Buddhini Samarasinghe – Australian Science

The Hallmarks of Cancer: Fighting Back

Buddhini Samarasinghe — Thu, 24 Oct 2013 00:12:09 +0000

Fighting back How can we use our knowledge about growth factors (detailed in the previous articles here and here) to fight back against cancer? This is where the magic words ‘targeted therapies’ come in. Since cancer cells hijack normal growth factor response pathways to become self sufficient, it is logical for us to target these errant pathways specifically. If a growth factor receptor is stuck on ‘always on’, for example as a perpetually active kinase, then finding a specific inhibitor to stop the activity of this kinase would starve the cancer cell of the signal it is dependent on for uncontrolled growth.

Glivec (as sold in Germany) is a specific kinase inhibitor. Inhibition of this kinase quells the sustained signaling required for uncontrolled growth and division of a cancer cell. Image credit: Wikimedia Commons.

Two such drugs, discovered in the 1990s utilize this principle. Gleevec, used as treatment for chronic myelogenous leukemia and Herceptin, for the treatment of breast cancer, both inhibit specific components of growth factor response pathways to starve the cancer of this signal. Earlier in this series I mentioned the Ras protein, which is frequently mutated in cancers; work is currently underway to find small molecules that are capable of inhibiting Ras. An exciting era of targeted cancer therapies lie ahead of us, because we have a deeper understanding of how cancer happens.

Cover of Time Magazine in May 2001. Image credit: Wikimedia Commons. Copyright: Time Magazine.

Cite this article:
Samarasinghe B (2013-10-24 00:12:09). The Hallmarks of Cancer: Fighting Back. Australian Science. Retrieved: Apr 29, 2024, from http://australianscience.com.au/biology/the-hallmarks-of-cancer-fighting-back/

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A Tale of Two STEM Women

Buddhini Samarasinghe — Tue, 15 Oct 2013 00:22:56 +0000

Ada Lovelace Day is a day for celebrating the achievements of women in STEM (Science, Technology, Engineering and Math) fields. Recently, the New York Times published a fantastic article by Eileen Pollack, “Why Are There Still So Few Women in Science”. Women were leaving the profession not because they weren’t gifted but because of the “slow drumbeat of being under-appreciated, feeling uncomfortable and encountering roadblocks along the path to success”. In summary, the problem comes down to a lack of adequate support and encouragement for STEM women, whose confidence therefore slowly erodes over time, like limestone in an acid rain. Instead of beautiful stalactites however, we’re left with the ‘leaky pipeline’; the phenomenon where, although there appears to be gender parity, or even a majority, in the number of women in STEM fields at the undergraduate level, the senior staff ends up being almost predominantly male; the women have ‘leaked’ out of the pipeline.

I want to illustrate why support and encouragement is vital for women in STEM by presenting two stories. They are old; from the late 1800s and early 1900s, but their message remains as relevant today as it did back then.

For many people outside STEM fields, Marie Curie remains the go-to female scientist. Everyone knows about her fantastic work ethic and achievements, the only woman to win two Nobel Prizes, for Chemistry and Physics. A large part of her success comes from an uncompromising desire to excel at the things that she was passionate about, coupled with having people in her life who encouraged her to do so. Notably, both her father and grandfather were educators who encouraged her to pursue mathematics and physics, subjects that she wanted to study. She also married Pierre Curie, who treated her as an equal partner in every sense of the word. They supported and encouraged each other’s work constantly, and together were more successful than either would have been apart.

In contrast, the story of Clara Immerwahr is far more tragic and, to me, illustrates the loss faced by humanity when women in STEM are not encouraged. Clara Immerwahr was a chemist, and also the first woman to earn a Ph.D from the prestigious University of Breslau (now Wrocław). But unlike her (often-cited) contemporary Marie Curie, Immerwahr had the misfortune to marry Fritz Haber, who was definitely not an open-minded man like Pierre Curie was.

Fritz Haber is known for his contradictory contributions to society; on the one hand he is responsible for the Haber process by which ammonia is synthesized; this has applications in fertilizer production and is essential to our agriculture (he won the Nobel prize for this in 1918); on the other hand the scientists at his institute developed the gas Zyklon A, which the Nazis ‘refined’ into the notorious Zyklon B used in their concentration camp gas chambers. Haber was guilty too, of the development of other chlorine-based gases, infamously used in the German attack against the French in Ypres. Haber also developed Haber’s Rule, a horrific method to quantify the relationship between gas concentration, exposure time and death-rate. The mind recoils at the thought of what gathering data for this involved.

Haber’s views on women were no better than his views on gas warfare. According to an historian, Immerwahr “was never out of apron”, and she once confided to a friend about her subservient role; “It has always been my attitude that a life has only been worth living if one has made full use of all one’s abilities and tried to live out every kind of experience human life has to offer. It was under that impulse, among other things, that I decided to get married at that time… The life I got from it was very brief…and the main reasons for that was Fritz’s oppressive way of putting himself first in our home and marriage, so that a less ruthlessly self-assertive personality was simply destroyed”. She ended up translating his manuscripts into English and providing technical support on his nitrogen projects, her own dreams and potential ignored and forgotten; although she drew the line at helping him with his poison gas work.

Immerwahr was repulsed by Haber’s growing obsession with the development of poison gas. She confronted him numerous times but her pleas fell on deaf ears. On May 2nd 1915, she quarreled violently with Haber when she found out that he had come home for just the night and was leaving again in the morning to direct more poison gas attacks on the Eastern front. In the early hours of the morning, Immerwahr walked into the garden with Haber’s army pistol and shot herself in the chest. Haber of course did not let this inconvenience him, and left as planned the next morning without even making any funeral arrangements.

Marie Curie (left) and Clara Immerwahr (right). Two extremely talented women with vastly different stories.

When I first read this story, I was struck by how often we focus on happy stories like Marie Curie’s, and how the story of someone like Clara Immerwahr remains largely forgotten. She had a tremendous amount of potential, as evidenced by her being the first female to receive a Ph.D at the University of Breslau, an endeavor that is certainly not for the faint-hearted even now. One can only wonder at the ‘might-have-beens’ if she had had the same support and encouragement that Marie Curie did, if she had not married Haber, or if Haber had been a different kind of person. These examples highlight that talent alone is not enough; we need to encourage that talent by promoting equality and recognizing our own biases when it comes to women in STEM.

For Ada Lovelace Day, let us recognize that we not only have to celebrate women in STEM, we have an imperative to actively support and encourage them.

Cite this article:
Samarasinghe B (2013-10-15 00:22:56). A Tale of Two STEM Women. Australian Science. Retrieved: Apr 29, 2024, from http://australianscience.com.au/women-in-science-2/a-tale-of-two-stem-women/

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The Hallmarks of Cancer: Becoming Independent

Buddhini Samarasinghe — Mon, 16 Sep 2013 06:50:57 +0000

This article originally appeared on Know The Cosmos. I will be re-posting excerpts here for Australian Science with added commentary over the coming weeks!

“The Hallmarks of Cancer

Cite this article:
Samarasinghe B (2013-09-16 06:50:57). The Hallmarks of Cancer: Becoming Independent. Australian Science. Retrieved: Apr 29, 2024, from http://australianscience.com.au/biology/the-hallmarks-of-cancer-becoming-independent/

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The Hallmarks of Cancer: Growth Factors and Cell Signaling

Buddhini Samarasinghe — Mon, 09 Sep 2013 07:38:42 +0000

This article originally appeared on Know The Cosmos. I will be re-posting excerpts here for Australian Science with added commentary over the coming weeks!

“The Hallmarks of Cancer” are ten anti-cancer defense mechanisms that are hardwired into our cells, that must be breached by a cell on the path towards cancer. The First Hallmark of Cancer is defined as “Self-Sufficiency in Growth Signals”. What does this mean? In this post I will give an overview of growth factors and how they arhow growth signals are intimately involved in the development of cancer, it is necessary to define and understand what growth factors are, and explain how they control normal cellular behavior.

Growth Factors

Growth Factors are beautiful! This is a 3D schematic representation (also known as a ribbon diagram) of the structure of a growth factor known as Vascular Endothelial Growth Factor (VEGF). VEGF stimulates the development of new blood vessels, a process known as angiogenesis. Many large tumors secrete their own supply of VEGF in order to generate a supply line of oxygen-rich blood for the growing tumor to feed on. Image credit: Gizmag

Growth factors are, simply put, substances that control the multiplication of cells. There are many different types of growth factors, but they all have several characteristics in common. They are all proteins, and present at very low concentrations in tissues but with a high biological activity. They are responsible for controlling essential functions within the cell; growth, specialization and survival. Growth factors also do not circulate in the blood stream; instead, they act locally in areas near the cells that produce them. The image on the right shows a growth factor known as Vascular Endothelial Growth Factor (VEGF).

Cell Signaling

Growth Factors fit perfectly into Growth Factor Receptor Binding Sites. Two different types of Fibroblast Growth Factor (FGF1 and FGF2, left) shown bound to its specific receptor (center) and separate (right). Image credit: Alexander Plotnikov.

It is impossible to talk about growth factors and cancer without going over some of the basics of cell signaling. We are multi-cellular animals, and as such, our cells need to communicate with each other, so they can act in a coordinated manner in response to the environment. The basis of this communication comes from a process known as cell signaling.

The behavior of a cell depends on its immediate surrounding environment, known as the microenvironment. The assortment of growth factors in this microenvironment is the most important aspect regulating the behavior of that cell. All growth factors exert their effects by binding to a receptor. Receptors are proteins found on the surface of a cell that receive such chemical signals from the outside of the cell. Each growth factor has it’s own receptor; think of it as a key (the growth factor) fitting into a lock (the receptor). Growth factor receptors tend to be ‘transmembrane molecules’; this means that one end of the receptor ‘sticks out’ through the cell membrane into the microenvironment while the other end projects inside the cell. By spanning across the cell membrane, growth factor receptors are able to communicate signals from outside the cell (e.g. presence of growth factors in the microenvironment) to the inside of the cell. Revisiting the lock and key analogy, think of it as a key that fits into a lock that protrudes through the door-frame, instead of being flush against the door.

The binding of the growth factor to its specific receptor triggers a phosphorylation reaction inside the cell. Phosphorylation, or the addition of a phosphate group to a protein molecule, is an important step in cell signaling. This is because many proteins exist in an ‘on’ or ‘off’ state that can be switched by phosphorylation. Therefore, phosphorylation is a key step in regulating their activity. The enzymes that add phosphate groups to proteins are known as kinases; enzymes that remove phosphates are known as phosphatases. The exterior end of the receptor protein (the bit that sticks out of the cell) carries the growth factor binding site; the other end which projects inside the cell carries a kinase site. Binding of growth factor to the receptor binding site activates the kinase domain on the interior end of the receptor protein. This activated kinase, true to it’s name, then goes on to add phosphate groups to other proteins inside the cell, which then activate more proteins downstream, triggering a signaling cascade that finally ends with the activation of genes that bring about….you guessed it, cellular growth, specialization, or survival! The image below illustrates this process – I couldn’t find a decent one online so I made my own!

Mode of action of a typical Growth Factor. Growth Factor (red) binds to specific Growth Factor Receptor Binding Site (dark blue) on cell surface, which activates the kinase region (light blue). Activated kinase region now adds a phosphate group (yellow) to Protein 1 (blue) which activates it. Activated Protein 1 now adds a phosphate group to Protein 2 (green) further down the pathway, which activates it. Activated Protein 2 subsequently adds a phosphate group to Protein 3 (orange) which activates it. Activated Protein 3 moves through the nuclear membrane into the cell nucleus where it physically binds to the DNA and activates genes that control cell growth, specialization and survival. Image credit: Buddhini Samarasinghe

The description above is an extremely simplified version of what happens inside a cell; in reality, it is not so much a linear signaling pathway as it is an interwoven, intricate signaling web, with promiscuous proteins from many different pathways activating and repressing one another. The image below is not meant to frighten you (!) but rather to give you an idea how truly complex just one such signaling pathway, known as the MAPK/Erk pathway is.

A truly complex web of cell communication! These are some of the proteins we know that are involved in a single pathway known as the MAPK/Erk pathway. Signals from the outside of the cell go through this web of signaling, ultimately ending up with the activation of genes involved in growth, specialization and survival of the cell. Image credit: Cell Signaling Technology.

So there you have it. We’ve covered the basics of cell signaling and the molecular mechanisms that cause a cell to grow. Next time…I will explain what goes wrong with these processes in a cancer cell.

Cite this article:
Samarasinghe B (2013-09-09 07:38:42). The Hallmarks of Cancer: Growth Factors and Cell Signaling. Australian Science. Retrieved: Apr 29, 2024, from http://australianscience.com.au/biology/the-hallmarks-of-cancer-growth-factors-and-cell-signaling/

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The Ten Hallmarks of Cancer

Buddhini Samarasinghe — Tue, 03 Sep 2013 00:14:44 +0000

This series of articles originally appeared on Know The Cosmos. I will be reposting the articles here for AusSci with added commentary over the coming weeks!

In 2002, Robert Weinberg and Douglas Hanahan published a review article in the journal Cell titled “The Hallmarks of Cancer

Cite this article:
Samarasinghe B (2013-09-03 00:14:44). The Ten Hallmarks of Cancer. Australian Science. Retrieved: Apr 29, 2024, from http://australianscience.com.au/biology/the-ten-hallmarks-of-cancer/
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The post The Ten Hallmarks of Cancer appeared first on Australian Science.

Tear Down These Walls

Buddhini Samarasinghe — Tue, 27 Aug 2013 00:06:35 +0000

This article originally appeared on the Nature Soapbox Science blog. I am excited to be joining the Australian Science team, and wanted to re-post this article here as it encompasses my approach to science communication, and will set the tone for future posts from me.

On a cold weeknight in late November, 1660, a dozen men gathered in the rooms at Gresham College in London to found the Royal Society. Not all of them had a scientific background; some of them were lawyers, politicians, merchants and philosophers. The one thing they all had in common was a thirst for knowledge. The formation of the Royal Society was the coming together of a group of curious gentlemen determined to promote the accumulation and dissemination of useful knowledge. It represented a paradigm shift in the practice of science. The Royal Society invented scientific publishing and peer review, two major developments that redefined science from an amateur hobby to the rigorous beast that it is today.

Two remarkable characteristics distinguished the Royal Society from the other nascent scientific societies of its time. It was genuinely international, and being of noble birth was not a requirement for membership. It aspired to the ideal of meritocracy. External factors such as nationality, race, gender and wealth did not matter. This basic premise of science, that it is and must be open to everybody, began with its founding and should continue today. While the ability to practise science now requires a formal education in scientific theory and practice, access to science should not depend on nationality, wealth, geographical location or scientific training.

Two things stand in the way of public access to science. The first is obviously the paywall: the second is something that I describe as the ‘jargon-wall’. The language of science is precise and meticulous; it has to be. Somewhere along the way, it has also become esoteric, foreign and inaccessible to the public by existing only within the confines of the ivory tower of academia. This has contributed to the chasm of scientific ignorance we see today, and it has created a deep divide that could impede human progress.

Science shouldn’t be kept behind walls. Image credit: Scott Lewis.

So how do we bridge that divide? Open access publications can address the paywall, by allowing anyone with an Internet connection, anywhere in the world, to access scientific discoveries. Open access is not just about giving scientists free access to the science; it is also about giving the public access to the science. However, the jargon-wall is still present, and it prevents ordinary people from understanding the research. Ask yourself, how many non-scientists would understand the average paper published in a peer-reviewed open access journal?

Open access is meaningless without a scientist to interpret the findings. Social media can be a powerful tool for science outreach because it allows a general member of the public to contact and query scientists directly. And when scientists respond, the ivory tower is torn down. This engagement is key to breaking through the jargon-wall. The open access debate is a separate issue, but I want to make the point that open access by itself is not enough to make science accessible to the public.

As scientists, when we engage with the public, the benefits reach far and wide. The primary benefit is of course that the public gets to share and be a part of the adventure that is science. The secondary but equally important benefit is the windfall profits of educating the public. The anti-science movement, including (but sadly not limited to) anti-vaccinationists, climate change deniers, evolution deniers and pseudoscience believers, feeds on ignorance. By providing access to the science, by breaking through both the paywall and the jargon-wall, we reduce that pool of ignorance that the anti-science movement relies on. By getting the public involved in the scientific adventure, we defang the anti-science movement. As a tertiary benefit, it gives us, the scientists, a much needed dose of perspective. All too often we despair over a rejected manuscript, an unsuccessful grant application, or a botched Western blot. I know I do. We forget what we love about science. By engaging with the public, they can be introduced to the wonder, while we, the scientists, are reminded of it.

As an example, I recently came across a fascinating piece of research, published in PLOS Biology, about how a dying nematode worm displays a burst of intense blue fluorescence, generated within the intestinal cells as part of the necrotic cell death pathway. The paper was titled “Anthranilate Fluorescence Marks a Calcium-Propagated Necrotic Wave That Promotes Organismal Death in C. elegans

Cite this article:
Samarasinghe B (2013-08-27 00:06:35). Tear Down These Walls. Australian Science. Retrieved: Apr 29, 2024, from http://australianscience.com.au/open-access-2/tear-down-these-walls/
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