Connor Plumb April 22nd, 2020

Crohn’s disease: how the scientific understanding of this Irritable

Bowel Disease has changed over the years

Disease pathology, traditional methods, and historical accounts: An introduction to

Crohn’s disease.

Crohn’s disease is a condition that has had scientists perplexed for a long time. As
technology and education increases so has the knowledge of this disease.
Crohn’s disease is a condition that has been around for a long time, but for a while the
causes were unclear. To this day scientists continue to uncover how this disease is
obtained. According to a book accredited to De Moreno De LeBlanc and entitled
“Crohn's Disease: Classification, Diagnosis and Treatment Options”, Crohn’s disease was
first uncovered in 1932 by Burrill Crohn and his colleagues, Ginzberg, and Oppenheimer.
The disease is caused by a combination of hereditary and environmental factors such as
diet and lifestyle choices. Crohn’s disease is a certain type of inflammatory bowel disease
(IBD) that has perplexed scientists and doctors as to what causes the disease. As
technology advances, so has the information about what causes Crohn’s Disease (De
Moreno, et. al 2013).  According to the Crohn’s and colitis foundation, Crohn’s disease
expresses uncomfortable intestine inflammation characterized by chronic pain in the
gastrointestinal tract. Ileocolitis is the most common form of Crohn’s Disease and is
characterized by inflammation of the small intestine and the colon. The disease causes
inflammation in the intestinal tract, causing pain and discomfort by increased thickness in
the walls of the bowel. It is not just one disease; there are many underlying conditions
associated with the name Crohn’s disease and all are under the category of what is called
Inflamed bowel disease. The disease can have periods of flares where symptoms are
apparent followed by remission where symptoms are not present (Crohn’s & Colitis
foundation, 2019). According to healthline in an article entitled “Crohn's Disease:
Causes, Symptoms, Diagnosis, And More”, written by Kimberly Holland, she writes how
the symptoms can vary in severity and how there is no known cure for the disease. Some

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patients have anal fissures, or tears in the lining of the intestinal tract, which can be very
painful and cause bleeding. She expresses how certain factors have been pinpointed to
what could cause the disease such as hereditary factors, environmental factors and the
overall health of the immune system. The disease can be hard to diagnose but can be
done by using stool samples and observation of symptoms. There is no known cure for
Crohn’s disease other than temporary symptom alleviation (Holland, 2019).

Genetics of the disease

To this day no one definitely knows the exact cause of Crohn’s disease. Many
articles and studies suggest the disease can be attributed to chromosome 16. In an article
written by J.A Cavanaugh titled “Analysis of Australian Crohn's disease pedigrees refines
the localization for susceptibility to inflammatory bowel disease on chromosome 16”, 
Cavanaugh summarizes the work of scientific research group conducted by a team of
Australian scientists where they study the cause of Crohn’s Disease based on the
pedigrees of 54 families. While it was a small group of individuals, the findings of this
research support the idea that chromosome 16 and Crohn’s disease show a significant
correlation. The research ultimately found that there was a distinct correlation between
the affected individuals and the chromosome 16 IBD1 region, more specifically the
D16S409 region associated near the q11.1 region (See figure 1). The study found that the
LOD (logarithm of the odds) score associated with the D16S409 region was to be
statistically significant and was 6.3. For this system of scoring, any positive number
could hint at a correlation between the condition and the gene in question, so a number of
6.3 is saying there is a high correlation. The study elaborated that the findings of the
mutations associated with individuals with Crohn’s disease was located in the IBD1
region and was backed by multiple sources with many studies being done to prove this.
There is significant evidence to show the location of the gene responsible for Crohn’s
disease is located there. The overall findings showed there was significant evidence to
suggest that the region associated with Crohn’s Disease can be linked back to
chromosome 16 in the IBD1, D16S409 region. (Cavanaugh, 1998).  In 1996, Jean-Pierre
Hugot wrote the summary of research in regards to locating the gene associated with
Crohn’s Disease, entitled “Mapping of a susceptibility locus for crohn's disease on

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chromosome 16”.  The research conducted involved two independent studies, each
studying families with individuals affected with Crohn’s disease. The study found that
the locus associated with Crohn’s disease is located in the IBD1 region and again
highlights the D16S409 region to be statistically significant in terms of number of
individuals affected in relation to the location of mutations. (Hugot, 1996). Crohn’s
disease can be an uncomfortable condition as a result of gene expression from the
affected area on Chromosome 16. According to Genetics Home Reference, the genes that
have some form of mutation in this region that could cause Crohn’s disease would be the
NOD2 (known previously as the CARD15), ATG16L1, IL23R and the IRGM genes. The
NOD2 encodes instructions for creating certain types of proteins that assist in immune
system function. This NOD2 protein can be found in some macrophages and monocytes.
These cells help defend the body against certain invaders such as bacteria and viruses.
The NOD2 protein can also be found in regions of epithelial cells in the intestinal lining,
like paneth cells which are in charge of defending the intestinal lining from bacterial
infections. The NOD2 protein is responsible for detecting bacterial threats and
stimulating an immune system response. The NOD2 protein does this by activating the
nuclear factor-kappa-B protein complex. This complex regulates genes responsible for
regulating immune system responses and inflammatory reactions. The ATG16L1 and the
IRGM genes provide instructions for the synthesis of proteins responsible for autophagy,
which is a process in which cells group together to engulf and destroy pathogens like
bacteria and viruses. The IL23R gene is one that contains instructions for synthesis of the
protein Interleukin 23 receptor. This protein is in the lining of many cell membranes
contained within the immune system, like T cells and monocytes. The Interleukin 23
receptor protein, a type of cytokine, is able to detect pathogens and stimulate the immune
system reaction, causing inflammatory response. Crohn’s disease arises from mutations
to these genes in this certain area of the IBD1 region (www.ghr.gov). According to a
healthline article written by Erica Cirino and entitled “Crohn’s disease: is it in your
genes?”, the mutations in these genes can alter the body's mechanism for responding to
threats like bacteria or viruses. This triggers a response of inflammation within the
intestines and causes problems like diarrhea and other unwanted immune system
responses (Cirino, 2017). The mutations cause a series of symptoms including

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inflammation of the Gastrointestinal Tract as well as symptoms known as anal fissures,

which cause bleeding in the intestines. In severe cases, the small intestine can become
narrowed. All these symptoms are a result of the gene expression, or gene product,
mentioned previously, due to Crohn’s disease. In general, individuals with higher
expression levels show greater gene product, or a relation to the effect of certain genes
being expressed. The gene product can be linked back to what genes are expressed. In
both these studies, the individuals examined were ones that had high expression of these
gene products. While the rate of gene expression or gene product varies between
individuals, the more symptoms a person shows can be related to higher expression levels
of these genes. The gene products of Crohn’s disease are associated with the
inflammation of the intestinal tracts and can be different in each individual. While some
individuals show mild symptoms, others have higher expression of the gene products
associated with Crohn’s disease. Crohn’s disease is a complicated disease, showing a
wide variety of individuals’ expression in regards to the genes associated with it. The
findings of these studies were important in regards to locating the specific genes
associated with Crohn’s Disease. Both studies used many different samples and were
from different regions of the world, finding very similar results. The mutations in
chromosome 16 IBD1 D16S409 regions show significant correlation between that region
and individuals’ expression. The more mutations in the area, the greater gene products an
individual will have, meaning the individual will express a higher amount of symptoms
associated with Crohn’s Disease. According to Kathy King, in a scholarly article titled
“Identification, evolution, and association study of a novel promoter and first exon of the
human”, NOD2 (CARD15) gene, one of the genes most commonly associated with
Crohn’s disease is the NOD2 gene which is also known as the CARD15 gene encode for
the NOD2 protein. The mutation in this gene is well received to have been a potential
cause in the symptoms of Crohn’s disease. The gene is located within the IBD1 region of
the chromosome and the mutation is that of a frameshift mutation. (Kathy King, 2007).
According to Robert J. Brooker, in a textbook he wrote titled Genetics Analysis and
Principles 6th edition, “frameshift mutations involve the addition or deletion of a number
of nucleotides that is not divisible by 3” (Brooker, p. 462). As one could imagine, the
addition or deleting of a number of chromosomes will alter the genetic code for the

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amino acid sequence. This has all kinds of adverse effects on the gene products of these
amino acid sequences. The mutation can cause different kinds of inflammatory responses
to the immune system and which in turn leads to irritable bowel diseases such as Crohn’s
disease. This frameshift mutation is just one example of how mutations in genes can alter
the expression of genetic material. 

Scientist and stakeholders

Many of the views about Crohn’s Disease have changed throughout time. Before
Burrill’s discovery in 1932, little was known about inflamed bowel diseases. According
to an article written by Joseph B. Kirsner titled “Historical origins of current IBD
concepts”, Kirsner writes about the origin of Crohn’s disease and how it was first
discovered. Many autopsies of people with symptoms at the time showed inflamed
bowels. Around 1920, the disease was first thought to be a form of tuberculosis of the
small intestine. Many patients at the time described a group of symptoms like diarrhea
and abdominal pain involving the Ileum. Before the 19th century, doctors viewed the
abdominal pain symptoms as a disease they were not able to treat (Kirsner, 2001). Before
the discovery of Crohn’s disease, there was not much distinction between Crohn’s
disease and other IBD’s. It wasn’t until 1932 that the discovery was made and labeled as
a separate entity. In an article written by Daniel J Mulder titled “A tale of two diseases:
The history of inflammatory bowel disease”, Mulder and others write of the history of the
disease. At the time, doctors saw little distinction between Ulcerative Colitis (UC) and
Crohn’s Disease and both conditions were thought to be some sort of IBD. UC had
similar symptoms of Crohn’s disease like abdominal pain and bleeding and symptoms of
both conditions predate long before modern medicine. It wasn’t until 1932 that Crohn’s
disease was thought of as its own separate entity. The scientist widely credited with the
discovery of Crohn’s Disease was Burrill B. Crohn. Crohn, with the help of Ginzburg and
Oppenheimer, wrote an article that would become the foundation for the understanding of
Crohn’s disease. The disease was first termed ‘regional ileitis,’ which is the inflammation
of the ileum. The article is commonly regarded as the discovery of Crohn’s disease, but it
wasn’t until 1960 when Hugh Evelyn Lockhart wrote about the distinction between UC

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and CD (Mulder, 2014). Today, scientists continue to discover more about Crohn's
Disease in an effort to help those suffering today. 

Techniques. 
Many techniques were used in the novel discovery of Crohn's Disease. In the
article written by J.A Cavanaugh titled “Analysis of Australian Crohn's disease pedigrees
refines the localization for susceptibility to inflammatory bowel disease on chromosome
16”, Cavanaugh talks about the many different strategies used in locating the origin of the
genes associated with Crohn’s disease. The team of researchers used data from 54
different families with known cases of Crohn’s disease in the family and studied their
pedigrees. The research group then took blood samples and studied the individuals’ genes
in the IBD1 region, going off of Hugot’s previous study that showed to be proven the
correct location of the genes associated with Crohn’s disease. The team then
corresponded the affected areas to the families and noted the trends and location and
condition of the genes associated from these areas using blood samples and family
lineage. The team put together the gene map of the associated alleles using the data found
from their experimental studies (See figure 1). Note the area of the loci p11.1 and q11.1
and the respective loci D16S409. The findings resulted in pinpointing the location of the
genes associated with Crohn's disease as being in this area. The research team was able to
determine this by studying the affected families’ genotypes and the effective relation to
the genes in question (Cavanaugh, 1998).  In the study written by Kathy King mentioned
previously and titled “Identification, evolution, and association study of a novel promoter
and first exon of the human NOD2 (CARD15) gene”, King mentions her listed methods
in how the research team obtained their samples using primates and studying their
respective genotypes. The research team was able to gather that the specific primates,
Saguinus oedipus, were susceptible to chronic colitis, a type of IBD. Data showed that
there was lack of expression in the NOD2 gene. This led to discovery that a frameshift
mutation existed among individuals studied resulting in a stop codon and the lack of
expression in the NOD2 gene. (King, 2007). These are just a few examples of many when
it comes to studying the effect of the many genes associated with the IBD1 region that
causes Crohn’s disease. 

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Figure 1. The figure above illustrates the genome map of the chromosome 16 and IBD1
region. Note the area of the loci p11.1 and q11.1 and the respective loci D16S409. The
findings resulted in pinpointing the location of the genes associated with the IBD1 region.

Biological Connections
In conclusion, many techniques were used to reach the understanding the world
has today of Crohn’s disease. These were some amazing discoveries as it pertains to
biology. Not only is it amazing to understand how genes being expressed or not
expressed works in biology. The studies of Crohn’s disease give science a better
understanding of the hardships that people have with certain intestinal issues. It is
amazing to understand how the connections between the world of genetics can apply to
someone’s everyday life. These discoveries enable us to understand the world of genetics
in parts of the body that we normally can’t see. If it weren’t through marvel
breakthroughs like these, the world of biology would not have such a great
understanding. By learning the processes like this, scientists are able to grasp a better
understanding of the human genome. This in turn will hopefully lead to solving the case
of how to help individuals suffering with diseases such as these.

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References

Brooker, R. J. (2018). Genetics Analysis and Principles (6th ed.). New York, New york:
McGraw-Hill Education.

CAVANAUGH, J.A., CALLEN, D.F., WILSON, S.R., STANFORD, P.M., SRAML,

M.E., GORSKA, M., CRAWFORD, J., WHITMORE, S.A., SHLEGEL, C., FOOTE, S.,
KOHONEN‐CORISH, M. and PAVLI, P. (1998), Analysis of Australian Crohn's disease
pedigrees refines the localization for susceptibility to inflammatory bowel disease on
chromosome 16. Annals of Human Genetics, 62: 291-298. 

Cirino, E. (2017, February 7). Is Crohn’s disease genetic? Healthline . [Accessed 22

April 2020].

Crohn disease - Genetics Home Reference - NIH. (n.d.). Retrieved April 22, 2020, from
https://ghr.nlm.nih.gov/condition/crohn-disease#genes

Daniel J. Mulder, Angela J. Noble, Christopher J. Justinich, Jacalyn M. Duffin, A tale of

two diseases: The history of inflammatory bowel disease, Journal of Crohn's and Colitis,
Volume 8, Issue 5, 1 May 2014, Pages 341–348, 

De Moreno De LeBlanc, A., & LeBlanc, J. G. (2013). Crohn’s Disease : Classification,

Diagnosis and Treatment Options. Nova Science Publishers, Inc.

Holland, K., 2019. Crohn's Disease: Causes, Symptoms, Diagnosis, And More. [online]
Healthline. [Accessed 15 April 2020].

Hugot, J., Laurent-Puig, P., Gower-Rousseau, C., Olson, J. M., & al, e. (1996). Mapping
of a susceptibility locus for crohn's disease on chromosome 16. Nature, 379(6568), 821-
3. 

Kirsner, J., 2001. Historical Origins Of Current IBD Concepts. [online]

https://www.ncbi.nlm.nih.gov, [Accessed 16 April 2020].

King, K., Bagnall, R., Fisher, S. A., Sheikh, F., Cuthbert, A., Tan, S., Mundy, N. I.,
Rosenstiel, P., Schreiber, S., Mathew, C. G., & Roberts, R. G. (2007). Identification,
evolution, and association study of a novel promoter and first exon of the human NOD2
(CARD15) gene. Genomics, 90(4), 493–501. 

Overview of Crohn's Disease. (2019). Retrieved April 15, 2020, from

https://www.crohnscolitisfoundation.org/what-is-crohns-disease/overview