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Monthly Archives: May 2016

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:

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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:

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[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

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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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Why the Electoral College is Relevant Today

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Ms. Ginny Stroud

No one cares one bit about the electoral college until they suddenly pivot to extremely caring about the electoral college. That happens around the time a close election teases out the distinction between popular election and the buffer against the masses we call the electoral college.

 

A common argument against the current system is straightforward: it is in place to prevent the will of the people from overriding the will of the elite. That’s not very democratic now is it? The electoral college  is the inverse of universal suffrage, which is the direction the United States has been heading for most of its existence (slowly). On the one hand, ‘No taxation without representation’ was part of the rationale for the revolution against the English Crown (I know what you’re thinking D.C., sit down and be quiet).

The 15th amendment in 1869 prohibited the denial of the right to vote based on race, color, or previous condition of servitude. The 19th amendment in 1919 prohibited the denial of the right to vote based on sex. In 1971, the 26th amendment reduced the voting age from 21 to 18, in large part to ensure that draft age men could have a voice.

Yet, don’t forget what Ms. Ginny Stroud, the Civics teacher in Dazed and Confused, reminded her students about July 4th as they finished their last days of school before Summer:

Don’t forget what you’re celebrating and that’s the fact that a bunch of slave-owning aristocratic white males didn’t want to pay their taxes.

And if there’s one thing that slave-owning aristocratic white males wanted, it was to keep their position of being slave-owning aristocratic white males safe. Hence, the electoral college. Or, to put it in a more Hamiltonian manner (from The Mode of Electing the President. From the New York Packet. Friday, March 14, 1788.):

It was equally desirable, that the immediate election should be made by men most capable of analyzing the qualities adapted to the station, and acting under circumstances favorable to deliberation, and to a judicious combination of all the reasons and inducements which were proper to govern their choice. A small number of persons, selected by their fellow-citizens from the general mass, will be most likely to possess the information and discernment requisite to such complicated investigations. It was also peculiarly desirable to afford as little opportunity as possible to tumult and disorder. This evil was not least to be dreaded in the election of a magistrate, who was to have so important an agency in the administration of the government as the President of the United States. But the precautions which have been so happily concerted in the system under consideration, promise an effectual security against this mischief.

The choice of SEVERAL, to form an intermediate body of electors, will be much less apt to convulse the community with any extraordinary or violent movements, than the choice of ONE who was himself to be the final object of the public wishes.

That’s right, don’t convulse the community with extraordinary or violent movements. That’s been one of my primary reasons for being a supporter of Hillary this whole election cycle, because the older I get, the more unsettlingScreen Shot 2016-05-07 at 9.27.53 PM.png a revolution sounds. And this is not because I don’t think that the country could be better. It’s because I also think that it could be a lot worse.

A little taste of what convulsing the community will get you can be had in reading The Economist‘s article ‘Tethered by History’ recounting the failings of the Arab Spring in bringing about change in the middle east. Maybe I’m over-reacting, but the last time I looked, the world economy has yet to find its footing again after the recession beginning in 2008. Fortunately, many of the aftershocks of that quake were dulled by the stabilizing influence of the EU in keeping countries like Greece and Portugal from becoming failed states. After all, nothing puts pressure on a marriage like financial problems.

That all said, the Presidential primaries have been a good, safe place for the parties to work out their own problems and figure out what they believe in.

With that in mind, the greatest good I see coming from the Bernie Sanders Campaign is that it has shown that a substantial portion of Democratic voters are further to the Left than where the Democratic Party has drifted in recent decades. Sanders is a sign to Hillary that moving to the Right, as many Democratic Nominees have done, is not the only way to garner more votes.

The good that I see coming from the Donald Trump Campaign is much the same. The Republican have been moving to the Right and building grassroots support especially amongst social conservatives since the time of Ralph Reed. Ted Cruz was an excellent example of this in the current election cycle, which had nothing but party non-conformists for Republicans to choose from with the exceptions of Rubio and Bush.

The harm of these candidates is that the only way to move the parties was to unmoor the safety lines and push. My only hope is that if either of these outsiders gets into office,  the governmental ground game that has resembled trench warfare for the past decade will continue to spend time doing nothing until we can put saner minds in control again.

Which brings me back to my initial position, that separating the fickle will of the people from the actual reigns of power may be the only thing that keeps the US from turning directly into the tempest. I’ve been accused before of being an elitist when it comes to government, but frankly, it’s because I would much rather have the best person in office than the loudest. Isn’t that what being an elite is about? Not being subject to the wind, but still sensing its influence and understanding what it means?

Just like so many other multiple choice questions, when none of the answers look correct, select the best from what you have. And if you can’t see which is the best available, don’t vote.Cthulhu 2016.jpg

 

 
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Posted by on May 7, 2016 in Uncategorized

 

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