Environment, Genes and Disease

By  Lim Ju Boo

Note:  The blogger is pleased to post this article by the Great Sifu Dr. JB Lim on his suggestion via his email on Tue, Jun 23, 10:11 PM.

An email was sent to me by a good old friend of mine of many years since our college days.  He is now a Professor of Psychiatry and was the Head of the Department of Psychological Department at a University Hospital and a Senior Consultant Psychiatrist there for many years, and also a WHO Consultant in Mental Health. 

In that email there was a dialogue among other doctors on the question whether or not genes play a part in depression. 

Here was his answer shared among the doctors:

“Not entirely true though many are possibly pre-disposed to depression.  For genetic reasons, BUT develop the illness or the illness is PRECIPITATED by very real stresses of life.

Hence there is a need to control both. Obviously genetic factors are a long way off from being controlled?  Genetic engineering?  But coping with stresses of daily life are relatively at least possible,  through better recognition of warning signs, counselling on choices etc. and earlier multi-faceted interventions.”

Another doctor then gave his or her view below:

“Good points. Since it has a family history component, is it known how much is due to genes, how much from environmental factors and how much is learned behavior?”

Although their emails were not meant for me directly, except just a casual copy, nevertheless I felt the urge to reply and share with the doctors.

Here’s what I replied:

“I am not a psychiatrist to be able to answer the clinical aspect of depression and its causes.

But I do know some molecular aspects of medicine or other branches of genomic and evolutionary medicine to give a short comment. 

It was once thought that genes are unchangeable in determining the onset and outcome of a disease, and that genes also determine the genotype and phenotype characteristics and traits of a person among many other influences.

That knowledge was some 25 years ago when it was a fashion to speak of modifiable factors such as diet, lifestyle, occupation, medication, body weight, environment...etc. when we talk about physical health and disease.

Then factors that cannot be modified that determine physical and mental health and diseases are age, gender, ethnicity, the choice of parents, and of course genes and heredity. At least that was once thought some 25 years ago and earlier.

However with advances in our current understanding on transmission genetics, molecular genetics cytogenetics, proteomics, population genetics,  etc. and more importantly on epigenetics, we now think differently.

Epigenetics:

Epigenetics is a mechanism where genes can be turned on and off due to environmental influences without changing the genetic codes of the genes.

We have over 20,000 genes in our body and how each of these genes are  expressed, depends on how tightly it is wound with environmental chemicals and other trigger factors  with which the DNA is packed.

It is our personal DNA coupled with our environment that determines how our DNA is packed.

This environment includes diet, air quality, stress, friends, attitude, purpose in life, and spiritual beliefs. The environment triggers receptors, switches, hormones, and electrical signals, and it is these triggers that affect how our DNA is going to express.

In short, it is not only our DNA that regulate gene expression, but so does our physical and spiritual environment.

Gene expression means secretory proteins, hormones, neurotransmitters, neurochemicals that determines our moods, fear, anxiety, and depression, and all body chemicals that controls physiological functions and their subsequent chemical and physical pathology. 

Just to illustrate, if the environment is pleasant, it reduces stress with less stress hormones like adrenalin are being secreted, but if the epigenetic influence (environment) is adverse, hostile, challenging, threatening or stressful, these may influence the genes to express differently, such as secretion of neurochemicals like serotonin that affects mood, depression, fear, anxiety…etc.

It has been shown in mice and rats studies for instance, that not just physical, but even music has a spiritual effect on epigenetics and how rats behave” (unquote my reply to them).

My Further Views:

Continuing with what I replied to the psychiatrist and other doctors, let me explain further as additional notes here:

It must not be misunderstood that external environment can change our genes. The genetic materials or its codes are unaltered by the environment.

But it is their gene expression that may change, which in turn changes the character of the individual or the onset and outcome of a disease.

In other words, epigenetics is just a modification of gene expression rather than alteration of the genetic code itself.

It is what the genes produce, such as the type and nature of the proteins, the enzymes, hormones, signaling molecules that finally determines traits and characteristics  such as the texture of the skin or features, or the shapes and sizes of beaks, say in birds according to challenges in the environment or seasons such as during dry or wet seasons where only certain types of seeds are found for the size and shapes of beaks of birds to break open the seeds as what Charles Darwin observed among in the beak sizes and shapes among the finches in the  Galapagos Islands. 

It is the environment that causes the genes to express, and not the genetic codes in the genes themselves.

Genes express the appropriate proteins to form the morphological structures, size, shapes and even colours to adapt and change according to  organisms  biological needs and challenges, say against predators to survive.

That is the epigenetic influence on how the genes behave, and the subsequent behavior, characteristics and traits of the individual, what we call as phenotype characters. 

Genotype and Phenotype:

There is a difference between genotype and phenotype.

Simply put, genotype is the collection of genes responsible for the various genetic traits of a given organism. Genotype refers specifically to the genes, not the traits.

Phenotype, on the other hand, means the results or the expression of the organism's genotype such as the colour of the eyes, hair, features, height and body weight or the types of disease one gets. 

Cancers:

Coming to disease like cancer I have in recent years been mulling over the possibility that cancer is actually an epigenetic influence how genes express certain specific growth stimuli or signaling molecules for them and other neighboring cells to do exactly the same, namely to divide and spread in accordance to Charles Darwin’s Theory of Natural Selection when normal cells are continuously being injured, traumatized and stressed beyond their repair  mechanisms other than induced apoptosis or cellular self-destruction which they do when they age or becomes injured.

Thus according to Darwin’s Evolutionary Medicine, the cells need to survive when threatened to extinction when injured, say by free radicals, carcinogens, mutagens, food poisons, food contaminants harmful external chemicals and additives, injurious foods… the list goes on and on in their thousands. 

But we also know of protective foods that block epigenetic influence on oncogenes or cancer genes that express certain types of proteins that can cause the cells and other cells to mutate which is somewhat a kind of cellular mutiny against cellular insults

We are not exactly clear what these environmental and food trigger factors are, except a number of them that have already been identified, and the mechanisms at molecular levels on which they act that activates the expression. We shall give some examples shortly.

Counteraction by Inhibitors:

Once we can identify the precise mechanism of their influences, we may perhaps be able to produce a counter inhibitors to block off their signaling pathways, for instance their angiogenesis proteins that grow new blood vessels to feed the cancer cells.

For instance Axitinib is used as an angiogenesis Inhibitors for the treatment for kidney cancer.

So is Avastin an angiogenesis inhibitor option for colorectal, kidney, and lung cancers, Cabozantinib (Cometriq) as the treatment option for medullary thyroid cancer and kidney cancer, Everolimus (Afinitor, Zortress) for kidney cancer, advanced breast cancer, pancreatic neuroendocrine tumors (PNETs), and subependymal giant cell astrocytoma, which is a rare type of noncancerous brain tumor.

It is just a matter of understanding Charles Darwin’s principles how genes express, mutate and began to “speciate” into new cells and hence new life forms and the spread of its biodiversity.

This spread of cancer trying to survive when the environment becomes hostile such as damaging foods we consume or chemicals we inhale or apply on our body that threatens their survival and existence is no different from how life adapts to changing environmental hostility to speciate into new forms by Natural Selection so that they can survive and spread  

Environmental and Epigenetic Factors:

There are a lot of chemicals that can have an adverse influence on how genes are going to behave and act towards disease, especially the onset of cancers.

The first example of cancer due to chemical exposure was described in 1775 by Percival Pott who found that chimney sweepers had a high incidence of cancer of the scrotum which he attributed to exposure to soot.

Subsequently, many hundreds of other chemical carcinogens have been identified in the causation of cancers, such as beta naphthylamine in bladder cancer, bezo(a)pyrene from cigarette in lung cancer, asbestos fibres as the cause of  malignant mesothelioma of the pleural cavity, aflatoxin B1 from mouldy groundnut  in  hepatocellular adenocarcinoma. 

Even anti-cancer drug like cyclophosphamide was found to cause lymphomas and leukaemia.

Most carcinogens are electron-seeking (electrophilic) by chemically damaging  the DNA of the exposed cells causing them  to mutate. 

Some chemical agents are not themselves cancer-causing, but are converted into carcinogenic derivatives by metabolic enzymes into indirect carcinogens.

An example is aflatoxin B 1 found in mouldy peanuts and other cereal grains that requires conversion into aflatoxin 2,3 epoxide by the action of the cytochrome P 450 enzymes in the liver.

This compound then reacts with guanine residues in DNA and changes its characters. This is just one example of chemical epigenetic influence on gene expression. 

The activity of chemical carcinogenesis can be seen experimentally by checking the effects chemical carcinogens on experimental animals such as in mice.

Initiation and Promotion:

It was shown that a single chemical agent by itself may not be sufficient to cause cancer. It requires two factors, namely initiation and promotion.

Initiation is the getting hold of an agent that causes a mutation by a cell following an initial exposure. 

Initiation is rapid and irreversible but alone is not sufficient for cancer formation.

It requires another agent. If the initiated cell is then exposed to a secondary proxy known as a promotor only then can a  tumour  be formed.   

Likewise, a promotor without prior initiation will not lead to cancer formation. Cancer progression thus requires these two factors. 

Interestingly, it has also been shown in mice experiments that even several months later after the initiation, it will also result in cancer if a promotor was applied, suggesting that initiation has a memory.

This also means initiation is irreversible and cannot be erased from memory by the cell. 

Perhaps we may label it as part of an epigenetics factors in memory. 

There are many promotors such as phorbol esters, but unlike initiators they are not mutagenic, but are potent mitogens.  The primary role of promotors is to induce clonal proliferation of initiated cells which will finally result in tumour formation.

Unfortunately, some chemicals possess the role of two, the ability to initiate, as well as to promote as shown by their ability to induce tumour without other agents involved.

These are known as complete carcinogens to distinguish them from incomplete carcinogens which are only capable of initiating. 

Other Factors:

Of course there are other factors too in cancer genesis such as radiation, onogenic viruses, and other familial genetic factors.

There are also many other factors unrelated to genes or the environment that directly or indirectly cause cancers and other types of diseases. These factors include nutrition, stress, exercise, occupation, age, family history, social and economic status, ethnicity among others. Genes and the environment are just two among many.

Additionally, there are also many types of genetic diseases such as familial diseases not related to the environment.

To describe all of them even briefly requires several chapters and can run into several hundreds of pages. This is not the aim or the scope of this brief article.  

This very brief article giving only a few examples how genes can express differently when influenced by environmental challenges as one of the causes of mental disorders was written during a discussion.

It was actually a discussion among a senior consultant psychiatrist and a few senior doctors whether or not genes play a part in causing depression and other mental disorders. A copy of their discussion was sent to me, and I merely add my views.

Genes, environment, nutrition, physical activities, and lifestyles, social and other economic activities among many all play a role in the status of physical mental, social, and spiritual health, and not just  genes or the environment alone.

To describe and explain all of them require huge and lengthy chapters, and is outside the scope of this short blog.

Perhaps an example using virus and oncogene briefly described here should suffice.

Oncogenic viruses:

A large number of viruses including DNA and RNA viruses have been shown to be cancer- causing in a wide diversity of animals, including the development of human cancers.

But there are also genetic and hereditary predisposition factors involved as well besides viruses.

One good example is retinoblastoma, the tumour of the retina which is inherited in some families as an autosomal dominant disorder.

Affected individuals inherit a mutation in one allele of the retinoblastoma gene, a known tumour suppressor gene, so that only a single somatic mutation in the second allele is required for the growth of the tumour.

A defect in a tumour suppressor gene (NF-1) has also been demonstrated to be responsible for the increased risk of the tumour in Type 1 neurofibromatosis.

This autosomal dominant condition is portrayed by the growth of multiple benign tumours derived from Schwann’s cells (neurofibromas).  Unfortunately, some of these neurofibromas may become malignant in later life, possibly due to epigenetic influence.

Then there are of course host response to cancers where immunological surveillance of a person is capable of preventing potential cancers from rising such as seen in immunosuppressed individuals where cancers are more common.

Nevertheless, it has also been observed that only certain types of cancers such as lymphomas and leukaemias are more common in immunosuppressed individuals, whereas breast and lung cancers are not affected during immune suppressions. 

Genes in Mental Disorders:

Coming back to the original dialogue among psychiatrists and doctors emailed to me whether or not genes play a part in mental disorders, here’s what I can say to them. 

It has long been accepted that schizophrenia, for instance, is more prevalent in some families.

However, this does not necessarily suggest a genetic involvement  to this disorder  since social, cultural, and environmental factors are all collective norms shared within families systems.

Evidence for the hypothesis that genes contribute towards the aetiology of schizophrenia came from studies on adaptation of twins when it was shown that there was a  over a 50  percent  chance of schizophrenia being common between monozygotic twin.

It is likely that several genes are involved, but again this genetic disposition may be partially, but not necessarily fully responsible for most of the cases of schizophrenia since as mentioned earlier, other family cultural, social, belief systems, and  nurturing and upbringing influences may also play a part. 

These factors may also have a great epigenetic and environmental influence on how these genes are going to express specific neurochemicals in the brain that are the initiating factors in schizophrenia.  

My "Engineer's Lens" Published in IEM Bulletin JURUTERA in July 2020

Zhangjiajie Grand Canyon Glass Footbridge

by Ir Lau Tai Onn

The Grand Canyon Glass Footbridge at Zhangjiajie National Park, Hunan Province, China is said to be the world’s tallest (260m or 85 storeys high) and longest (430 m) pedestrian suspension bridge.  Needless to say, it is a hotspot destination tha attracts millions of visitors each year.

The bridge has a metal frame with more than 120 glass panels made of 3-layered, 50mm thick tempered glass. The deck is 15m wide at both ends of the bridge, tapering to 60m in the centre. The two main support cables curve inwards and the stringers soar outwards in a V-shaped pattern, opening the bridge up to the sky like a giant butterfly. The support pillars for the suspension cables are spaced at 45m apart on either side of the canyon and are encased in rock, making them look like natural stone spires.

The glass footbridge, completed in June, 2016, was designed by internationally renowned architect Professor Haim Dotan.  The structural engineering firm was China Railway Major Bridge Reconnaissance & Design Institute Co. Ltd (BRDI).

I visited the glass bridge in September, 2019 and found the spectacular view of the gorge through the glass panels below my toes an exciting experience.

Dr. JB Lim’s Brief Introduction of Himself to IEM

Dr. Lim Ju Boo

Date: May 30, 2020

Dear Elite Members of the Professional IEM,

It is a great honour for me to be requested by Ir. Lau Tai Onn to write an 800 word message to the esteemed members of your Institution of Engineers Malaysia (IEM).

It is such an honour and privilege I least deserve. Thank you for having me to pen just a few words of introduction to members of your elite profession.

Perhaps before I pen further, I need to introduce my small self at least once.  I was asked this by the Honorable Ir. Lau Tai Onn to give my CV and a photo. It sounded like making a spectacle out of me to give my photo and profile.

On second thought it may only be fair to the rest of the respected members of the IEM before I can write a short 800-word message or a story of small myself which unfortunately is a “round peg in a square hole” or a “square peg in a round hole”.

Either way I am a misfit among the elite members of your privileged profession of engineers.

Briefly, I was born in Batu Pahat, attended High School there, and in Johor English College, did my A-Level at Singapore Polytechnic before attending various universities and landed up in the opposite profession as a doctor.

But more importantly to me was, I was later trained to be a medical researcher to allow me to work as one at the Massachusetts Institute of Technology (MIT) in United States and at the Institute for Medical Research (IMR) in Kuala Lumpur.

It took me a very long time – over 15 years across 5 universities, namely  in Calcutta, London, Reading, Cambridge and Oxford starting from my Bachelor’s degree in Chemistry, Physiology, Zoology to my Post Graduate Diploma in Nutrition, then my Master’s in Food Quality Control, my MD and my PhD in Medicine, and recently (2019) my post-doctoral in Evolutionary Biology at the University of Cambridge and later in Forensic Science (Toxicology) also from Cambridge once again, and lastly in Astronomy from the University of Oxford  (Dec. 2019). 

After my PhD in London, I was admitted as a Fellow of the Royal Society of Medicine also in London, and was also admitted as a Fellow of the Royal Society of Public Health, London. That was in the late 1990’s till 2000 - a long time ago.  That is all briefly my CV.

Actually my love is in the physical sciences such as astronomy, mathematics, physics, especially in nuclear or particle physics, nuclear engineering and it has never been in any of the biological or biomedical sciences.

Alternatively I also wanted to be a pilot, an astronomer or an astronaut but an ill wind kept diverting me to land in the wrong medical runway. 

Allow me now to briefly tell you a childhood story.

I was born and brought up together with my 8 siblings in my parent’s cold storage shop house in Batu Pahat in the 1940’s to 1950’s.

In those days there was no television except the radio and we used to listen to Radio Malaya playing the same Chinese and English songs over and over again.

For lack of entertainment, our school mates used to come to our shop house to visit us almost daily, and the only entertainment we can offer them was some biscuits, kuaci, peanuts, F & N drinks, then  turn on the fan,  and  tune on the radio for some songs.

One day one of my sisters’ classmates as usual came along to visit her.

So the only entertainment for her was to turn on the radio. But it was not working. So my sister called me to see if I could fix the radio. I was very proud to be called in as an “expert”.

So I did. What I did was, I looked at the back of the radio and shook some loose wires behind.  There you are it started “singing” those old tunes again.

Both my sister and her friend were very amazed at my “performance”. 

You know what? My sister’s friend was so impressed that she remarked that I shall one day become an engineer. I can never forget those remarkable words. 

My head swelled instantly with pride like a balloon for at least 3 days thinking one day I shall become an engineer.

In those days for anyone to become an engineer, a doctor or a scientist was very much respected. So I couldn’t help thinking how I could one day become an engineer by merely shaking some loose wires behind our radio set?

It was too much of a dream for me to be an engineer one day, because all I wanted then was to be able just to pass my Senior Cambridge to become either a teacher or a clerk to earn some money. 

How was it possible to become an engineer one day by shaking some loose wires, I asked myself?

My head swelled and swelled with such pride for days.

(Added by Dr. Lim later in a WhatsApp message to the blogger: “Not only my head swelled up with pride instantly but I went somersaulting around the house for many days, and stood on my head for half an hour everyday for two weeks or more that I would be an engineer one day when I only wanted to be a clerk or a school teacher if I can pass my Form 5 Senior Cambridge.

My parents wanted to send me to see a doctor about my abnormal behaviour.”)

I am afraid I cannot continue anymore.  I need to stop here as it is approaching 800 words as my limit. 

I truly like to tell, tell and tell many stories, and about my admiration for all the stupendous feats of engineering which to me are some of the Wonders of the World. 

But I need to abruptly stop here.

Thank you for having me.

Lim Ju Boo

(901 words)

The blogger’s note:

Ir. Dr. Wang Hong Kok

On May 22, 2020, Ir. Dr. Wang Hong Kok, the IEM Chairman of Standing Committee on Information & Publications cum Chief Editor of the Bulletin Editorial Board, after reading my blog-posting of Dr. JB Lim’s write-up regarding Covid-19 (see: https://taionn.blogspot.com/2020/05/dr-jb-lims-challenging-questions-on.html) that I shared with him, approached me to invite Dr. Lim to contribute an article of 800 words relating to Covid-19 for the August 2020 issue of IEM monthly “JURUTERA” bulletin.

Ir. Dr. Wang initially proposed two titles as follows:

1.  Coping with covid-19 pandemic: A Malaysian doctor’s perspective

2.  The origin of Covid-19 virus - The myth

He later told me that, “The audience is not engineers only, it can include any working person or the boss of a company.  Maybe the victims should consider short-term challenges and long-term challenges to tie over this monstrous pandemic”.  He subsequently suggested, “Leave it to Dr. Lim.  Under 800 words. Include a photo and a brief biodata.”

I have duly transmitted all the above messages word-for-word to Dr. Lim for his attention and reference in contributing an essay to IEM.