OUR FRIEND, THE ZEBRAFISH

The Patchy-Kitty, World's most beautiful cat

Linda loved her

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:

http://www.nytimes.com/2016/01/29/health/how-skin-cancer-develops-melanoma-zebra-fish.html?smprod=nytcore-ipad&smid=nytcore-ipad-share&_r=0

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.



Linda and sleeping kitten



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!



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:

http://ljb-quiltcutie.blogspot.com/2014/12/the-richest-guy-in-la-and-also-most.html

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? 



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:

http://ljb-quiltcutie.blogspot.com/2014/06/the-truth-in-small-doses-at-long-last_7.html



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.

https://www.google.com/?gws_rd=ssl#q=google+news

  

 



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:

http://ljb-quiltcutie.blogspot.com/2012/12/a-universal-cancer-cure-maybe-start.html

http://ljb-quiltcutie.blogspot.com/2013/03/p53-apoptosis-cancer-and-babushka-dolls.html.

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.

Read it and weep.  http://newsroom.ucla.edu/releases/ucla-scientists-test-new-strategy-that-could-help-fight-ovarian-cancer

*So why is all this underlined?  Ask the computer, not me.

   

 

 

 

 





CANCER: YOUR YEAR in REVIEW

Flower Time in Borrego

With our recent rains, February may be spectacular

Here is a “Cancer:  Your Year in Review” article, written by Arlene Weintraub, who covers “Pharma and Healthcare” for Forbes Magazine.

http://www.forbes.com/sites/arleneweintraub/2016/01/01/8-milestones-of-2015-in-the-war-on-cancer/

Forbes is heavy to business matters, so it is not surprising that Ms., Weintraub’s piece is equally heavy to discussions of which drugs are in trial, what they do, and what their potentials – for societal value as well as  profit – may be.  The cancers discussed include colorectal, multiple myeloma, thyroid, melanoma, lung, leukemia, lymphoma – and ovarian.  The therapies mentioned include immunotherapy, “personalized treatments” (treatments developed from study of the genetic mistakes involved in the tumor), and use of genetically engineered viruses (!), off-the-shelf T-cells, (that is., not genetically engineered for a particular cancer), and even low-toxicity therapies  suitable for old timers – Jimmy Carter is discussed.   

Ovarian cancer is considered in the context of the ROCA blood test that we have discussed previously.  Nothing new here.

Okay, so if you have a general interest in cancer drug research, read this article – it’s actually pretty interesting.  Another reason to read it might be that you have lots of cash sloshing around in your bank account and are looking for a good investment in the pharma field.  For whatever reason, if you read Ms. W’s essay it would help to know the following:

Checkpoint inhibitor and PD-1.  The immune system is prevented from attacking the body’s own cells by the presence of certain proteins – called checkpoints – on the cellular surface.  Some cancer cells present their cell exteriors festooned with a protein called PD-L1 which prevents the protein PD-1 (our old friend the “programmed death molecule”) from doing its number on the cancer cell.  PD-L1 is a checkpoint, and the plan is to “inhibit” it, to the detriment of the cancer cell.  Got that?  I’m not sure I do.

Mismatch-repair deficiency.  When a cell divides, its DNA must be duplicated.  Something called DNA polymerase does the trick.  Although highly reliable, it makes mistakes.  These mistakes are repaired for the most part by a biochemical repair crew.  If this biochemical repair is somehow “deficient” (an alcohol-intensive party the night before?) some serious errors may sneak through.  Cancer may result.  Interestingly, one approach to cancer therapy involves deliberately disabling the mismatch repair crew.  This operates on the assumption that rapidly dividing cancer cells mean lots of mismatches.  If such mistakes are not repaired, the cancer cell may die.  And, we all agree, good riddance. 

Just a reminder:  If you want to see more blogging about something, Google “Myrl‘sBlog” and use the little question line at the upper left.  For instance, searching for “checkpoint” yielded four entries.  In one of them I appear to be in the act of kicking a lobster. 





MORE BIOLOGY THAN YOU REALLY WANTED

In the Galapagos, I think

Swimming with penguins

 

Frolicking and imbibing over the holidays have left me so far behind in combing the Web for interesting cancer news that I would need at least two Research Assistants to catch up before next Christmas.  So, next best thing: I plan to make good use of the old Delete button.  But here is one (from 12/22) that needs to be discussed.  Here is the Web address:

http://newswise.com/articles/study-uncovers-inherited-genetic-susceptibility-across-12-cancer-types

It is short and easy going, so take a look.

The research was done at Washington University School of Medicine, in St. Louis.  The question addressed was: What fraction of various kinds of cancer are owing, at least in part, to heredity?  What demanded my attention was a graph showing these fractions for 12 common cancer types.  Right up there at the top of the graph was ovarian, at 19%!

The work made heavy use of The Cancer Genome Atlas, which we have discussed previously.  See, for instance:

http://ljb-quiltcutie.blogspot.com/2013/05/the-cancer-genome-and-its-uses.html

Let me nutshell the article.  The study used people known to have one of twelve common cancer types.  The “sample” is reported as “more than 4000”.  The methodology involved comparing “germline” genes (what you are born with*) with the genes expressed in the tumor cells themselves.  Some mutated genes are well known to be implicated in cancer; your old friends BRCA1 & 2 for instance, or a particularly nasty bastard called RAS.  If a disabling mutation was present in high quantity in the tumor, and also found in germline cells, the tumor was classified as hereditary.

But what, you shout, about the same gene from the other parent?  Well, if both parents contribute the same defective gene, the poor offspring is – it seems to me – toast.  Likewise if the mutated gene is strongly dominant, toast again – although this raises the question of how the parents remained alive themselves.  But most of the time there will be one functioning gene to provide the proteins that keep cancer in check.  The problem arises as time and repeated duplication of DNA invite mutation.  If you have one defective gene, and then a random mutation puts the other one out of commission, then – well, heck, toast.

You probably noticed that this was a pretty big nutshell – a coconut, for instance.  So, enough.  Stop reading here, unless you’re a masochist.

Okay, game for more, eh?  If you read the article you probably will stumble over the term “truncation mutation”.  As you are aware, DNA is “transcribed” into RNA, which then interacts with a tiny protein-manufacturing plant to produce the proteins upon which all life depends.  DNA (and RNA) are said to “code” for the amino acids of which proteins are composed.  The code is “triplet”: three consecutive nucleotides indicate a unique amino acid:  for instance, UAU codes for something called tyrosine.  There are also combinations that tell the little protein plant (it’s called a ribosome) when to stop.  So let’s say that the ribosome is chugging away and encounters a codon that should read UAU but, because of a mutation, actually reads UAG.  UAG is a STOP codon – it tells the ribosome to stop synthesizing the protein and kick it out into the cell.  The protein is thereby “truncated”, and furthermore, useless.

Now wasn’t that fun?

*This germline-sampling stuff makes me cringe.  You know where germ cells are stored, right? Do they use a needle to get their sample?  I hope not

 



A CHEERFUL LITTLE ESSAY TO START YOUR NEW YEAR RIGHT

 

Don't know when, don't know where

But she is smiling, and that's all I care

 

 

Now here is a depressing little essay to start your new year.  It is based on an article in the NYTimes

http://www.nytimes.com/2016/01/03/us/politics/fda-regulator-widowed-by-cancer-helps-speed-drug-approval.html?smprod=nytcore-ipad&smid=nytcore-ipad-share

and was brought to my attention by Dick Ingwall.

From time to time I have spewed greenish-yellow venom at the FDA for what I perceive to be its excessive caution and bureaucratic incompetence in approving new drugs, especially cancer drugs.  I have not been alone, not by a long-shot; there have been many complaints about the plodding pace of the FDA.  As a perhaps extreme example, the Wall Street Journal once headlined an article “FDA to Patients:  Drop Dead”.

Well, it transpires that the guy catching muvh of this flak was one Richard Pazdur, who is chief of the oncology section of the FDA.  Dr. Pazur’s wife recently died, of ovarian cancer.  Not surprisingly, I guess, the pace of FDA investigation has picked up notably since then.  Also not surprisingly, there is a lot of complaint and suspicion directed at this fact.  I have some thoughts.

It appears that the backbone of medical ethics, the Hippocratic Oath, does NOT contain the phrase” First, do no harm”, although that is held to be the gist of the thing.  But there are many kinds of “harm”.  With regard to a patient suffering from ovarian cancer, “harm” can be inflicted by prescribing a drug that makes matters worse, but equally well harm can stem from refusal to use an untested drug that might help.  A sin is a sin, whether it is one of commission or of omission.  (And thus endith the First Lesson – I sound like old Dr. McMartin in the Beaumont Presbyterian Church of the 1940,s)

In many jurisdictions it is permissible for a patient who is terminally ill to take his or her own life.  Why, then, should it not equally be permissible for such a patient to elect to take an experimental drug – after counselling about possible side effects, of course.

AND, it turns out that it IS possible for terminally ill persons to get access to experimental drugs*.  According to the NYTimes article, every year the FDA receives about 1,000 requests for “compassionate use” – and approves 99% of them.  Maybe I should cut them a little slack, eh?  Ah, maybe not. 

So, anyway, it turns out that Mrs. Pazdur did try an experimental drug – and suffered horribly.  Subsequently she stopped chemo and entered Hospice care.  She had been an oncology nurse and knew what she was doing.

Well, wasn’t this fun?  I think I will go and watch the Seattle Seahawks get the stuffing kicked out of them by the Arizona Cardinals. 

 

* I just learned this.  Stupid me.