Sunday, February 7, 2016

ZINC FINGERS AND PROGRESS

Linda, in the midst of chemo, entertains a
great nephew
Heron Island, Maine, 2009
A tip from Google Alerts to an article by one Maggie Fox published by NBC News has lured me into a downward spiral into the black depths of bio-genetics.  To get the reference out of the way:
So, anyway, some people at the National Human Genome Research Institute, a part of NIH, have been looking for genetic markers that would reliably predict the presence of cancer in the absence of symptoms – and they may have found one.  They performed what I believe is called a GWSA – a Genome Wide Association Study – and found something exciting.  Specifically, they saw that tumors in the colon, breast and stomach, as well as in endometrial cancer all showed abnormal methylation near a particular gene, ZNF154.  Fifteen discrete types of cancer were involved.  Why this unusual methylation pattern exists is not yet clear, but present results strongly suggest that this observed association will be valuable for early detection.  They are testing it on ovarian cancer at the present time.
Okay, that’s all you really need to know.  However, it you want to follow my doomed spiral into biochemical oblivion, read on. 
First, methylation.  A methyl group is a molecule consisting of three hydrogen atoms bonded to a central carbon: CH3 in chem-speak.  Methylation itself is the attachment of a methyl group to a specific spot on the DNA molecule, in order to “regulate” something – usually, shut off (inactivate) a gene.  Methylation is an important epigenetic process.  Read all about it here:
Now, how about gene ZNF154?  Well, ZNF is short for zinc finger.  Apparently there is what any sane observer would regard as a ridiculous number of ZNF genes.  Each codes for a protein that is characterized by finger-like protrusions containing a zinc atom.  These ZNF proteins perform a variety of functions: ZNF154 is described as a “transcription factor”, which I take to imply that it has something to do with “transcribing” the information on DNA onto a messenger RNA molecule.  In the literature I read the downward spiral continued, but I was already thoroughly drowned.  I wish I had studied biochemistry.
As an aside, heretofore “zinc finger” molecules seem to have been used to “edit” DNA, but this has been superseded by the CRISPR technique, with which you are  certainly familiar.
Also, the bottom of this article shifts direction and gives you some details about current Moonshot planning.  I worry that it will merely involve more money.  Cancer cannot be drowned in money.  Joe Biden: for God’s sake, read my blogs!

 

Sunday, January 31, 2016

OUR FRIEND, THE ZEBRAFISH


The Patchy-Kitty
Linda loved her
So did I
If you are a cancer scientist and want to test a new idea, you do not just visit the nearest cancer ward and start injecting.  Oh, no – that would get you at least fired, and just possibly jailed to boot.  No, you try out your idea on some innocent animal and then, if it seems to work you may progress to human cancer cells in a Petrie dish.  Then, and only then, do you screw up your courage and approach the NIH or some equally august body for permission to deal with real human beings.
There are all sorts of “animal models” in play at any one time.  They range from nematode worms and fruitflies (not much like us, but cheap) through mice (genetically a surprisingly close match, but much more expensive) to dogs, chickens and, finally, apes.  (However, currently it is illegal to experiment with chimps – even if they give written permission.)  A surprisingly useful animal model is the zebrafish.
A zebrafish is an ordinary looking fish from SE Asia, about two inches long; apparently it is a favorite of people who keep fish tanks.  The overwhelming advantage of zebrafish in cancer research is that they are transparent, at least when young.  You can see right through the little creatures and observe what your drug is doing to their organs, without cutting them open (and thereby ending the experiment.) 
Well, zebrafish figure hugely in the story I am about to tell you.  It comes from the NYTimes (courtesy of Joanne Ingwall.)  If you want to read it, click here:
Apparently cancer researchers have long known and puzzled over the fact that cells can have all the mutations necessary to go cancerous (e.g., mutated oncogenes such as our old friend BRAF, together with a defective tumor suppressor gene – p53, say –) and still not go cancerous. Working with melanoma, and zebrafish, people at Boston Children’s Hospital have shown that more than a “cancerized field” is needed to kick-start the development of cancer.  What is needed is a functional gene named “crestin”, which normally is active only in the embryonic state.  These Children’s Hospital docs first “cancerized” (with melanoma) every pigmented skin cell in a bunch of poor, long-suffering zebrafish – and then watched for cancers.  Instead of explosive development they observed that only a few cells went bad – and these all contained active crestin genes. 
Why the crestin genes – supposedly inactive since the gastrula stage of embryogenesis – arose from the dead in these few cells is an object of intense curiosity and, one hopes, diligent research.  If these observations apply to other kinds of cancer, and if we can discover how to prevent resurrection the crestin gene , we will have a powerful weapon.  Let it be so.
Thank you, little transparent fish.




Friday, January 29, 2016

LET'S OVERTHROW THE EMPEROR

Linda poses beside a superb example of a Yorkshire Dales "dry stone wall"
 
I am re-reading Siddhartha Mukherjee’s book The Emperor of All Maladies: A Biography of Cancer.  I sleep very poorly these days, and so often find myself reading serious stuff at 2:00 am, waiting for some pill to take effect.  Last night I ran on something I really want to share with you.
First, the book:  I rated it very highly the first time through.  You could check my evaluation here:
http://ljb-quiltcutie.blogspot.com/2014/10/the-cancer-researcher-wannabes-bookshelf.html
On a second reading, I like it even more.  This may be because I know a bit more about cancer now, and also because I remember where the gruesome parts are located, and how to duck.  But, anyway: this is a great book and I hope all of you get a chance to read it.  Now as to what got me all excited in the middle of last night:
Three important figures, co-conspirators in the campaign that led up to the Nixon era War on Cancer:
Mary Woodward Lasker:  Rich socialite, friend of everyone of significance in politics, accomplished add executive, lobbyist at a time when lobbying was rare.  Ms Lasker was quietly irresistible and absolutely dedicated to the task of eliminating cancer from the list of human woes.
Sydney Farber:  Oncologist and early researcher into the potentials of what we now call chemotherapy.  Farber was a maverick amongst oncologists, but a perfect partner to Mary Lasker.
Lister Hill:  Representative, then Senator from Alabama.  Son of a medical doctor, he was active in legislative matters concerning medicine.
So, after 250 words of introduction, all I want to do in this blog is to pass on some words by Lister on how something like our “Moonshot” ought to be conducted.  It is from Mukherjee, p. 107.  I couldn’t agree more.
….. I am aware of some alarm in the scientific community that singling out cancer for…….a direct presidential initiative will somehow lead to the eventual dismantling of the National Institutes of Health.  I do not share these feelings. ……. We are at war with an insidious, relentless foe.  We rightly demand clear, decisive action – not endless committee meetings, interminable reviews and tired justifications of the status quo.      Lister Hill, as reprinted by Mukherjee.
Amen, brother!


Monday, January 25, 2016

The "MOONSHOT", Part 2


The World's Cutest Picture
My friends Brad and Dave have just left, after a very pleasant visit that was far too short.  Both are accomplished birders (they expanded my “life-list” by nearly 6% - from 102 to 108).  They also are enthusiastic desert explorers and general naturalists, and so my wonderful little jeep got plenty of exercise. And in addition, Dave always comes bearing many bottles of excellent wine, and Brad provides multiple peanut butter cookies of a quality unexperienced by me since my mother hung up her apron long ago.  Needless to say, I invited them back!
But then I started thinking about the “Moonshot” – and realized I have very little left to say.  As many have said, this is a propitious moment to multiply our efforts to cure “cancer”.  Here is a short list of why:
1)       Largely owing to such genome-wide investigations as ENCODE and The Cancer Genome Atlas (both of which I have written about previously}, we are aware of the diversity of “cancer”, and have formed an appreciation of how difficult conquering “it” will be.  So much so, in fact, that I will stop using the quotation marks and take it as given that you are aware that what we have called “cancer” is many separate, but closely related, diseases.
2)      Also, resulting from research into the significance of our “junk” DNA, we are beginning to get a handle on how our genes are controlled – turned on, turned off, muted and modified.  Most cancers are the result of genes behaving badly; this new knowledge may – should -  help us correct their behavior.
3)      Progress is being experienced all along the front lines.  Immunotherapy, personalized therapy, early detection, increased understanding of environmental factors – it almost seems as though each of these, and more, are only lacking a swift kick in the butt to take off.  Note that money will help, but more than money is needed.
4)      Available technology of ridiculously sophisticated complexity has come on line.  To cite the one that has generated the most squawk, the CRISPR Cas9 will let us “edit” our very genes!  This is an inconceivably powerful weapon for good.  And, yes, it can be scary.
5)      And finally – we still are rich enough to afford one more Moonshot.
So, go get ,em, Joe!!   (Joe Biden, that is.)
My one remaining worry – a big one – is that future increases in funding will be distributed to researchers following current practice – peer-group review.  I have railed against this procedure several times previously; I feel that it inculcates excessive caution, incrementalism and delay, while simultaneously suppressing creativity.  I think we need a top-down approach, with one person or maybe two completely in charge.  My history may be faulty, but a am fairly certain that’s how we beat Hitler to the atomic bomb, and Russia to the moon.  So here, off the top of my balding head, are a few suggestions.
First, don’t give the money to the NCI or NIH.  Instead, create a new entity – call it NCA, for the National Cancer Agency – and put someone like Joe Biden in nominal charge.  Joe is an experienced and adept politician; Joe not only knows where all the bodies are buried, he also knows where they stacked the shovels!  Someone like Joe is indispensable in dragging ideas through government and into fruition.
However, entrust scientific decisions to someone who is broadly abreast of what’s going on, and can make hard decisions.  This person must be an accomplished scientist, but have attributes of an effective administrator.  Previously I have suggested Dr.  Soon Shiong: read about him here:
Or maybe somewhere there is another hyperactive genius polymath who would be even better.  But, whoever is selected, put him or her totally in charge.  No committee votes, no peer reviews.  Top down.  Sounds like a horrible job, doesn’t it, but I would bet that there are plenty of qualified adrenalin junkies who would love it.  Another top candidate might be Jennifer Doudna of U.C., Berkeley, who is riding the CRISPR express full blast into parts unknown and hitherto undreamed of:
http://www.nature.com/news/genome-editing-revolution-my-whirlwind-year-with-crispr-1.19063
And, of course, give her/him an advisory panel – maybe the heads of the half-dozen top cancer labs in the country: Sloan Kettering, Fox Chase, M.D. Anderson, Fred Hutch, etc. , etc.  Let them rotate, perhaps.  But it should be clear that this panel is advisory only; where the money goes is entirely the responsibility of the Cancer Czar.  At least then we would know who to blame!
Okay, I started this by saying I had little to say, then wrote two pages, 750 words.  Imagine how long this would have been if I’d had some ideas!
And thanks to any of you who read this far; your dedication does you credit.  Right, Dave? 


Saturday, January 16, 2016

The "MOONSHOT". Part 1


Western Michigan University, 1999
It might be considered stupid and a bit churlish of me to complain about the Obama/Biden “Moonshot” to cure cancer (see SOTUA).  After all, it means more money for cancer research, right?, and every little bit helps.   Just the same, in this blog I plan to toss out a few sour grapes.  My plans are to do some heavy pondering for a while,  and then, if my brain churns out anything worth writing about I will inflict it on you.  For the moment, though – here is where I’m at:
1)      We tried an anti-cancer “Moonshot” 45 years ago.  It didn’t work.  The notion was that we could simply smother the disease in money.  The problem was two-fold.  First, we didn’t know enough about cancer to attempt efficient remedies, and second, the money (and it was ample) was distributed ineffectively.
2)      We know much more about cancer now than in 1971, but the more we learn, the more we realize how ignorant we really are.   For instance, recent studies of the human genome, in particular the ENCODE project, have shown that the “junk DNA” that makes up over 90% of our genome (the part that doesn’t code for proteins), is responsible for producing molecules that “regulate” (turn on or off genes) gene-coding stretches of DNA, or otherwise affect their behavior.  This behavior can be  spectacularly complicated, and in general is very poorly understood. So, for instance, there is no “gene for ovarian cancer” which we might hope to “fix”.  In fact, there is no such thing as a unitary OVCA; about a half-dozen separate diseases are recognized, each with its own distinct genetic markesr.  The same goes for other cancers; probably most.  Thus, you can’t hope to cure “cancer”, but perhaps it is legitimate to hope that these separate, often quite distinct, maladies can be overcome, one by one.  This will take time and, yes, lots of money.
3)      From most of the news commentary it would appear that all the nation’s cancer big-wigs are delighted with the "Moonshot".  Don’t be misled; spokespersons for big research agencies are ALWAYS delighted to receive more funding.  When was the last time you heard of such a guy remarking “Well, we’ve got plenty of money.  Wish we knew what to do with it.”   
4)      To conquer “cancer”, then, I think that a more centralized, top-down administrative structure will be required.  We made it to the moon so fast because NASA was not structured like the NSF or the NIH.  Same way with creating the atom bomb.  If NASA had relied on peer review to make decisions we would still be trying to decide whether to use solid or liquid fuel.
Okay, this is my starting point.  As to where I might be going, read this:


Wednesday, January 13, 2016

IT HITS THE FAN

Enjoying Borrego Springs
 
Oh, boy! – Something dark and gooey is about to hit the fan.
I ran on this article in Google News for Wednesday, 1/13:  Scientist argues her case for UK license to “edit” human embryos.
The scientist is Kathy Niakan.  Dr. Niakan is employed by the Francis Crick Institute, in London – named after the more consistently  brilliant of the co-discoverers of the DNA double helix.  I am sure that were Crick alive would applaud Dr. Niakan’s efforts.
Dr. Niakan is asking permission to use CRISPR Cas9 technology to experiment with human embryos.  Presumably these embryos would be “left over” from in-vitro fertilization procedures.  They will not be implanted in human females, the article states.  The controversy stems from the fact that these bits of cellular material are potential human beings, even though they are not on track to become so.  Thus, by one popular and arguably reasonable test – they are people already, and what is proposed is tantamount to murder. 
The decision yes or no will be made by the UK Human Fertilization and Embryology Authority.  Whichever way it rules it should expect to be buried in rotten fruit and other disgusting substances.  In parts of the U. S., armed guards might be needed.
This is important stuff.  I will follow up.
  
 


Sunday, January 10, 2016

THE ANGEL OF LIFE (??)

Have I used this before?
Well, I don't care - it's a nice picture
 
Back in the 1970s, bubbling over with confidence after our successes in space, America declared war on cancer.  Forty year and many billions later, 15,000 American women will die of ovarian cancer this year.  Yes, there have been some wonderful successes, but we are still a long way from a biochemical moon landing.  In fact, for some cancers, at least, we have yet to reach a stable orbit.  Anywhere.
In the 1990s a gene named TP53 was all the rage.  TP53 codes for the protein p53, known in some circles as the Angel on Death.  P53 patrols the body, searching for defective cells.  When it finds one it may order the cell to die (apoptosis).  As such it is a vital tool against cancer.  If p53 is disabled, cancer may run wild.
Science writer Matt Ridley, in his book Genome: an autobiography of a species in 23 chapters was so enthusiastic that he predicted imminent victory in the cancer war.  About that same time p53 was declared “Molecule of the Year”, presumably because of its promise as a weapon against cancer.  So, what are we doing, a quarter-century later, still talking about p53’s potential?  I think most of you know what I think.
Here are two blogs on p53:
So why is this important?*  Well, a bunch of folks at UCLA have found that one way ovarian cancer fights off the Angel of Death is to induce the p53 proteins to get all balled up in little knots.  They have adapted a molecule used to combat Alzheimer’s and Parkinson’s to unravel these ineffective little balls of p53.  When this molecule is introduced into a solution containing tiny ovarian cancers (in a culture dish, naturally), the tumors are attacked with great vigor.  So, hurray, I guess.  I’m not holding my breath.
I am feeling uncommonly cynical this afternoon, so I will comment on one thing further.  UCLA has given the patents on this discovery and its attendant technology to a bio-pharma concern recently started – by the head of the lab that did this work.
One more Ferrari on the streets of Los Angeles.
*So why is all this underlined?  Ask the computer, not me.