102 || AWSAR Awarded Popular Science Stories - 2019

Guardian of the Malady

Mr. Anirban Sarkar*

Email: as.anirban.sarkar@gmail.com

H
ow many cells we have in our body?
Are they more than the number of stars?
asked Arko, my 12-year-old cousin
brother, gazing through the starry sky.
My birthplace, Ajhapur, is a small village,
about 70 km from Kolkata. After almost a year,
I went to my village this weekend. Autumn has
arrived. Our place has a very common problem
of a frequent power cut. Today is Sunday. Like
other evenings, after load shedding, Arko and
I went to the roof. The moonlight had covered
the entire view. We sat on a mat; branches of
an old neem tree made shadow over us.
“Our body is made up of trillions of cells.
One trillion means 14 zeros after 1, and the
stars are approximately 1 billion trillion in the
universe, which means 21 zeros after 1,” I
added.
“Cells are a lot more than I can ever
imagine! How can they stay and work together
then? Even we cannot take unanimous
decisions when playing cricket!” asked Arko.
“That is one of the mysteries of nature.
All of our cells work in harmony. Their division,
growth, functions, etc., are highly synchronized.
Any deviation from this homeostasis leads to
some kind of disease,” I said.
“What kind of disease is cancer then?” he
asked.
“Well, that’s a long story for you to
understand. Cells of our body are pre-
programmed when to grow, when to divide,
even when to die. When a cell becomes rogue,
it divides rapidly. They escape death signals
and thus become immortal. These growing
cells form a tumor in our bodies. They force
blood vessel–forming cells called endothelial

* Mr. Anirban Sarkar, Ph.D. Scholar from Chittaranjan National Cancer Institute, Kolkata, is pursuing his research on
“Immunometabolism in Cancer and its Modulation by Neem Leaf Glycoprotein (NLGP)”. His popular science story
entitled “Guardian of the Malady” has been selected for AWSAR Award.
 Mr. Anirban Sarkar || 103

cells to form blood vessels around them to types of therapy is also used.”
fulfill a high nutrient requirement. Moreover, “What is your research interest among
they become metastatic.” these?” Arko stopped me and asked curiously.
“What is that?” he wondered. “I am working on cancer immunology and
“Metastasis is the most dreadful property immunotherapy,” I said.
of cancer cells. Sometimes the cancer cells “Immunotherapy is comparatively new.
loosen themselves from their original site, Our body has its own defense system, called
sneak into blood vessels by passing through the immune system. The immune system has
the gap between endothelial cells, circulate an arsenal of soldiers that can kill a wide array
throughout the body, again exit the blood of deadly pathogens that are trying to infect
vessel, and make a secondary tumor in another us daily. Cytotoxic T cells, dendritic cells,
distant organ. Cancer cells from the skin, for macrophages, neutrophils, etc., can detect
example, celled melanoma, can migrate to cancer cells and kill them.”
lung, liver, lymph nodes, and brain, even to “Like the Avengers!” he said astonishingly.
bones.” “Yes, like the Avengers,” I said. He is a
“Why do people die of cancer? Isn’t big fan of Marvel Comics and very recently he
there any medicine to treat this?” He looked has seen Avengers Endgame.
crestfallen. I continued, “In this therapeutic approach,
“Of course, there are a number of different kinds of immune components such
therapies to treat cancer. First is surgery, in as specific antibodies against tumors such
which doctors surgically remove the affected as – anti-PD-1, anti-PDL-1, and anti-CTLA-4
part if possible. But some antibody, or engineered
residual cells may still be there, immune cells such as CAR-T
which can develop a tumor cells, etc., are used. Even in the
in the near future. Second is previous year, two scientists
Metastasis is the most dreadful
chemotherapy in which some James P. Allison and Tasuku
property of cancer cells.
chemical compounds are Honjo won the Nobel Prize in
Sometimes the cancer cells
injected into patients, and Physiology and Medicine for
loosen themselves from their
they can directly kill rapidly their discovery of CTLA-4 and
original site, sneak into blood
growing cancer cells. But very PD-1, respectively. They are
vessels by passing through the
often, these drugs cannot the checkpoint inhibitors.”
gap between endothelial cells,
discriminate between rapidly “What is a checkpoint
circulate throughout the body,
dividing healthy normal cells inhibitor?” he asked.
again exit the blood vessel, and
and malignant cells. Thus, “Checkpoint inhibitors
make a secondary tumor in
our normal cells get affected, ensure that our immune system
another distant organ.
too. You may often find that does not attack our own cells.
cancer patients undergoing Cytotoxic T cells have the
chemotherapy have developed checkpoint inhibitors on their
baldness. The third is surface, and if they attack a
radiotherapy in which the particular affected healthy cell, our body can suppress them
site is exposed to a special kind of ray is given through these checkpoint inhibitors, like an off
to the particular affected site. This can also switch.”
affect the nearby normal cells. Fourth approach
is immunotherapy. Even a combination of two “So, our immune system has its own
104 || AWSAR Awarded Popular Science Stories - 2019

regulation?” we isolated immune cells from their spleen.

“Exactly, some regulatory cells are there Spleen is an organ, even present in us. It has
in our immune system. Cancer cells hijack a large reservoir of immune cells. Then, we
these cells and make them work for them. injected those isolated immune cells into a
These are regulatory T cells (Tregs), myeloid- group of tumor-bearing mice. This procedure
derived suppressor cells, tumor-associated was called adoptive cell transfer. Surprisingly,
macrophages, and even some non-immune it worked! Mice that received NLGP-educated
cells such as mesenchymal stem cells, etc.” immune cells showed restricted tumor growth
“Hmm, a team of Thanos.” and survived longer than the mice that did
“Something like that,” I patted on his not receive the treatment. Our next goal was
shoulder. to find out which immune cell NLGP worked
“Now, I am going to tell you about the through. We depleted CD8 T cells by using
ancient Ayurveda of India. In ancient India, antibody against them and observed that this
there was an ayurvedic doctor Sushruta. In time NLGP could not work. Therefore, NLGP
his book Sushruta Samhita, he wrote about so worked through CD8 T cells. Now, this CD8 T
many plants of medicinal importance; one of cell cannot work alone; it requires signals from
them was this.”, I told him by pointing out to the dendritic cells or macrophages to become
neem tree. “He mentioned the neem tree as cytotoxic. We found that NLGP activated
sarbaroganibarani, meaning medicine for all dendritic cells and dendritic cells, in turn,
diseases. Recently, a number of natural anti- activated CD8 T cells.”
cancer compounds have been found in plants “It seems from your words that cells can
from different research groups. talk to each other,” Arko asked.
Like curcumin from turmeric, “Of course. They can
vinblastine, and vincristine from communicate with each other
periwinkle, etc.” either through direct contact
we found a protein in this
I drank some water from a or through some signaling
extract held responsible for this
bottle and continued, “We found molecules. These signaling
in our preliminary research that anti-tumor effect. We named it molecules bind to their
an extract from mature neem neem leaf glycoprotein, NLGP, respective receptors present
leaves could restrict tumor in short. But, outside the host either on the surface or inside
growth in mice. But it could not body, in a culture that is called of a cell. After binding, this
kill cancer cells directly.” in vitro setup, it could not kill molecule initiates a signal inside
“Wow!” he wondered, cancer cells. the cell and makes a change.
“This is astonishing.” NLGP could even suppress the
“Yes, later, we found a immune suppressor cells, such
protein in this extract held as Tregs, myeloid-derived
responsible for this anti-tumor suppressor cells, and tumor-
effect. We named it neem leaf glycoprotein, associated macrophages. Very recently, we
NLGP, in short. But, outside the host body, in found that NLGP could rectify the immune-
a culture that is called in vitro setup, it could suppressive activity of mesenchymal stem
not kill cancer cells. We hypothesized that it cells, MSCs in short, within the tumor. Within the
might work through our immune system. To tumor, which is called tumor microenvironment
validate our hypothesis, we injected NLGP (TME), these MSCs suppress the export
into a group of healthy mice and after that of cysteine from dendritic cells. Cysteine

is an amino acid necessary for CD8 T cell
metabolism for proper anti-tumor activity.
Without this amino acid, CD8 T cells cannot
work properly and become non–functional.
NLGP rescues these T cells by inhibiting
MSCs within TME. It may be difficult for you to
understand all of these at your age.”
“Well, I can understand some of them,” he
nodded.
I continued, “Most surprisingly, NLGP
cannot harm normal cells by any means. In
mice without a tumor, it does not hamper normal
physiology. It is a non-toxic immunomodulator.”
“Wow! That’s great!” he wondered. “Is this
medicine available in the market?” he asked.
“At present, no. NLGP has to go through
a number of hurdles before it comes into the
Mr. Anirban Sarkar || 105
market. Our in vitro experiments using human
tumors have shown similar results in mice.
We need to test it first on human patients,
which is called a clinical trial. Only after a
successful clinical trial, we are able to make it
into the market. And most importantly, as it is
a natural product, it will be cheaper than other
conventional medicines.”
Before our conversation continued further,
aunty interrupted, “Do you two have planned
to spend the entire night on the roof gazing
stars? Come down quickly. Let’s have dinner.”
We did not notice when the power came back.
“We will discuss it further after dinner if you
like,” I said.
“Certainly. Let’s go for dinner,” he said. I
nodded.