NOT OC. WHY I AM NOT A BIOCHEMIST

Linda and her good friend Pat Beechem

probably about 1989

With my new mission(s) in life – cure ovarian cancer and win the Noble prize in medicine – I have taken a close look at why I did not become a biochemist.  There are, it seems, two reasons: Linus Pauling and Samuel J. Sims.  I will explain.

I was at Caltech during the early 50s.  According to something I read in “The Eighth Day of Creation” (an excellent book, by the way), Linus taught chemistry to the freshman class at that time.  Insisted on it, I think was said.  Well, that is only partly true, and a small part at that.  What he actually did was lecture at us, every so often, seemingly on a topic that happened to interest him that morning.  He was unlike others who tried to teach us; he seemed to enjoy what he was doing.  He hammed it up.  I remember one lecture – probably about refraction of X-rays through crystals – he talked to us while looking at us sideways through a highly refractive piece of something.    I must have felt that, if a world-renowned chemist could behave in such an unserious manner, then chemistry itself must not be all that serious, either.  Nobody in the room paid him much attention, except when, once in a while, he would say “Every Caltech chemistry student should know ….X”.  You knew that"X" would be on the test, so you wrote it down.  So, Linus is to blame.  But even more to blame is …. Sam Sims. 

Sam Sims and I were freshmen together at Tech, and we went to all our classes together as well.  Sam was a better football player than me, but I could beat him at freestyle wrestling.  We did the latter every evening after dinner – Tech students need ways to blow off steam, God knows: we were nerds, and there were no girls.  Anyway, we played lots of catch with the football.  (Sam actually started with the Tech varsity.  I might have been on the team, too.  I was asked to turn out.  That shows how desperate they were.)  During the spring-quarter chem final (Tech finals then lasted four hours, and were unsupervised) I discovered that Sims had brought his football to class.  After several hours of misery we climbed out through the window and tossed the football around for a long time.  Then, refreshed, sweaty and desperate, we finished the test.  Sims got a good grade.  I passed.  The next year I was at Stanford, studying political science.  It was a long road back to science, and on that road I never stumbled across any chemistry, nor biology for that matter.  Thus, when I started to volunteer at Fred Hutch, my ignorance was pure and complete.  Unfortunately, after six months of study, it still is.

NOT OC; The problem solved. Duh!

 Borrego Springs, 2007

Well, actually, the Sonny Bono bird refuge at the southern end of the Salton Sea. 
plenty of bird sign, I see

Some of you have been struggling to get "notified" by email whenever something new is added to this blog but, so far, to no avail.  Well, it turns out that there is a reason - apparently only I have control over that function, not you.  You can "Follow" all you want and it won't do a lick of good.  So now I have added immediate relatives to a list to be notified by email whenever anything happens.  You chosen few should get alerted to this post as soon as I finalize it.  I can still put about a half dozen people on the list, so if you want on email me.  Please just email me; don't add a Comment here or the chosen few will read it.  My email address is myrlbeck@msn.com.  First come, first served. 

EAT YOUR GREENS, Myrl Jr.!

Linda, her mother, & unidentified friend.  1987

A brief and airy blurb in Quest, the quarterly magazine of Fred Hutch, drives what should be the final few nails in the coffin of food supplements as a preventative for cancer.  Well, maybe some will work, but the following don’t.

Multivitamins:  Of no earthly use (for cancer prevention.)

Vitamins E and D:  Likewise

Vitamin D + selenium:  Downright dangerous if taken in enough quanitity.  (Of course, you can say that about anything.)

Fish oil:  Jury still out.  Noted that Eskimos, who eat ~20 times as much ometa-3 fats as we southerners have fewer instances of diabetes and heart disease.  Another study suggests, but cannot yet prove, that the same fat is associated with less incidence of cancer.  Of course,  Eskimos also are smaller than us, wear much more fur, probably eat less, live closely with dogs, and are generally cold.  So which difference is key?  Stay tuned, I guess. 

The bottom line:  Shop in the produce section and not in the drugstore.

GEMS OF "WISDOM" YOU MAY HAVE MISSED

First year in our new house (1987)

We could only afford one chair

I have been writing fairly long “Comments” to earlier posts, usually based on something new or interesting I’ve stumbled upon – but something that doesn’t merit a post of its own.  It occurs to me that, as only three of you are “Following” this blog you may not know of their existence.  On the off chance that you want to read these comments, here they are:

A rant about too much paper work, under” Let’s Get Real.”

A few words about chemotherapy-induced cognitive impairment (chemo brain), under "CIPN:  Who needs it?”

Another comment about aspirin, under “Aspirin to the rescue?”

Several comments, some amusing, under “Men Only: the prostate cancer wars.”

Another attempt to be funny while talking about biology: miRNA & Intelligent Design, under "MicroRNA: A potential break-through?  Also, more good stuff about miRNA in a second comment.

Another comment, possibly ill-advised, about chemo-brain.

And yet another comment on chemo brain and its durability

If you would only “follow”, I wouldn’t have to do this.

CIPN: Who needs it?

 Linda really did like Egypt, but she wasn't overly fond of camels.

Linda was treated with taxol- and platinum-based drugs.  Her first course of chemo was successful, in that it knocked down her CA125 level to a number well within the normal rate.  For six months she felt great.  It was during that time that we went to Egypt.  She enjoyed that trip very much; much more than she had expected to do.  Even the camel ride didn’t faze her.  However, there was one lingering result from chemo that wasn’t so pleasant –chemotherapy-induced  peripheral neuropathy.  In keeping with all medical articles I have read, I will now introduce an acronym - CIPN.

During her first course of chemo Linda’s fingers tingled and, I think, sometimes hurt.  (Brave and loving as she was, she wouldn’t always tell me how she felt.)  She had CIPN.  CIPN affects 20 – 30% of cancer patients.   Sometimes it goes away (it did with Linda), but sometimes it doesn’t.  Occasionally, it gets worse.  Cancer patients have enough to contend with, without having to deal with unnecessary pain.  That’s why this news is important.  During Linda's time with CIPN it was hard for her to quilt - but, of course, she did.  Her courage was amazing.


A randomized clinical trial (sponsored by whom? – it doesn’t say) reported in the NCI Cancer Bulletin  found that a drug (duloxetine; sold as Cymbalta) reduces discomfort from CIPN to a statistically-significant extent.  If I understand the article, duloxetine is approved for PN caused by diabetes, but not for CIPN.  Let’s hope this study prods the FDA to get its bureaucratic butt in gear.   

MUSINGS: Pretty boring stuff, I'm afraid

 

The late '60s look.  Deep Thoughts, Happy Thoughts
Also, fashionably short skirts

I am at Fred Hutch, reading things I only partially understand, and occasionally going to a window and admiring the sunshine and springtime blossoming visible outside.  I should be home, tending to my garden – but I’m not.  I sure hope I’m doing some good here.

Some of the things I am reading (and partially understanding) are research proposals.  In nearly every instance my eyes glaze over when I get to the “methods” sections, but part of the rest I understand and can comment on.   Here are some comments.

Cancer research is damned expensive.  Many of the gene-sequencing and “proteomics”  or “metabolomics” surveys I read about must be conducted on machines that cost roughly the equivalent of a battleship.  In my former line of work – paleomagnetism – measurements are made on a “cryogenic magnetometer”, after treatmens using things like a “non-magnetic oven” and/or an “alternating field demagnetizer”.   All this is conducted in a special room which has the earth’s magnetic field reduced to near-zero intensity.  All of this sounds expensive and, in a way, it is.  When I was active, during the late Pliocene, I could never aspire to such extravagant machinery.  It was only with the coming of Bernie Housen that we could afford some of this stuff.  We now have one of the best paleomagnetism labs on the West Coast – the PNWPL.  (I use this acronym to get back at the biologists who may read this blog – in the articles I have been reading every fourth word is an acronym, and not all of them are defined.  PNWPL stands for Pacific Northwest Paleomagnetism Laboratory.)  I suspect that the total cost of the equipment housed in the PNWPL would nearly pay the sales tax on some of the gadgets we have on the top floor of this building. 

Cancer research is highly inductive.  This contrasts fairly sharply with what I used to do.  (Most geologists proceed this way.)  Having noticed something geologically strange, I would sit down and ponder on possible explanations  for its strangeness.  Having done that, I would then ask myself:  “If reason A is true, what would be some other geological consequences – that is, if A is right, then shouldn’t something else have happened?”  Then I’d go out and check to see if it had. If it hadn’t, I’d go on to possibly explanation B.   I call that the semi-deductive approach to science.  Actually, that’s the way you are supposed to do it.  Probably most geologists have a preferred explanation in mind from the beginning, and they will fight hard for its verification.  Only if A really, absolutely doesn’t work will you turn to B. 

The inductive method works more like this.  You identify a “problem”.  (As a problem, cancer will do.)  Possibly guided by your knowledge of the biology of cancer, you identify as many suspicious molecules as possible, and then determine if they actually are extra-abundant in cancerous tissue.  This requires massive studies, requiring the machines aforementioned.  Having thus identified the suspicious molecules you next can: (1) use them for biomarkers – warning signals – of cancer; (2) begin to study what they do so you can figure out a way to stop them from doing it.  I have a preference for this later stage of cancer research, because it may lead eventually to the Holy Grail: prevention and/or absolute cure.

Cancer research relies on statistics to an enormous degree.  To do inductive research properly one needs very large data sets.  Enormous data sets are the playground of statisticians.  They give us  rules by which such sets are interpreted.  They tell us with what confidence one can make certain assertions based on the data set.   They help us to design empirical experiments that are likely to yield interpretable results.  They keep us humble by using terms like “parametric empirical Bayesian longitudinal algorithm.”  When I die, I want to be reborn a statistician. 

Many enormous trials cost so much money that only a drug company can afford them.  A Phase 3 trial may have thousands of participants.  If each one is to be given a course of medication costing $1000, then very quickly the cost rises above $10⁶.  Even in today’s economy that’s a load of money.  However, if a drug company has a drug that it is fairly certain will work, it might gladly fork over the wherewithall – and rebuild the investigator’s lab on the side.  I suspect that if Pfeizer has funded your research, built you a lab, and perhaps even paid part of your salary, it would be damned hard to tell them that their drug is crap.  After all, even scientists are human.

I have  lots more to say, but I have work to do.

MicroRNA: A POTENTIAL BREAK-THROUGH? Maybe so

In 1981.  Courting days.  

I have been reading about these little buggers a lot lately, and I think they’re exciting.  They may help “clinicians” decide what treatments to use in cases of advanced ovarian cancer (OC), they may serve as early-warning signals, enabling doctors to get at the tumor before it spreads – and they may even give us a clue as to what causes OC, possibly facilitating prevention and/or cure.  Let’s hope.

 

Many of you are far more familiar with RNA and protein synthesis than I will ever be, but let me start with a little background.  Proteins do almost everything worth doing in our bodies.  The blue-prints for the thousands of proteins we need are encoded on our DNA molecules in the form of sequences of four “nucleotide bases”, A (Adenine), G(Guanine), T(Thymine), and C(Cytosine).  To make a protein, an RNA molecule is created by “reading” the DNA sequence, then goes to a strange object called a Ribosome where it is read in turn, to form a protein.  The process of transcribing the DNA blue-print onto what is known as a messenger RNA is called “transcription”, for fairly obvious reasons.  The RNA molecule – called a “messenger” RNA, mRNA  - may undergo all sorts of complicated modifications thereafter, before arriving at at the ribosome, where it in turn is read, leading to the construction of a protein molecule.  As the “language” of proteins (strings of amino acids) is different from that of DNA and RNA (strings of nucleotides), this last step is called “translation”.  As anyone who has had Biology 101 will recognize, this is a gross over-simplification.

 

The typical mRNA may be many hundreds, even thousands of nucleotide bases long.  Recently, a species of RNA has been discovered that is much shorter than mRNA – average length about 22 nb.  These are called microRNAs, abbreviated miRNA.  They were found first in a tiny worm, but now are known to be in virtually everything, so long as it’s alive.  There are hundreds of them.  One thing they do is to modify some mRNAs “post-transcriptionally”.  Sometimes they even “silence” the mRNA, so that some protein or other doesn’t get built.  They were discovered only a decade or so ago, and their functions are still being investigated.  They tend to be “up-regulated” in some kinds of cancer.  They can be detected and their abundance estimated by use of blood samples.  They may serve as “oncogenes”, by suppressing generation of proteins that would signal cells to die.  Heck, who knows what the little things can and can’t do?  I keep trying to learn about them, but I tend to get stymied by sentences such as “*A similar situation has also been described for one mammalian miRNA, mirR-196; the near perfect base paring between miR-196 and Hoxb-8 directs cleavage of Hoxb-8 both in mouse embryos and in cell culture⁴⁴”.  Mice, again.  Where would we be without them?

If I turn up anything exciting, I’ll post it as a comment to this blurb.   

(*On a quick-read-thru I find that I can almost understand this sentence.  Believe me, there are much worse.) 

LET'S GET REAL!

Linda and Amanda, 1987

She loved babies.

I am writing this at the Hutch, as a break from my real work – “QC-ing” a bunch of forms. To” QC” is to do Quality Control on various official documents.  This activity involves either re-entering the data, then letting the computer system compare the original with your effort, or actually going over the form with the original data in hand, checking to see if all adds up.  Either way, it is pretty boring.   If any errors are detected, somebody with a pay grade far above mine does the fixing.  I take comfort in the thought that, if I weren’t doing this, somebody of real value to the outfit would be doing it.  All this caution and care is dictated by the granting agencies and whatever governmental committees or task-forces  are responsible.  I guess it’s all worthwhile.   Sometimes I amuse myself by imagining Bob Butler and Bill Dickinson QCing forever, as punishment for their multitude of scientific transgressions.  (That’s an in-group joke.  Don’t ask.)

What I really want to write about is secrecy, privacy, the hobbling of medical research, and the destruction of trees.   Start with trees.  Long ago, when we went to the doctor, we were greeted by a nice lady who knew our name and told us: “Sit down.  Doctor is running a bit late.”  Often the “bit” turned out to be 45 minutes, or seemed like it, but there were always magazines from the previous decade to keep us amused.  Nowadays, of course, after you identify yourself and state your business you are asked to make an immediate co-pay, then given a thick pile of forms to fill out – no time to read magazines.  The forms ask for information that you gave them just last week.  Almost invariably one of the forms concerns privacy – you are asked to confirm that they – the medical establishment you are visiting – have informed you of your rights to privacy.  I suppose that if one were to ask for such information one would be given yet another sheaf of papers to read.  I don’t know; I’ve never asked.  All I know is that an awful lot of paper is used to no obvious human benefit.  I hope it’s all recycled.

Which brings me, finally, to what I really want to talk about:  I may be wrong, but it seems to me that an excessive concern with privacy and “patients’ rights” is threatening to throttle medical research.  I was aghast to learn the following:  Patient A may contribute blood and/or tissue samples for medical research.  These samples, having perhaps been used for their initial purpose, live on in our freezers (or those of many other medical research institutes.)  Someone, sometime later, decides to study something else.  Let’s say that the original study was to determine the efficacy of CA125 measurements for early detection of ovarian cancer.  Later, it is decided to check for the presence of microRNAs in the blood, also as an early-warning signal.  Before A’s samples can be used, she must be contacted and asked for permission: even if she had originally donated the samples for something as non-specific as “medical research”.   If A has died, her family must give permission.  If her family can’t be located, tough luck.  I have it on good authority that California – that fertile breeding-ground for bad ideas – is introducing some new rules that are particularly pernicious and that  promise to make finding cures for cancers and other bad things slower, more expensive, and – conceivably – impossible.  All in the name of privacy.  Can it ever transpire that a person, having given blood or tissue for study of one medical problem, would balk at the use of those same samples for another study?  I don’t think so.  Is all this another example of CYA, in response to the pack of malpractice lawyers circling the campfire, as I suggested earlier?  Or is there really something important here that I don’t get?  Comments, please.        

LINDA'S TEAM, Part 3.

Linda & Carolyn, the '70s look.

Are they sisters, or what?

I think we have it all figured out.  On Sunday, July 22^nd, Linda’s Team (meaning all of you who can come) will gather at Marine Park in Bellingham.  I have the shelter reserved for four hours: 10:00 am to 2:00 pm.   As we are having this event in lieu of driving to Seattle to do the Summerun (starting at 8:15 am!) some of you may want to do a run or walk.  We suggest walking/running from Marine Park into Fairhaven, then taking the trail to Boulevard Park – and back.  That should be about 3 miles or so.  Those of you who don’t feel athletic can just hang around the shelter and help me put things together.  We can eat around noon. 

The following items will be provide:.  Hotdogs, buns, and a grill or two to cook them on.  Also, the usual condiments.  Soda, plates, utensils, cups.  Potato salad.  And lots of good cheer.  We’d like to make this a potluck, so bring anything else you think might be enjoyable – including healthier stuff to grill, if hotdogs don’t strike you as health food.  We have the place until 2:00 pm, so we can sit, talk, and drink more pop.    Excellent weather is guaranteed.

As this is a fund-raiser for the Marsha Rivkin Center for Ovarian Cancer Research, please consider doing  the following*.  Go to http://www.summerun.org/.  Punch the button “Donate”.  When asked where you want your donation to go, choose “Linda’sTeam”.  Choose the amount you want to donate, feed them your credit card number, and hurray: you are an unofficial member of the team.  Note, do not “JOIN” the team.  If you do they will use part of your donation to pay for the hoopla accompanying the event.  As we are not going to get to enjoy the hoopla, we don’t need to pay for it.  If anybody tries this and it doesn’t work, please tell me and I will try to figure out what I told you wrong.

As with most events, there is a T-shirt.  And, as with most things in life, it costs money:  $22 to be exact.  (If we get lots of orders it will be slightly less.)  The T-shirt was designed by Carolyn and is gorgeous – and in teal, the official color of ovarian cancer.  To see the shirt and order, go to http://www.customink.com/signup/11nscvbr.  The deadline for ordering is July 1^st.  To pay for your shirt, either send the money to me or to Carolyn and we promise to get it to the shirt people. 

We (Carolyn, Florence, Myrl) hope to see you there, and those of you who can’t make it will be missed.

*Note that you can donate and not come, or vice versa.