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My Wife Steered me to a New York Times Magazine Article that stirred thoughts of Glycolysis

Figure2a.pngThe late 19th / early 20th century was an interesting time to be alive. My wife and I have recently been reading about the lives of several people living at that time including, Elanor Roosevelt, Dietrich Bonhoeffer, and most recently for me, Nils Bohr. Reading about it naturally leads to talking about it and marveling at the way that this was a time of awakening across the world. Not quite the same as the Renaissance, but more with respect to the nations of the world becoming intertwined and the actions on one side of the globe had real repercussions on the other side. Others living at that time included Mark Twain(1835-1910),  Herman Melville(1819-1891), James Joyce(1882-1941), Franz Kafka(1883 – 1924), Pyotr Tchaikovsky(1840-1893), Johannes Brahms(1833-1897), Vincent Van Gogh(1853-1890), and Auguste Rodin(1840-1917).There are many brilliant minds at all points in history, we’ve recently had scientists such as Richard Dawkins and Craig Venter; Computer makers Steve Jobs and Bill Gates; Musicians Paul McCartney, Yo-Yo Ma and Joshua Bell; and filmmaker John Lasseter, to name a few (not to forget the Kardashians and Paris Hilton).

It was a time of great artists and great scientists. Mark Twain(1835-1910),  Herman Melville(1819-1891), James Joyce(1882-1941), Franz Kafka(1883-1924), Pyotr Tchaikovsky(1840-1893), Johannes Brahms(1833-1897), Vincent Van Gogh(1853-1890), and Auguste Rodin(1840-1917) could run into one another. Mark Twain could have taken Vincent Van Gogh for beer and an earful of clever conversation that acknowledged a crazy world, but didn’t fall into despair because of it.There are many brilliant minds at all points in history, we’ve recently had scientists such as Richard Dawkins and Craig Venter; Computer makers Steve Jobs and Bill Gates; Musicians Paul McCartney, Yo-Yo Ma and Joshua Bell; and filmmaker John Lasseter, to name a few -and lest we forget, we have the Kardashians and Paris Hilton to show us that, while the unexamined life may not be worth living, one populated with innumerable selfies is just HOT!

As there have been brilliant minds at all points in history, we too live in exciting times.  We live in times with scientists such as Richard Dawkins and Craig Venter who make it their duty not to just pursue science, but to share it with the rest of us; Computer makers Steve Jobs and Bill Gates revolutionized the amount of work on person or a small team can do; Musicians Paul McCartney, Yo-Yo Ma and Joshua Bell touch us and unite us with their music; and filmmaker John Lasseter brings life to the lifeless and makes cartoons parents can enjoy just as much as their children do. A.J. Abrams brought Star Wars back from the brink and reminded us why we fell in love with the franchise back before it was a franchise. to name a few (not to forget the Kardashians and Paris Hilton).

But, back to the article.

The  article she told me about that brought up the turn of the last century was part of an ongoing series about Cancer from the New York Times Magazine discussing the Warburg Effect, named for Otto Heinrich Warburg (1883 – 1970). Otto_Heinrich_Warburg_(cropped).jpg I knew of the effect, wherein tumor cells engage in aerobic glycolysis, primarily from the perspective of Craig Thompson’s work unravelling the link between Type II Diabetes and Cancer. That connection is based on Tumor cells’ overexpressing the glucose transporter, GLUT-4. The working model states that: given a sufficient supply of sugar and the ability to mop it up quickly via GLUT-4, the limiting factor in cell growth is not energy, but carbon.

It takes a lot of food to support rapidly growing cells (just look at teenagers). Much of that sugar goes to energy (not as readily apparent in teenagers), but a lot also goes to making the building blocks required for cellular proliferation. But to use the carbon in sugar for building rather than energy means that the sugar cannot be completely broken down to CO2 to be exhaled. Instead, cells break the sugar in half by glycolysis to make pyruvate for a net benefit of only 2ATP per glucose (as opposed to 36 possible). Then the intermediary molecules can be diverted to alternative synthesis pathways for those building blocks.

The basic reactions of Glycolysis are these:

glycolysis.png

However, the last enzyme in the pathway, Pyruvate Kinase can take two forms. The first is a tetrameric enzyme (M2-PK), which efficiently processes PEP into Pyruvate, which can either go on to be aerobically metabolized to generate more ATP or diverted to fermentation reactions.

An alternate, dimeric form, emerges when Pyruvate Kinase interacts with oncoproteins. This form (Tumor M2-PK) reduces the production of pyruvate to a trickle allowing for the buildup of metabolic intermediary molecules which may be diverted to alternate synthesis pathways for building materials.

An illustration comparing the pathway with either dimeric or tetrameric forms is shown here:

glycolysis2.png

[The figure above came from Sybille Mazurek and has been modified for emphasis. Thank you Sybille!]

All this is a much more mechanistic description than Warburg was able to offer in 1924. At that time, it was recognized that tumor cells were switching to glycolysis even with sufficient O2 available, but the best explanation was that perhaps the mitochondria, where the aerobic reactions of cell respiration occur, were broken. He also thought that this disruption was actually the cause of cancer rather than a consequence of other factors leading to cancer and the switch to aerobic glycolysis amongst the sequelae of more fundamental problems.

So, despite the details of his hypotheses proving to be incorrect, what he did get right was the recognition of an important shift in metabolism that occurs in tumor cells.

A lot of research has gone into understanding cancer and into understanding diabetes. An unexpected connection between type II diabetes and cancer led to an unexpected synergy between their research efforts. The connection arises as a result of individuals with  type II diabetes overexpressing insulin as a compensatory measure.

Recall the definition of diabetes and the difference between the type I and type II varieties…

Diabetes is an inability to properly regulate the amount of sugar in the blood. When you eat, insulin levels increase to tell cells to take up the elevated blood sugar that comes soon after.

Type I diabetes is a result of the body destroying the pancreatic islet cells that produce insulin early in life so that the insulin signal never happens and unhealthy amounts of sugar accumulate in the blood.

Type II diabetes (formerly called ‘adult onset’ diabetes before children started getting it) is a result of cells becoming unresponsive to insulin. The association with obesity roughly means that cell so often see insulin that they become accustomed to it and don’t respond appropriately. This is very much like an addiction response. To compensate, the pancreas makes more and more insulin until, eventually, cells are so unresponsive that they just don’t do their job any more and unhealthy amounts of sugar accumulate in the blood.

Two pathways; same outcome.

What this has to do with cancer is that cancer cells are, by their nature, unbounded by many of the rules of other cells. The ones that outlive the others come to dominate the population and before you know it, they’re so numerous and

nrc487381.fig2.jpg

What this has to do with cancer is that cancer cells are, by their nature, unbounded by many of the rules of other cells. The ones that outlive the others come to dominate the population and before you know it, they’re so numerous and resistant to death that they become a health hazard. (If you’re thinking this sounds like evolution on a cellular scale, you’re thinking the right thing.)

One thing that gives one cell an advantage over other ‘lawabiding’ cells in the body is being greedy when food comes around. this is another central problem with cancer. In healthy organisms, cells ‘recognize’ their place and are willing to sacrifice themselves for the good of the body. Cancer cells have reneged on that agreement and look out only for #1.

On a cellular level, this means that they put up receptors for energy-rich molecules like sugar and take it whenever available. One example receptor cancer cells often use for this is GLUT-4. The very same receptor that we saw providing sugar for energy and carbon for building above. It turns out that Insulin binding to insulin receptors triggers the mobility of GLUT-4 receptors from intracellular vesicles to the cell surface. The environment that makes this all possible for tumor cells to do so well is one in which there is excess insulin – like in the circulation of someone who has type II diabetes and has been producing more and more insulin to try to coax cells to take glucose out of the blood.

The take home message:

  • Type II diabetics have very high levels of circulating insulin.
  • Cancer cells can use insulin signals to upregulate glucose-capturing receptors.
  • Cancer cells begin to favor dimeric form of pyruvate kinase.
  • Cancer cells can also perform aerobic glycolysis, the Warburg effect, to get both energy and biological building blocks from this sugar.
  • The cells that do it best have the most (cellular) progeny.

Therefore:   Obesity –> Type II Diabetes –> Cancer

 

 
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Posted by on May 30, 2016 in Uncategorized

 

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Cancer Immunotherapy Continued: Non-transgenic T Cell Therapy

A number of adoptive T cell therapies are being examined for cancer treatment including isolation and culturing tumor infiltrating lymphocytes (TILs), isolating and expanding a specific T cell or clone, and generating novel T cells with chimeric receptors designed to target tumor cells and provide robust activation signals to the T cell. 1,2

Recently, I wrote a short essay about CAR T Cell therapy and how this therapy uses genetically modified T Cells to generate a large number of your own cells, capable of targeting tumors bearing a known antigen (e.g. CD19 as a Lymphoma marker).

T Cells are one of the immune system’s specific attackers, capable of recognizing cells bearing specific antigen only. They are engaged and activated via interactions with APCs presenting antigen bound to MHC molecules as well as other ‘secondary’ signals.  For a more complete description, see

In the case when the T Cell recognizes the antigen, it proliferates and activates if provided sufficient secondary signals in addition to TCR stimulation. In the absence of recognition, the T Cells will not stably bind the APC and therefor not receive sufficient signaling to activate.

T Cells ‘see’ antigen through presentation in the context of MHC molecules on the surface of Antigen Presenting Cells (APCs)

T Cells ‘see’ antigen through presentation in the context of MHC molecules on the surface of Antigen Presenting Cells (APCs)

Some benefits to that therapy include incorporation of a well-designed chimeric antigen receptor capable of providing normal T Cell Receptor (TCR) signals as well as signals from co-receptors required to generate mature effector cells. Because this construct targets the CD19 molecule directly, it does not require processing and presentation of antigen via MHC I by the tumor cells (important because one strategy tumor cells use to evade immune detection is to down-regulate MHC I). Using the patient’s own cells also means that immunosuppressive drugs aren’t required to prevent the body from rejecting the therapy.

One drawback though, is that the construct is made synthetically and can only include antibody binding regions specific to known cell surface antigens. So, if you know the cells you want to get rid of, and you can make an antibody to bind those cells preferentially, CAR T Cells are a good therapy for you.

Using Non-Transgenic T cells, similar effects can be obtained with an inverse set of pros and cons. Because this therapy does not utilize chimeric receptors, cells specific for a known  antigen aren’t singularly generated. Rather, a diverse array of cells is generated against tumor targets without requiring the isolation and characterization of one particular antigen. As opposed to the CAR T Cells these cells can only interact with target cells that present antigen via their MHC I molecules, which can be a drawback in situations where the tumor cells have downregulated antigen presentation molecules.

The Non-transgenic cells used may be generated in several ways. One method includes the harvest of tumor tissue from the patient, followed by killing these cells and re-injecting them (possibly in the presence of an adjuvant) to illicit a targeted immune response. 7-10 days later, peripheral T Cells enhanced for target specificity by the vaccine can be harvested and amplified outside of the body. In this way, cells can be amplified to numbers far outpacing what might be found in the patient, while also providing additional activation signals to promote effector cell development.

A second way of utilizing non-Transgenic T Cells in therapy is to isolate only those T Cells found to be actively invading the tumor. This biases toward cells already selected for by the immune system that may simply not be able to keep pace with the tumor’s growth. Ex vivo amplification can provide these cells the boost in numbers required to tip the balance in favor of the patient.

Screen Shot 2015-11-15 at 12.08.22 PM

Coupling any of these therapies with other treatments, such as the human monocloncal antibody anti-CTLA-4 (ipilimumab) 4, can further support T Cell efficacy – in this case by blocking checkpoints used to dampen the immune response following a period of activation. In healthy patients, these checkpoints allow the immune system to revert to a state of homeostasis once pathogens have been cleared. In cancer patients, the tumor may not yet be eradicated before checkpoint molecules begin to dampen the response. By interrupting these, the window during which T Cells are most effective is widened — at least in some patients.

This article has been cross-posted on Medium

A Few References:
1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315690/
2. https://depts.washington.edu/tumorvac/research/t-cell-therapy
3. My Medium Post
4. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1951510/

 
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Posted by on November 15, 2015 in Uncategorized

 

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The Skinny on Cancer Immunotherapy: focus on CAR T Cells

Screen Shot 2015-10-22 at 9.47.44 AMOne of the more interesting modern therapies being used to fight cancer aims to coax, or engineer a patient’s own T Cells to fight disease.
In very basic terms, the principle is not dissimilar to vaccine strategies used against infectious disease. That is, they direct and boost the patient’s immune system against target cells. One reason vaccinations have been so successful in fighting disease is that they leave much of the hard work to nature – the same nature that has been keeping you and your ancestors healthy enough to successfully reproduce for millions of years. Give the immune system a push in the right direction with a well designed, safe vaccine and the body does the rest leading to (at least theoretically) life-long protection. At this point, the most limiting factor to how long protection lasts is because we live so much longer than humans have ever lived before.

William-Coley_206x236Immunotherapy against cancer has been an area of interest since the 1890s, when William Coley observed that cancer patients who had infections at the site of surgical resection fared better than those without infections. Rather than dismissing this observation as uninformative, he speculated that the immune system plays an active role in preventing or regressing tumors.

In fact, the immune system is constantly performing ‘immune surveillance’ to prevent newly-generated cancer cells from developing into tumors. Direct evidence for this involves ‘knocking out’ elements of the immune system and watching for cancer. As predicted by the theory, immunodeficient animals develop spontaneous tumors at a higher rate, and earlier than do immune-competent animals.

The pudding: (from : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1857231/)

Evidence for Immuno Surveillance

Evidence for Immuno Surveillance

But vaccinations used against infectious diseases are given before the patient is infected (known as prophylactic vaccination).

How can we immunize people against all the cancers that may crop up in all their various forms?

The answer is – we don’t. In the case of cancer, we perform vaccinations ‘therapeutically’, or after disease has started. Otherwise there really would simply be too many possible targets.
So, we wait, and help the body to fight the challenges that actually do arise.
A number of methods have been developed and tested to accomplish this, here, I want to specifically address a personalized therapy that takes cells from the patient, ‘aggravates’ and expands them, and then re-infuses them into the same patient.
Currently, there are several ways this is being done with various outcomes.

One method involves immunizing the patient against killed cancer cells isolated from the themselves (via surgery), then harvesting the reacting cells and expanding them to numbers much higher than those reached in vivo, and then re-administering to the patient as a jump-start to immunity. The advantages are that these immune cells are ‘self’ and therefore do not have to be ‘matched’ to the recipient a la transplantation surgery. It is also possible to remove any regulatory cells (T regs), that often impair immune responses, prior to re-administration.
A more engineered response has been investigated by investigators such as Carl June, of the Abramson Cancer Center at the University of Pennsylvania. These cells, known as CAR T Cells express ‘Chimeric Antigen Receptors’ directly target tumor cells using transgenic antibodies that incorporate the intracellular signaling domains of up to three immune-activating receptors. See the illustration below for details of this receptor’s design (taken from ‘Breakthroughs in Cancer Immunotherapy webinar by Dr. June )
Screen Shot 2015-10-21 at 7.20.04 PM
In the case of CAR T Cells, most have been made to fight B Cell Chronic Lymphocytic Leukemia (B Cell CLL). These cells are a good test case for the technique for a number of reasons, including the fact that they uniformly* express a marker called CD19 on their surface and also because they are a ‘liquid tumor’ – meaning that the cancer cells are individual cells moving through the body (at least many are). Treatment of solid tumors can bring added complications such as the need to infiltrate the tumor in order to find target cells.
As I said, CD19 is a common protein expressed on these cells. Therefore, at least the CAR receptor part is standardized between patients – this is the piece that is added to cells transgenically so that they will bear a receptor known to engage the target cells with high affinity. Because it must be added to the patient’s own cells, this is accomplished using a viral vector that infects the T Cells in culture and provides the DNA required to make the receptor. (In case you’re worried about the virus, these are engineered to only infect the first cell they encounter, they cannot reproduce themselves and continue an infection)
So, let’s walk through it:

Screen Shot 2015-10-21 at 7.20.04 PM
1. Blood cells are isolated from a patient
2. T Cells are purified (i.e. isolated)
3. T Cells are infected with virus in culture.
4. T Cells grow up with the chimeric antigen receptor expressed on their surface
5. These cells are then re-injected into the patient via I.V. drip over about 30 minutes time.
6. Let the cells do the work

Screen Shot 2015-10-22 at 10.33.53 AM
This therapy has an impressive track record so far with studies with success rates from ~60%- 90% of patients responding and remaining disease free for years (Maude et al).
Following the initial infusion of cells, CAR T Cells proliferate in vivo to very high numbers and can even form immunological memory cells to come to the rescue in the event of a relapse.
So, what next?
A number of startup companies have emerged to tackle the logistics of bringing this type of therapy – an extreme example of personalized medical care – into being. Unlike traditional drug therapies where a single compound is mass produced and distributed world-wide, each patient must have their own cells processed and returned to them for infusion. This therapy is much more of a service, and as such, will require physical locations across the country that can manage the handling of cells.
The up side, however, is potentially transforming fatal diseases into manageable ones with a high quality of life after therapy.
Just ask Emma:
widget_custom_image_1_1391564604

*Well, most do, anyway.

 
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Posted by on October 22, 2015 in Uncategorized

 

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Devilish Tumors

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     You poor devil

RadioLab recently updated and rebroadcast their Tumors episode (RL link). This includes a story about President Grant’s tumor kept in a cigarbox in museum archives and one about the transmissible facial tumor plaguing Tasmanian Devils. The tumor, known as Devil Facial Tumor Disease (DFTD) is a rare case of an infectious cancer. This is the one that I wanted to think about some more.

What do we know about tumors? How do they arise? Why is cancer so much more prevalent today than ever before? What makes these Tasmanian Devil tumors especially nasty?

What do we know about tumors?

Actually, quite a lot. And many new therapies are very successful – especially those that target very specific kinds of tumors. In 1963 Todero and Green   (http://jcb.rupress.org/content/17/2/299.full.pdf+html) established both a cell line and a precise methodology for growing cells in culture that permitted researchers the ability to recognize specific changes in cells grown in culture – changes such as becoming non-responsive to the presence of other cells that should control cell division.

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                                              30 years of p53 research

Over the years a number of tumor suppressor proteins and proto-oncogenes have been identified. These are the proteins responsible for restraining cell cycle in the event of DNA damage. Among these is p53, the most frequently altered protein in cancer. It was originally identified in 1979 and has since been shown to arrest cell cycling in the event of DNA damage, initiate repair protocols and start a ‘countdown’ to self-destruction (apoptosis).

A number of additional mutations have been defined in proteins that either promote cell cycle progression (proto-oncogenes) or arresting cell cycle progression. Each of these proteins may be mutated in a different way, but the outcome is always the same: cells are pushed through their cycle despite the presence of DNA damage.Image

Beyond this, more processes have been found to contribute to tumor success. Some tumors promote angiogenesis (the growth of new blood vessels) to feed the tumor. Some have mutations that allow them to break off of the main tumor mass and survive in the blood or lymph and migrate to new areas. Some tumors perform tricks to escape recognition by the immune system.

In time, successful tumors may do all of these things. And how can they mutate so quickly and skillfully? It all goes back to p53. When a cell doesn’t slow down and correct errors in its DNA – and when it does not self-destruct when these errors are too damaging, the cell is free to mutate again and again. Each mutation is like a new child that either does better or worse in its environment, with only the successful ones living to spread their genes.

How do they arise?

Tumors arise when DNA damage occurs in just such a way that it escapes notice by the cell and starts to multiply. Actually, we think that a lot of tumors start up, but get weeded out by our immune system again and again. The ones we see are those that were successful enough to evade our defences and grow up. (immune surveillance: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1857231/

Why is cancer so much more prevalent today than ever before?

Because we live so much longer. The increase in cancer rates does not come from cancer becoming worse over the years, but comes from the fact that we live long enough to get it

Image

      We’re getting old … Unfortunately, that means we’re getting cancer too

 

 

What makes these Tasmanian Devil tumors especially nasty?

Transmissible tumors are rare because of the conditions required to allow for them are also very rare. In the case of DFTD the stars aligned in just the right way to allow this to occur.

The first requirement is that a tumor must have evolved sufficiently to be able to spread throughout the body of the initial host and be expressed on the face of this animal.

Second, this tumor was amazing in that it could start growing even in new animals if cells should be transferred from one to another. This may have something to do with the uniformity of the devil population and/or the way that these tumors ‘hide’ cellular markers that would otherwise expose them as bad/ foreign cells. The latter of these explanations is supported by data such as: pnas “reversible epicene tic down-regulation of MHC by devil facial tumor…” Siddle et al vol. 110 no. 13

(my question now is: don’t these devils have NK cells that should eliminate these MHCI-deficient cells?)

 

Perhaps most importantly, these tumors affect animals that are naturally aggressive towards other members of their species in both feeding and sex. Because devils bite one another so often, they provide just the right opportunity for cells to jump from one animal to another.

There is a similar case of a canine transmissible tumor (“tumor cells spread canine cancer” in the scientist, August 10, 2006 by Melissa lee Phillips.) but other than that, these types of tumors are not often seen.

Altogether, this is a fascinating case that illustrates some peculiarities of tumors, DNA damage control and immunology.

The devastating effect of this tumor epidemic is that it has precipitated a dramatic decline in devil numbers now making them endangered of extinction.

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Visit the ‘Save the Tasmanian Devil’ website for more information about their condition. (:  http://www.tassiedevil.com.au/tasdevil.nsf)

 

 
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Posted by on October 27, 2013 in Uncategorized

 

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Cell Division, Contact Inhibition and Cancer

imagesIn my general biology class we are now reading chapter 5 of Mader et al, on Cell Division. This chapter is a bridge between those chapters on descriptive cell biology and those describing the activities of the cell and how we explain the inheritance of traits from one generation to another.

We focused our attention on Mitosis and Meiosis of diploid Eukaryotic cells and followed how these two types of nuclear division manage the sorting of genetic material into daughter cells ensuring that each cell gets an appropriate set of instructions for life.

The body is comprised of somatic cells that include everything from skin to muscle and nerve cells. These are called somatic because soma comes from the greek word for body.

The other type of cell is the gametic cell, referring to germ-line, or sex, cells.

Each of these type of cells goes through its own type of division in order to end up with the correct amount of genetic material ( or ‘ploidy’) in the resulting cell or organism. Ploidy refers to the number of complete sets of genetic material a cell has. We, humans, are diploid organisms having two sets of genetic material in each cell.

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Mitosis in Diploid Cells

Somatic cells undergo mitosis in a way that maintains the diploid state of cells creating two exact replicas of the parent cell.

This mechanism makes sense, because one skin cell might replace a neighboring skin cell following its demise in order to maintain a confluent layer. We would expect every skin cell to be genetically identical to every other and mitosis delivers just that.

However, if we imagine sex cells that were made from mitosis, these would also be diploid (2n). Then a diploid sperm would fuse with a diploid egg and make a tetraploid offspring. Then that organism would have octaploid offspring and so on. This, of course, does not happen.

ImageSex cells are instead produced by a different kind of division called meiosis. Meiosis is merely a specialized form of mitosis in which the genetic material (ploidy) is ‘halved’. The resulting cells are then haploid (1n or n). As part of the specialization, meiosis occurs in two steps so instead of producing two cells, it produces four (at least theoretically). Also, instead of being identical, each of the resulting sex cells is unique.

But this discussion is supposed to be about cancer, so let’s ignore meiosis for now. I’ve discussed cancer before here, but I just found a couple of good animations that I wanted to include.

The first is an excellent animation on cell cycle and contact inhibition. See how cancer is defined here as the lack of respect for cell-cell signaling, that would otherwise result in a healthy monolayer of cells.

The second, discusses how cancer cells would need to alter their environment in order to get the nutrients they need to survive. It can be tempting to think that cancer cells don’t need these things, but they certainly do.

http://bcove.me/uc5vydod

Once cells mutate in a way that initiates cancer, the constant struggle with the immune system amounts to a selective pressure allowing only the strongest cells to survive. 😦 A brief article describing this battle can be found on the HHMI website. A more thorough treatment of the subject can be found in a freely available review by my friend Dr. Ezekiel Fuentes-Panana.

Here’s one last animation showing a tumor mass producing metastatic cells that leave the mass and migrate to new locations within the body. I’m not that fond of this video, but it does communicate the message I wanted to get across.

Alltogether, cancer cells are those that no longer obey the rules of polite cellular society and continue to reproduce through unchecked mitosis when such division is not in the best interest of the organism as a whole. One way these cells do this is to cease responding to contact inhibition signals. This results in the production of a tumor mass that will need to obtain energy and will often do so by sending out pro-angiogenic signals resulting in new blood vessel formation. As the tumor continues to grow, it may invade neighboring tissue and ultimately even metastasize into the blood or lymph leading to a number of secondary tumors throughout the body.

 
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Posted by on October 14, 2013 in Uncategorized

 

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Experimental Flaws -Uncontrolled variables

I had an interesting text message from my cousin today. He was asking, ‘What is meant when a  study is deemed to be flawed due to uncontrolled variables? i.e. what does it really Imagemean to have uncontrolled variables?’

It’s an excellent question – and one that is well addressed in a book I recently recommended here called How to Lie With Statistics.

I gave him the following answer:

‘A simple example might be someone looking back through historical data and seeing that the number of cancer cases (of all kinds) has been on the sire over the past twenty years. In terms of absolute numbers, this is true. Some people use this to raise the alarm that we have to get more aggressive in our fight against cancer because it has become a leading killer. Perhaps that’s not a bad idea either, but if someone were to look more closely at the details they would quickly see that these absolute numbers aren’t the right data to make this conclusion by. There are uncontrolled variables.

here’s some real data:

The unaltered or crude cancer death rate per 100,000 US population for the year 1970 is 162.8. Multiply this rate by the US population of that year, 203,302,031 and divide by 100,000, we obtained the total cancer deaths of that year, 330,972. Divide this number by the number of days in a year, we obtain the average number of Americans who died of cancer in 1970 at 907.

Twenty years later, the unaltered cancer death rate for the year 1990 is 505,322, the total population, 248,709,873. The cancer death rate per 100,000 population rose to 203.2. The daily cancer death rate was 1384.

(http://www.gilbertling.org/lp2.htm – original data:The 1970 cancer death rate was taken from p.208 of the Universal Almanac, John W.Wright, Ed., Andrews and McMeel, Kansas City and New York. The estimated 1996 cancer deaths figure was taken fromTable 2 in “Cancer Statistics” by S.L. Parker et al, in CA, Cancer Journal for Clinicians, Vol. 65, pp. 5-27, 1996.The 1970 US population was taken from the World Almanac and Book of Facts, 1993, p. 367; the estimated 1996 population was from the 1997 edition of the World Almanac and Book of Facts, p.382. The 1997 total cancer death figure was obtained from S.H. Landis et al in CA, Cancere Journal for Clinicians, Vol. 48, pp.6-30, 1998, Table 2. The US population for 1997 was obtained from The Official Statistics of the US Census Bureau released on Dec, 24, 1997)
ImageHowever, if this is the limit of the analysis, it’s useless. In 1970 the life expectancy was about 67 years for a white, non-hispanic male, while in 1990 that number was about 74.
Since cancer is a disease of the aged, it is likely that the increase in cancer is directly linked to the increase in population of the elderly.
What this means, it that in order for the study to be meaningful, the authors should look at cancer rates among a more comparable group, perhaps white, non-hispanic non-smoking males living in some certain region  that has not undergone drastic demographic changes or excessive immigration / emigration. By taking these additional steps, we reduce the number of differences in our two populations, allowing us to make a ‘more controlled comparison.’
 
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Posted by on September 20, 2013 in Uncategorized

 

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Obesity, Diabetes and Gastric Bypass Surgery

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             Glucose

Several semesters ago, I was teaching a course called ‘Human Biology’ as an adjunct. As opposed to my normal class in General Biology, this one contained an anatomy and physiology component. My own history in the lab is one of a molecular and cellular biologist. The only system that I know reasonably well from personal experience is the immune system, so I was learning a lot by teaching this class and doing the reading to remind myself of what I learned many years ago.

I particularly enjoy making class a discussion about specific topics that my students are interested in (even if I cannot always answer such varied questions) and one day a student asked why it was that gastric bypass surgery immediately cured diabetes.  

As I said, I’m something of a novice in these areas of systems biology, and given what I knew I could not come up with a reasonable explanation. In fact, I doubted that this could happen and the weekend digging for any publications describing the effect. To my surprise, it was well known. Unfortunately, no one else had a very good explanation for it either. However, as asserted in the associated Perspective article, “gastric bypass surgery pImageatients can stop taking diabetes medications before substantial weight loss has occurred” –  a surprising feature of the intervention also seen by my student (who had this surgery himself). This suggests that the surgery itself must trigger a hormonal change in patients, rather that weight loss simply reversing the condition over time.

Happily, the most recent edition of Science caught my eye with an article titled, ‘Reprogramming of Intestinal Glucose Metabolism and Glycemic Control in Rats After Gastric Bypass,’ by Saeidi et al that examined the effect in a rodent model. As Hans-Rudolf Berthoud explains in his review of the work, 

“glucose preferably enters the pentose phosphate and other glycolytic pathways that provide substrates for nucleotide and protein synthesis, consistent with accelerated tissue growth. Most important, and as an “unintended” by-product of increased glucose uptake by the expanding gut tissue, systemic glucose concentrations are reduced and the diabetic state is reversed.”

As satisfying as this finding may be, it remains a mystery why this effect would persist long term after the new gut has completed its transformation. An alternate, or perhaps complementary explanation for this effect in humans may lie in the extreme calorie restriction patients are required to adopt post-surgery. “When control subjects were given the same low amounts of food eaten by surgical patients, the same rapid improvements in glycemic control were observed,” providing evidence for a non-surgical pathway to the same endpoint. 

——-

One last point…

This article immediately reminded me of work done by Craig Thompson and others on the relationship between obesity, diabetes and cancer, summarized in a review article in a 2009 issue of Science. This article described how it is that obese individuals suffer higher rates of cancer than non-obese persons. Among the links they described was how obesity leads to type 2 diabetes resulting in higher blood sugar concentrations, a condition favorable to oncogenesis.

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                    Explaining the Warburg Effect

The same article went on to add that cancer cells often use glucose in a way that that is surprisingly inefficient in terms of the energy it captures (known as the Warburg Effect). This paradox of rapidly dividing cells apparently underutilizing glucose was resolved once it was observed that cancer cells get not only energy from glucose metabolism, but building materials to keep up with the unusually high demand that rapid grown imposes.

Altogether, these articles do much to clarify how the body utilizes fuel, regulates blood glucose and the what the overall health affects of these regulations.

 
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Posted by on July 27, 2013 in Uncategorized

 

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HPV Vaccine Success in Australia

The April 18, 2013 edition of the British Medical Journal contained the results of Australia’s new campaign to vaccinate young women against the Human Papillomavirus (HPV), associated with genital warts and an increased incidence of cervical cancer. This news was brought to my attention by a Slate article by Phil Plait discussing the politics of vaccination and how they get particularly how when the vaccine in question is against a STD. I suggest you read that article if you have any interest in exploring that hot-button topic and how it goes head-to-head-against an abstinence-only policy.

Although those questions intrigue me, I simply want to point out the data behind HPV and how the new vaccines are dramatically effective. First, I think it’s important to examine just who has HPV.

ImageAccording to the CDC’s report on HPV, approximately 79,000,000+ people in the USA have HPV. That’s a pretty high number given that the Jul 2011 US census reported that the US population is only 311,591,917 – and about 70 million of those people are under 17, the average age the Kinsey Institute reports that kids lose their virginity. Let’s call it half of Americans who have had sex, also have HPV – this estimate agrees with the CDC’s data on HPV.

ImageThere are a number of different HPV viruses and some of them are more dangerous than others. Of the ~40 strains of HPV, two of them (6 and 11) are responsible for most genital warts, but are not associated with cancer, whereas two different strains (16 and 18) are linked to the majority of cervical cancer cases. Gardasil, a quadrivalent vaccine made by Merck, protects against all four of these strains, while Cervarix is a bivalent vaccine made by GlaxoSmithKline and protects against strains 16 and 18.

In 2007, Australia began offering free vaccinations against HPV for girls 12-13 years old. Fortunately, the vaccine being offered was the Merck vaccine, so the efficacy of the vaccine could be readily tracked by using genital warts as an indicator rather than having to wait to measure cervical cancer rates at a much later time point. The caveat is that this trial assumes that the reduction in genital warts accurately models an expected reduction in cervical cancer, despite the two conditions resulting from different strains of the virus. I’m comfortable with this assumption, but I do think that caveat needs to be kept in mind.

So, what are the results? It’s been five years. According to estimates from the US population, these girls should be starting to have sex now. Are they getting genital warts?

“In the vaccination period, the proportion declined dramatically by 92.6%, to 0.85% in 2011”

Image Further, not only are fewer vaccinated girls developing genital warts, but it looks like the vaccination campaign in also benefiting unvaccinated girls as well (although this is an assumption about causality on my part). 

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Remember, not ALL genital warts are caused by the four strains in the vaccine – and, these vaccines will only work on people who have not caught HPV already.

   Altogether, this looks to be a whoppingly successful campaign – one that the US should strongly consider mimicking.

 

 

 

 
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Posted by on May 3, 2013 in Uncategorized

 

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From J. Coyne’s blog

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what kind of protein is p53 an example of / why would Mark be so sad?

 
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Posted by on February 18, 2013 in Uncategorized

 

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Cancer and the immune system (briefly)

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Macrophage engulfing bacteria

 What a breath of fresh air! A good old friend of mine, who I met while in graduate school and is now living in Mexico city has been working on a couple of papers that he is submitting to some English language journals. I’ve only read one of them so far – it’s an interesting review of work that suggests that tumors actively co-opt processes of the immune system to their own advantage. His spoken English is quite good, but it’s another thing altogether to write well for a scientific publication. Lucky for me, I guess, because it gives me a way to be involved.

It is well established that the immune system functions to prevent tumor formation known as immunosurveillance. This is pretty consistent with the basic role of defending the self against any non-self target it encounters. If you’re unfamiliar with immunology and want one thing to learn, that’s it: The immune system is there to recognize a black and white world of self vs non-self. The details are complicated, but it’s fairly well worked out that through a series of positive and negative selection events you can train your immune cells to be tolerant of you (self), but reactive against anything new (non-self).

With respect to cancer, it’s important to recognize that these cells start out as self and are ignored by the immune system, but they change in a way that they are not acting the way they should. The problem for the immune system is that these changes typically just mean that the cells are acting abnormally, but they don’t necessarily look foreign. Despite this, we know that animals that lack a functional immune system will succumb to tumors at higher frequency earlier in life than those with competent immunity.

My friend’s article extends this relationship beyond immunosurvellience and suggests that the tumor cells undergo a selection process by the immune system that will eliminate weaker cells, leaving only cells that either escape the notice of the immune system entirely or are extraordinarily resistant to attacks. Further, he describes that the remaining cells will often co-opt signals of the immune system to advance their own function and survival. 

I look forward to finishing up this paper and hope to be able to point you toward a journal that it is published in sometime in the near future. Until then, it’s so refreshing to think about immunology again. I miss it.

 

 
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Posted by on November 3, 2012 in Uncategorized

 

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