas9 enzyme follows the gRNA and essentially acts as small scissors that make incisions within both strands of the DNA, allowing for sections of DNA to be added or removed [1][4]

At this point, the cell recognises the damage within the DNA and works to repair it, allowing scientists to use external machinery to introduce one or more new genes to the genome. This causes the genetic makeup to differ from the “normal” human genome, causing mutations and noticeable changes in the phenotype to occur such as the “super-variants” including super-sprinter variant (ACTN3), super-sleeper mutation (hDEC2), and the super-taster variant (TAS2R38) [5][7].

There is also extensive research being put into eliminating the “off-target” effects of CRISPR, where the Cas9 enzyme makes cuts at a site other than the intended one, introducing a mutation in the wrong region. Whilst some of these changes are inconsequential to the overall phenotype, they may affect the structure and function of another part of the genome. It is suggested that the use of Cas9 enzymes that only cut a single strand of target DNA as opposed to the double-strand may be the solution to eliminate this problem [4].

The next generation of enhanced individuals?

Though the alteration of the human genome is very much already a reality, the creation of ‘mutant’ individuals with more fantastical powers such as Wolverine’s special healing and animal keen senses, and the Scarlet Witch’s telekinesis and matter manipulation remains purely fictional. As of right now, the use of CRISPR in medicine is solely therapeutic, used for repairing or altering innate mutations, as opposed to creating them. Yet, it can be argued that these genetic changes allow the patient to have better DNA than the one they were born with, making them the first generation of genetically modified humans to walk the earth – mutants indeed.

In the X-Men franchise, all mutants carry an ‘X-gene’ which bestows upon them their aforementioned abilities. Unfortunately, no such gene exists – our phenotype arises from a much more complicated relationship between genes and presenting characteristics, and the effects of current gene editing pale in comparison to what is shown in blockbuster movies. That said, hope is not lost: extensive research and development within this field continually offer the possibility of giving individuals similar ‘powers’ to those of the X-Men and Professor X on an increasingly real scale. 

Below, are some examples of X-Men’s superpowers against their real-world human genetic mutation counterparts [5][7]:

X-Men abilityExisting human genetic variation
Animal-keen senseshDEC2 (super-sleeper mutation)  
Super-speedACTN3 (super-sprinter variant) 
Super-strengthLRP5 (unbreakable bone mutation)  
Enhanced sensesTAS2R38 (super-taster variant)  

Do scientists think it is possible for some of these powers to be attributed to genetic mutation? The simple answer is yes. But unsurprisingly, the uncertainty and unpredictable nature surrounding new treatments will always generate some degree of ethical controversy in the scientific community, and CRISPR is no different. The use of CRISPR technology in medicine will undoubtedly become more mainstream in the near future, and once the door is open for genetic modifications to embryos, babies, and adults alike, there is no going back. As with many medical technologies in the past, human health and safety may fail to be at the forefront of CRISPR’s use, leading to all kinds of unnecessary complications. The impact that CRISPR-Cas9 will have on the medical field, now and in the next generation, is undeniable – whether it’s curing a rare form of cancer or creating the first generation of real-life X-Men [8].

There are many unanswered questions surrounding this topic, and this is unlikely to change. But as the research continues and our questions go on, I would like to leave you with only one… What would your superpower be?

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Works Cited

1. Yourgenome.org. 2022. What is CRISPR-Cas9?. [online] Available at: https://www.yourgenome.org/facts/what-is-crispr-cas9 [Accessed 15 March 2022].

2. Beumer, K.J., Trautman, J.K., Christian, M., Dahlem, T.J., Lake, C.M., Hawley, R.S., Grunwald, D.J., Voytas, D.F. and Carroll, D. (2013). Comparing Zinc Finger Nucleases and Transcription Activator-Like Effector Nucleases for Gene Targeting in Drosophila. G3: Genes|Genomes|Genetics, [online] 3(10), pp.1717–1725. doi:10.1534/g3.113.007260.

3. Cen.acs.org. 2022. [online] Available at: https://cen.acs.org/pharmaceuticals/gene-therapy/One-time-CRISPR-hit-lowers-cholesterol-monkeys/99/i19 [Accessed 15 March 2022].

4. 2022. [online] Available at: https://futurism.com/crispr-genetic-engineering-change-world [Accessed 15 March 2022].

5. Business Insider. 2022. 8 genetic mutations that can give you ‘superpowers’. [online] Available at: https://www.businessinsider.com/genetic-mutations-that-make-you-more-awesome-2016-1 [Accessed 15 March 2022].

6. Newscientist.com. 2022. Gene tweak creates supermouse – and prevents diabetes | New Scientist. [online] Available at: https://www.newscientist.com/article/dn21156-gene-tweak-creates-supermouse-and-prevents-diabetes/ [Accessed 15 March 2022].

7. Business Insider. 2022. 8 genetic mutations that can give you ‘superpowers’. [online] Available at: https://www.businessinsider.in/science/8-genetic-mutations-that-can-give-you-superpowers/slidelist/50514398.cms#slideid=50514417 [Accessed 15 March 2022].

8. Pinkstone, J., 2022. Human beings could achieve immortality by 2050. [online] Mail Online. Available at: https://www.dailymail.co.uk/sciencetech/article-5408425/Human-beings-achieve￾immortality-2050.html [Accessed 15 March 2022].

Categories
Commentary COVID-19 Health and Disease Neuroscience

When is the Next Pandemic after COVID coming? Sorry, it’s already here.

Bill Gates warned us that it was coming. Five years ago, Microsoft’s co-founder and multi-billionaire warned the world about an impending global pandemic during a Ted Talk, which has now amassed over three billion views worldwide. In the talk titled “The next outbreak? We’re not ready.”, Gates discussed the lessons learnt from Western Africa’s 2014 Ebola crisis and declared that international governments were not prepared for the foreseeable pandemic that would hit them.

Sadly, Bill Gates was right. On January the 5th, 2020, the COVID-19 virus was officially declared a global healthcare level threat by the World Health Organisation and now almost two years in, we are not yet clear of this one-in-a-generation global contagion.

So, if Gates was right the first time when should expect the next pandemic?

Unfortunately, it is bad news for us……. The next pandemic is here already and unfortunately, we don’t have any vaccines or monoclonal antibody therapy to fight it. The death rates that come with it will be higher than COVID 19, and social distancing or lockdowns will only make it worse. Because this time the cause is not an infective viral disease, it’s a mental health pandemic.

And just because this pandemic is not caused by an infection, it doesn’t mean that it won’t be more devastating if we don’t deal with it in time.

What are the common mental health impacts of the COVID-19 pandemic?

Due to the COVID 19 pandemic, there has been an exponential increase in the number of mental health problems reported over the past 18 months. An investigation conducted by Statista showed that the percentage of adults living in the United States displaying symptoms of anxiety and/or depressive disorder tripled between 2019 and 2020, increasing from 11% to 42.4%.

So what does mental health got to do with a viral infection? You never hear of it this issue when it’s influenza season.

Quite simply, this COVID 19 pandemic has been longer, harder, and far more damaging than we could ever have imagined. Although whilst people like Bill Gates have said that should have been prepared for such events, even they could not have predicted the severity of this once-in-a-generation pandemic.

Similarly, the mental health effects of COVID 19 are also more profound than usual and can even affect those who don’t actually contract the virus. The devastating problem with mental illness is that, unlike other medical conditions, it does not just affect the one person, but also has a knock-on effect on those around them, especially close family members. In this regard, it is more “infectious” than the virus itself. A WHO report suggests that mental health issues play a part in the death of over 40% of individuals and those with mental health disorders tend to die 5 years earlier than those not afflicted.

From an individual standpoint, COVID can have several ways to exert its effect on mental health. Firstly, just contracting the virus can cause the patient to feel stigmatized especially if they pass it on to family or friends. The sense of harming a loved one especially if it causes the death of that person will have a devastating effect on the person’s psyche.

Secondly, if the patient develops severe symptoms of COVID, especially for those who need intensive care, they will be forced, for maybe the first time, to face their own mortality. The elation of survival can be quickly replaced with the horrors of the near-death experience, similar to those who suffer from post-traumatic stress disorder.

Finally, the COVID 19 virus can have long-lasting medical effects for those who do contract the virus. From research so far, up to 1 in 3 people who have contracted COVID described experiencing lethargy, persisting pains as well lingering neurological and cognitive symptoms such as difficulty thinking and fumbling over simple words. Whilst it appears that most eventually will “shake off” these effects, it is believed that for a small number, this may become a chronic condition. The loss of self-worth associated with this, for the individual, is incalculable.

These effects have been even worse for members of the healthcare profession. Faced with the initial unknown nature of the pandemic and the lack of adequate protective equipment, frontline medical workers have been described as “ being on their knees” in response to the crisis by media representations, with many warning us of an even worse mental health epidemic amongst the frontline healthcare workforces.

For the most part, healthcare workers are psychologically resilient professionals highly trained to deal with death and loss. But the elevated death toll, mental and physical burnout from working overtime, and the constant stress on their own safety and the people around them have undoubtedly placed healthcare workers at additional risk for developing mental health problems. The magnitude of the sacrifices made daily by these dedicated people will not be without consequences. In fact, prior to the pandemic, this group was recognized as having the highest rates of stress, mental burnout, drug and alcohol dependence and high suicide rates. Large numbers of individuals working long-term in the NHS have quit their jobs and the loss of this talent will need time and resources to replace.

From a family standpoint, COVID has created a different, but no less devastating effect on mental health. One of the most direct manifestations of this is due to the infective nature of COVID 19. Many relatives have been unable to comfort, personally care for or be able to be at the last moment of a loved one that unfortunately lost their battle with the virus. Being able to care for and say goodbye to a family member can be a great help in the grieving process. Being robbed of this “sense of closure” is likely to make the grieving process harder and further increase the mental burden on surviving family members.

Lockdown itself has caused a number of interpersonal issues. The rates of domestic violence, separations and divorce filings have skyrocketed over the past 18 months. Families who were able to co-exist happily with each other during a normal routine found themselves unable to tolerate each other when they have to be together 24/7. Physical violence both for the victim and the perpetrator can carry a high mental toll and the ensuing separation and divorce is likely to widen the psychological damage to the entire family unit, especially the children. If unresolved, these children could potentially carry the scar of this trauma into their own adult lives and perpetuate this trauma for the next generation.

With the global lockdown has come the massive global recession which has hit world economies and the financial status of everyone around the world. Many people have lost their jobs and with it their financial stability and self-esteem. It is well known that depression and unemployment go hand in hand and with millions out of a job, this has added further to the mental health burden of those affected.

So how do we deal with this?

The difficulty in tackling this mental health pandemic is the common misconception that most believe “it won’t affect me”. Most sufferers will be in denial that they have a mental health problem. But the first step in dealing with any problem is to first admit that there is one.

So, in order for any solutions put in place to be fully effective, responses from local, nationwide, and worldwide representations must be called on to collectively decide on how best we can educate the public about the current pandemic on our mental health and come up with strategies to tackle the inevitable mental health crisis coming our way. Without public education, those affected just will not recognize that they have a problem.

Given that the majority of psychological cases will be dealt with by emergency first-responders and frontline healthcare workers with relatively low experience in mental health, many cases may be missed at the patient’s first time of contact with the medical profession.

The creation of specific guidelines must be set out by health departments and governments to help all first responders and frontline healthcare workers seamlessly diagnose, care for, and treat patients with psychological illnesses. Increasing direct access to mental health care professionals and informing the public how they can do so will also help to reduce the number of those who “slip through the net”.

Healthcare workers, teachers and governments are well-positioned to support students, patients, and the general public during this trying time. Simple solutions such as offering stress management and coping methods to the public/ students at schools should be put into effect as soon as possible. Increasing the availability of walk-in appointments with a mental health specialist in schools and workplaces will also help decrease the number of undiagnosed mental illnesses and new psychological problems being developed.

Addressing the social stigma associated with such illnesses must be another first step taken by governmental bodies, influencers and people in higher positions when tackling this crisis. People suffering and living with mental health issues should stop feeling ashamed of their condition and speak out about their own experiences to inspire others to see mental health specialists if needed.

As for hospital staff and health departments, there are a number of strategies they can implement, to ensure that patients in their wards are as well-supported as possible. For example, panic-inducing news channels constantly bombarding us with statistics on death tolls and the pandemic should be turned off. The staff can instead encourage patients to engage in mindful activities such as reading, solving puzzles and non-strenuous exercise. It is important that nurses who have direct contact with patients try to understand the world from their patient’s perspectives and tailor their care accordingly.

For better or for worse, the COVID-19 pandemic has changed us, the people around us and the world around us. But as we come closer to reaching herd immunity and a possible end to the COVID 19 pandemic, it is paramount that, more than ever, we do not turn a blind eye to the mental health crisis brewing just beneath the surface.

Dealt with wrongly, the mental health pandemic could be more devastating than the COVID pandemic we are facing now.

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Works Cited

1.  Business Insider. 2021. Mental health problems to be next pandemic after COVID-19 crisis, says study. [online] Available at: [Accessed 13 November 2021].

2.  Dias, M. and Bunn, S., 2021. Mental health impacts of the COVID-19 pandemic on adults. [online] POST. Available at: [Accessed 13 November 2021].

3.  Mind.org.uk. 2021. [online] Available at: [Accessed 13 November 2021].

4.  Governmentevents.co.uk. 2021. Flattening a Different Curve: A Blueprint for Covid-19 Recovery? – Government Events. [online] Available at: [Accessed 13 November 2021].

5.  Daily Maverick. 2021. Sponsored Content: Is Mental Health the next pandemic?. [online] Available at: [Accessed 13 November 2021]