TCGA. You'll have to read it to find out what that means.

The world's cutest picture

 

 

Linda’s sister Carolyn sent me a tip to a news article floated by Yahoo! about The Cancer Genome Atlas.  I wrote about TCGA earlier, but I can’t remember when.  (Maybe I should keep a running  log on what I’ve already written.  That way I can avoid making myself a liar.)  Anyway, Carolyn’s article dealt with the impact of TCGA on research, especially research into targeted therapies – fitting the drug to the specific problem(s).  I made a lazy attempt to run down the original article, but to little avail.  The clues I had at hand were that the article was about TCGA, published in Cancer Research, in 2013.  No author was mentioned.  I used Google Scholar to search on “The Cancer Genome Atlas”, “Cancer Research (journal)”, and “2013”.  Guess what?  Google Scholar furnished me with 126 papers meeting all those criteria!  One of them had already been cited 13 times – in eight months!  Heck, if I got 13 hits on one of my papers in a DECADE I would feel a success.  What is the answer?  Are there whole armies of cancer researchers, all writing papers and reading the literature most of the time?  If so, when do they do their actual work?  In geology, piling up multiple papers was legitimate, because – the content of our research being of vanishingly small actual importance – amusing ones colleagues with clever essays was a acceptable goal.  Cancer researchers, on the other hand, are supposed to spend most of their time and energy working on ways  to eliminate the damned thing – emerging  only rarely to report what they’ve found.   Ideally.

When you stop to think about it, dedicated cancer researchers are expending their energy trying to put themselves out of work.  Rather like dentists who campaign for fluoridation. 

As you can clearly see, I don’t really have much to write about today.  My main reason for doing so is to repeat the picture of Linda and Patches from the last blog.  For some reason Blogspot wouldn’t let me enlarge the picture at the end of the entry.  So here it is, full scale.

Here is the link

http://news.yahoo.com/largest-cancer-gene-database-made-public-232153763.html



EPIGENETIC APOCALYPSE NOW: I warned you.

This is going to be so boring that I will insert the picture LAST, and put you on your honor to read all the way to the bottom before you look at it.

Things you may already know:

                DNA consists of an enormously long sequence of four “bases”,  abbreviated A,C,T, & G.  These are types of organic molecules (nucleic acids) and are very similar, but with important differences.

                A sequence of three bases, called a “codon”, will “code for” an amino acid.  These things we call proteins are nothing more than long strings of amino acids, which naturally assume some characteristic shape.  The shape depends on the sequence and the chemical and electrical properties of the amino acids.
                Proteins are the workhorses of the body.  They can only do their jobs if they have the right shape.

                To make a protein from a DNA blueprint the sequence must first be “transcribed” onto a DNA-like molecule called a messenger RNA (mRNA).  Once transcribed the information is transported to a copying machine (ribosome) and “translated” into a chain of amino acids, which then folds and scrunches to make a protein.  Making a protein from a DNA sequence is called “expressing” it.

                All cells have the complete DNA sequence, but in specialized cell only a few are “expressed”.  You do not, for instance, grow hair in your teeth – although in your dissolute youth you may at times have thought you had.

Things you may not know:

                There are things called “promoters” that initiate “transcription” of a sequence of bases (a gene).  If the promoter is screwed up, the gene doesn’t get expressed properly, or at all.

                mRNA  frequently is modified after being transcribed by things called micro RNAs (miRNA),as well as by other proteins.  miRNAs are  a relatively new discovery, and I predict they will play a large role in cancer research.

                Sometimes the protein coming newly hatched from the ribosome also is modified before going to work.

I must say, the entire process strikes me as so blindingly and unnecessarily complicated that, in a way, it proves natural selection; natural selection by environmental conditions acting on completely random deviations..  It provides good  evidence against Intelligent Design;  if “designed”, the process   resembles a Rube Goldberg contraption slapped together  by a Designer with a peculiar sense of humor.

NOW, some things I think I know and partially understand that I would like to share with you:

                “Epigenetic” means “on top of, in addition to” – stuff like that” –genetics.  It is a science which treats of the ways that gene expression is regulated.  The reason that you do not grow hair in your teeth is because the genes for hair growth are blocked(in your teeth) by things called “epigenetic markers”. 

                An epigenetic marker can consist of something (a molecule) attached to the DNA strand.  Often this is a “methyl” group (one carbon atom attached to three hydrogens and carrying a positive charge.)  If a methyl group gloms onto the promoter for a gene (a specific length of DNA) it may stop that gene from being expressed.  Apparently patterns of methylation can be inherited, and after studying Nessa Carey’s book I even know how – but I know you don’t care, so I will spare you.  Another way that epigenetic markers modify gene expression is called “histone acetylation.”  This calls for more biology – but hang in there, I’m almost done.

Histones are proteins.  They form little knots (“octomers”, called “nucleosomes”) around which the DNA strand can be tightly wound.  Winding is essential; cells are so small you can’t see them, but a typical strand of DNA is six ft. long!  Clearly, to transcribe a stretch of DNA into RNA the knot has to be partially unwound.  The ability of a nucleosome to be unwound can be affected by a process called “acetylation”, which is the addition of an acetyl group to the histone proteins.  (For you would-be chemists and any other masochists, an acetyl group is CH₃CO-).  Apparently acetylation is not inherited.

There are many other kinds of epigenetic markers; Wikipedia will give you an entire paragraph-full of them.  But these are enough.

So why have I put you through all of this (you didn’t just skim, did you?)?  I did it because many novel cancer-fighting methods are based on epigenetics.  Say you have a gene that, when mutated, serves as an oncogene and stimulates cell division.  How to silence it?  Methylation!  Or, acetylate the hell out of the nearby nucleosomes, prevent  unwinding and thus transcription – ergo, no active oncogene.  They are hard at work on epigenetic drugs, and if they succeed they will deserve their BMWs, in my view.

I won’t do this to you again.  I promise.  Well, maybe once or twice more.  You know me; I never lie!

               

Linda and Patches, awake

If there is a cuter picture anywhere, I've yet to see it

MEA CULPA: but I have an excuse

 

 

In the Chilcotin, British Columbia

 

Cattle country.  Texas, with trees

 

Don’t give up on this blog!  I know, I know  ….. I haven’t written anything for several weeks, and you are tired of checking to find out if another little essay has appeared - mainly you are interested in the added attraction (the principal attraction?); a new picture.  I know that because my “hit counter” recorded only seven hits the past week, a new record low.   No, I am not lying in a gutter somewhere after celebrating the successful conclusion of Summerun North too enthusiastically.  Neither am I absorbed in my golf game, nor simply goofing off.  I am busy.  I am reading stuff (lots of stuff) at the behest of  Dr. Rivkin at the Marsha Rivkin Center, and writing a few things for my Fred Hutch group.  Also, I have had relatives, blood and in-law, as house guests for several weeks.  AND, I am writing my most blindingly boring and biologically challenged essay ever, on epigenetics.  Be warned, it is on its way!  But anyway, I want to reward your loyalty to this erstwhile barren site with another picture – and give you the good news.  Dr. Rivkin is full-time in pursuit of ovarian cancer.  I will help him in any way I can, or at least try to keep out of his way.  Ovarian cancer, your days are numbered!



WHAT IS CANCER, ANYWAY?

Linda with French-Canadian goat
Or is that a sheep?

 

Well, Summerun North 2013 is part of history.  About two dozen people walked through the tourist swarms in Old Fairhaven on a warm and sunny Sunday, wearing their “Linda’s Team” T-shirts.  They accosted anyone who couldn’t creep away fast enough, and gave them potentially life-saving literature, furnished by the Marsha Rivkin Center.  Then they came back to my house and lunched delicately on hot dogs (cooked by Joe Mortimer), beer (I opened the bottles), and many sorts of salads and desserts provided by the nice ladies of Linda’s various organizations, quilting and otherwise.  I seriously over-estimated the thirst of the participants, resulting in an ambient beer supply sufficient to open a bar.  I think everyone had a good time, and we raised almost $2K – a bit more than the $750 I had hoped to raise.  Stay tuned for Summerun North 2014.  Thanks to all, but especially to Linda’s sister Carolyn and Linda's good friend Florence.  And, by the way, our shirts really looked good.

So, anyway, Dick Ingwall has again spotted a story in the NYTimes concerning cancer – in this case, what it is & what it isn’t.   A “working group” of the National Cancer Institute has just published the results of its deliberations concerning what we should call cancer, and what we should call something else.  To boil the issue down to its dry essence, there are lots of things our medicos refer to by long names including words like “carcinoma”.  Many of these things are being detected as direct results of progress in early detection (I almost said early “cancer” detection, but maybe I shouldn’t.)  Some of these things may in fact develop into full blown metastatic cancer and do us grave harm, but many of them won’t.  The problem arises, then, because, given the current state of medicine, telling which is which is an uncertain at best.  So, if your doctor says that you have (to make it up)a squamous neoplastic porous yellow lesion” you might go home content, but if she says you had a squamous neoplastic porous yellow protocarcinoma you might be terrified – and demand to have the damned thing cut out immediately.  This, says the working group, results in lots of unnecessary surgery and needless anxiety.  So, they say, ditch the word carcinoma (sarcoma, etc.).  Call it something bland, until you know what the damned thing really is. 

Do you agree?  I guess I do, somewhat.  What I really want my doc to say is: “Well, the path report says you have this thing with a long name.  As far as we know, it has a 5% or less chance of growing into a full-blown cancer.  As far as we know, yeah, but we really don’t know all that much.  I would suggest watchful waiting.”  If he phrased it that way I probably would take his advice.  But if he said “…. 30% chance…..”  I might say “Take it out.  Now.”  I don’t think our docs need to worry overmuch about disillusioning us with their lack of certainty.  In my somewhat post-disillusioned state I realize that much of diagnosis, despite the multiply fortunes being spent on bio-medical research,  remains a cosmic crap-shoot.    

But – progress is being made.  I have faith.

To read the story yourself:  http://nyti.ms/1aSMm6a

 

 

DO CLINICAL TRIALS WORK?

Linda Joyce Beck, pro miniature golfer

 

Leavenworth

 

You know how clinical trials work.  Let’s say that a research team develops a drug that cures (or more likely inhibits) lung cancer in mice or chickens or monkeys.  To check if it works in humans they first perform a Phase I trial to determine maximum safe dose.  Then they get permission and funding for a Phase II trial, perhaps involving a few dozen to a hundred or so people.  In Phase II they seek to determine whether the drug does humans any good, while continuing to monitor for side effects, etc.  If the drug still looks promising after Phase II, Phase III may be attempted, involving several hundred to several thousand subjects.  If once again the drug appears to be effective they leap with joy, order their BMWs, and apply to the FDA for permission to market.  (Most likely they actually wait for approval before buying the BMW.)  Most drugs never even make it to Phase III, and fewer still are approved for use.  Drug development is a costly, tedious, and frustrating process. 

The “gold standard” for Phase III trials is the “double blind” version.  The trial cohort is divided in two; half receive the drug and the other half get a placebo*.  Neither the patient nor the doctor administering the drug knows which is who.  Only the computer back at headquarters knows that patient A is getting the real stuff and patient B is getting a sugar pill.  When the trial has run its course, that same computer assists sage statisticians to determine (with impecable mathematical rigor) whether the drug arm of the study experienced better outcomes than the placebo arm.  If it did, head for the FDA office nearest you…

Now, however, an article appearing in the NYTimes (thank you, Dick) questions the validity of even “gold-standard” trials.  The example cited is Avastin, which targets angiogenesis in tumors.  (No, I did not use that big word just to impress you.)  Angiogenesis is the process whereby fast-multiplying tumor cells build a blood supply; without sufficient blood they will croak, like any other cell.  Avastin was used to combat a nasty species of brain tumor.  The drug had helped significantly in an earlier, much smaller Phase II study, but the double-blind Phase 3 trial showed no significant difference in survival between the two arms.  In other words, from a much larger selection of patients, very few benefitted from Avastin.  The odd thing was, though, that some benefitted a lot.  Which brings us, I think, to the point:  maybe clinical trials of the traditional sort don’t work mainly because cancers are so heterogeneous.  Maybe it doesn’t make sense to speak of “pancreatic cancer”, for instance, as if it were a single disease that can be confronted by a single remedy.  If one were to examine the genetic damage that lead to cancer in the pancreas, one might find that several different kinds of genetic errors were involved.  Thus a treatment that worked on tumor A might not work on tumor B, even if both were located in the pancreas.  Get my drift?  We come once again to the necessity of matching the treatment to the individual genetic (or epigenetic?) mistake.   More laboratory analysis, more testing – and more money.  

There is a lot more stuff in the original Times article, but I’ll let you read it for yourselves.  It is lunchtime and I’m hungry.  http://nyti.ms/12vDZvw

*Commonly Phase III trials are run with the “standard of care” treatment used in what I have called the placebo arm.  That way you can see if the new drug, which almost certainly is expensive, will do a significantly better job than the usual treatment regimen.

 



EVEN THE ARMY GETS INTO THE ACT

WHAT A DIFFERENCE A FEW DECADES MAKE!

Did you know that the Department of Defense (DoD) funds ovarian cancer research?  If you are like me, your initial response probably was – what the heck?  When I was in the Army very few soldiers had ovaries, that’s for sure.  Some did, of course – WACs, nurses, and maybe a few others, but I wouldn’t have thought that there were enough to merit a special research program.  Even now it seems odd, to a dinosaur like myself.  However, it’s true and it’s well appreciated, even by dinosaurs.

It turns out that, in 1992, Congress established something called the CDMRP, which codes for Congress-Directed Medical Research Program, which has been funded to the tune of $7.4 billion to date.  Funds for medical research are added to the annual DoD budget.  The DoD then divvies these funds up between various programs, one of which is the OCRP; Ovarian Cancer Research Program.  OCRP was initiated in 1997 and so far has spent $216 million on a large number of disparate, promisingly innovative, projects.  Several of the people I work with at the Hutch are partially funded by the DoD. 

 

So, I tend to be a bit incredulous that these funds are being administered by the Department of Defense.   Don’t these guys spend billions on advanced weapons systems that, just occasionally, don’t work worth a damn?  Isn’t $216 million a rounding error for them?  Pocket change, that you might toss in a change dish?  I would have thought that, just maybe, the NIH could look after the money better.  But what do I know?  I’m  a dinosaur.

 

But, anyway, the CDMRP exists, and it has put out a document – a readable document - stuffed with interesting information about ovarian cancer.  You can read it yourself at the following web address:

 

http://cdmrp.army.mil/ocrp/  For the easy-to-understand pamphlet, click on the image on the left of the page. 

 

On another matter, I am pleased to report that I have finally met Dr. Saul Rivkin, the founder of the Marsha Rivkin Center for Ovarian Cancer Research.  He just retired, at 77, from active duty as an oncologist at Swedish Hospital.  I admire (and envy) his energy – but, after all, he IS younger than me.  His wife Marsha died early of OVCA, earlier even than my own Linda.  I imagine that his dedication to eradicating that particular disease is at least as great as mine, if that is possible.  He has the advantage of a medical education, good contacts and – as I said before – a surplus of energy.  He is going to be devote full time and attention to ovarian cancer, now that he’s retired.  I  hope I can help.



THE SEQUESTER HITS HOME

 

A quilt shop in Mahone Bay, Nova Scotia

She could smell 'em at 50 miles if the wind was right!

 

 

Remember back on March 2^nd when I told you (TIME TO BURN SOME SHOE LEATHER) about the effect this moronic thing called the “Sequester” was about to have on the NIH and NCI budgets”   and politely exhorted you to write your Congresspersons to complain?  Sure you do, because I kept hounding you for weeks thereafter.  I am certain that most of you did the right thing and raised hell.  However, as you certainly know, all your efforts did no good – “Sequester” not only took, but now seems to be permanently installed as the new norm.  Well, yesterday I learned something that again rubbed my nose in this monumental stupidity.  I had a talk with Dr. Bonnie McGregor.

You will remember Dr. McGregor.  I wrote about her in my blog “CHEMO BRAIN AND CROWDSOURCING” on May 26^th.(Well, after actually re-reading that little contribution I see that I didn’t say anything at all about Dr. McGregor – although if  (as I am sure you did) you followed the link I gave you would know her and her project).  Anyway, she has given us several tote bags, which I will dole out to the winners of various aspects of Summerun North 2013, on July 28^th.  She also wanted to attend, but has other commitments.  Anyway:  Dr. McGregor told me a little of what is happening because of the big “S”.  She is awaiting word on how much her various grants, already awarded, will be cut.  Some salaries will feel the pinch as well.  I know that the unit I work with is sweating bullets trying to get their master grant re-funded.  I suspect that terror roams the halls of most cancer research institutes these days.   And all because Congress (and the body politic at large, it seems) has forgotten the arts of compromise. 

I have several times lately used  the Aussie expression “Goodonem” -  translated” Good on you, them, it” whatever.  It may be time for a similar expression:” Apoxonem”.

I know, I wrote two blogs today, and two per day is too many.  It’s just that my cats have stopped barfing on the rug, so I had some time on my hands.  It won’t happen again.

By the way: http://community.swedish.org/page.aspx?pid=608&tab=0&frtid=1183, and of course
 http://www.customink.com/signup/3a9v6j52