ANOTHER BOOK REPORT. and some incoherent babble

Linda and unidentified baby

definitely her cute and freckle-faced stage, but when was that?

 

As many of you know, I am in Borrego Springs, in the middle of the Anza Borrego Desert State Park, located in the extreme south of California.  I am avoiding the gloomier aspects of life in Bellingham, WA, which in many respects (but not winter weather) is the perfect place to live.  Carolyn (Linda’s sister) and Florence (her best friend and quilting buddy) have been visiting me for about a week.  They left this morning.  Owing to the recent residence of two women, the house is unnaturally clean, leaving me nothing in the housekeeping line to do.  It is blowing a hurricane outside , which makes me reluctant to go hiking.  So, time for another blog.

I am reading a book that I highly recommend: Genome, The Autobiography of a Species in 23 Chapters, by Matt Ridley.   Ridley is an excellent writer, if you forgive him his penchant for trying to be too cute in places.  What he has done is to take each of the 23 human chromosomes, identify a gene on it that has some interesting effect on human life – and tell its tale.  You might expect it to be tough sledding, but for the most part it isn’t.  It beats  reading vampire novels, anyway.  I like it well enough to have ordered another of his books just now.

But what I really want to talk about is breast cancer.   It has taken me the better part of a year to finally realize how closely related breast and ovarian cancer really are.  It’s not just that they are diseases of women – in fact, men get breast cancer, although not frequently.  The two conditions can be considered closely related because to some extent they result from the same genetic abnormalities: mutations in the BRCA1, BACA2  genes, for instance.  (Only a minority of breast and ovarian cancer victims have  these mutations, but a woman who has them is at much greater risk.)

 It turns out that the same external (non-genetic) factors also affect both types of cancer.  Whether or not you have been pregnant, given birth (are "parous"), breast-fed, and when in your life these things occurred, help control the likelihood of contracting both diseases.  For instance, research* described in the latest Fred Hutch newsletter shows that women who have their first baby late in life (30+, say) are less likely to develop “triple negative” breast cancer.  (Triple negative refers to the lack of “receptors” for several hormones – 3, in fact – which results in rendering the usual chemo agent in breast cancer - Tamoxifen - ineffective.  Triple-negative breast cancer is breast cancer at its nastiest.)  The statistics underlying these conclusions seem  rock solid.  Earlier I reported that having babies, and having  breast fed, reduce the risk of ovarian cancer.  This would seem to place one in a  bind: put off childbirth and lower your risk of breast cancer, but increase your risk of ovarian cancer.   As my father would have said: You can’t win for losing.  The way out of this paradox is to realize that for the most part ovarian cancer is encountered fairly late in life**.  Thus, if you have a baby early – and don’t contract breast cancer – you have improved odds against contracting ovarian.  This is getting too complicated   and I am beginning to confuse myself.  Sorry.

*by Dr. Christopher Li, of U.W. Medical.

**but sometimes ovarian strikes early.  A particular painful example is Rosalind Franklin, the woman who almost beat Watson and Crick to the double helix, who died of OC in her 30s.

 



PROFILES IN RESEARCH EXCELLENCE, 2: Heidi Gray, M.D.

 

Linda at Welburn gourd farm

She was good at gourding

She was even better at quilting

 

Remember back on  June 14^th of last year when I wrote about “chemo-brain”?  Actually I was writing about CIPN – chemotherapy-induced peripheral neuropathy, but in two Comments to that blog I introduced   CICI – chemotherapy induced cognitive impairment – chemo-brain.  Linda didn’t have it, thank God, except perhaps in her last few weeks when she wasn’t herself.  However, some women do suffer from  it, and for some of them it last a lifetime.  Thank goodness then for Heidi Gray, M.D.  Dr. Gray is one of our (MRC – Marsha Rivkin Center) grantees for 2012.  She is going to do something about chemo-brain.

What is she going to do, you might legitimately ask?  Well, I don’t rightly know.  Her MRC citation states that she “will examine the ability of a 7-week cognitive rehabilitation intervention to improve memory and thinking abilities in ovarian cancer survivors.”  Additionally, she will “measure changes in brain activity patterns from the treatment using neuroimaging”.

The reason I don’t rightly know is that nowhere can I  find what is meant  by “intervention”, precisely.  It isn’t the administration of drug; that much is certain.  Maybe if I had a proper education the matter would be clear, but I’m just a dumb geologist.  When a geologist stages an “intervention” he usually is breaking up a fight between two of his graduate students over which one gets the last  beer.

But I don’t need to know – Dr. Gray obviously is a smart cookie (actually, you probably shouldn’t refer to cancer scientists as “cookies), as is amply demonstrated  by the fact that she has been  involved in over 20 original research papers in the last five years. The work is innovative (she got an MRC grant didn’t she?), and, given her record, will be well done. She is on the faculty of the U.W. medical school.  She got her M.D. degree at UCLA in 1997.  She is fortunate enough to work with Dr. Elizabeth Swisher, who collaborates with my group at the Hutch. 

And, - I must say it – she looks like she is 25 years old.  Studying medicine and biochemistry apparently imparts a certain ability to resist time – at least to women.

 



COMPLICATIONS MULTIPLY, THE NOBEL RECEDES. But, maybe good news.

Linda went to the Borrego hairdresser.  Once.

 

I thought I had securely wrapped my noticeably aging brain around the concept of nucleic acid.  There were, I rather smugly thought, two kinds – DNA and RNA*.  DNA carries the molecular code, thus assuring that when we humans reproduce our offspring are also human, and moreover somewhat resemble us.  We do not give birth to toads or lungfish, for instance.  RNA also has important functions, chief among which is to act as a “messenger”, relaying  the information stored on  DNA to the machinery for manufacturing proteins.    DNA was double-stranded (usually), RNA mostly single-stranded. Double-stranded  DNA was shaped  in the famous “double helix”, and consisted of a sugar-phosphate backbone to which were attached nucleic acids.  There were four nucleic acids: adenine (A), cytosine (C), guanine (G), and tyrosine (T).  These “nucleotides” occur in pairs – A always pairs with T, and G pairs with C.  Hydrogen bonds between these pairs hold the two strands of the double helix together.  RNA is nearly the same, except that it usually is single-stranded, and in the place of the base tyrosine (T) was the very similar base uracil (U).

And that was that.  End of story.

Imagine my consternation then when, during a really rotten breakfast (cheese melted over last night’s spinach, on toast) I read a 25-line article in the latest The Week news magazine, the title of which was “Shape-shifting DNA”.  It appears in the Feb 8 edition, page 21.  The gist of the article is that there is some hope of using the existence of something called “G-quadruplexs” to combat cancer!  What in hell is a G-quadruplex, you might ask. I certainly did.   It turns out to be  four-stranded DNA, held together by some sort of screwy chemical bond – between guanines.  Four of these Gs form a square with another kind of an atom – a “cation”, frequently potassium – in the middle. Furthermore, there are several  varieties of these G-complex things, each with different properties and structures.  They seem  to form in stretches of DNA where there are a plentitude of guanine – our famous telomeres, for instance.  They also are abnormally plentiful in cancer cells.  Which is why this is interesting.

G-quadruplexes have been know from the laboratory for some time, but the recent work of the rather unfortunately named Dr. Shankar Balasubramanian at the Cavendish Lab, Cambridge – yes, the  same place where Watson and Crick worked – has shown that they are fairly common in human cells.  Furthermore, Dr. B has discovered that he can somehow “disable” the things, using something called a “small-molecule ligand”.   Furthermore, when the G-things in telomeres are disabled, the cell dies.  This suggests that if it were possible to target cancer cells with this miraculous ligand, we might cause cancer cells to expire, to no one’s regret.   Dr. B and his lab are working on it**.  But, as someone said about this work, “it’s early days yet.”  So, get cracking.

*Even this turns out to be wrong.  There are four species of nucleic acid.  The two others are LNA and PNA.  Fortunately these other NAs exist only in the lab, so we can forget about them – for now.  No telling what smart people like Dr. B will come up with.

**I actually know quite a bit more about G-quadruplexes, but I have a hunch you've heard quite enough already.  Also - Carolyn and Florence are coming soon and I've got to clean house.

 



 

 



THE SYMPTOM INDEX: Have I been lying to you?

Linda Joyce Beck, queen of the desert

Actually, this was on Catalina Island

 

 

Okay, let’s start with some fascinating stuff: math.

Suppose you plan to run a clinical trial to ascertain whether a particular “test” – blood marker, urine chemicals, symptoms, etc – is “useful” in detecting the presence of a medical condition.  You administer the test to a large number of people, and it either comes back “positive” (it says that the subject has the condition) or “negative” (it says he/she does not have the condition).  Of course, in a real world the test will make mistakes.  Let

TP = # of subjects  who tested positive and who do have the condition.  (True Positives)

FP = # of subjects who tested positive but do NOT have the condition.  (False Positives)

TN = # of subjects who tested negative and do not have the condition.  (True Negatives)

FN = # of subjects who tested negative but in fact DO have the condition.  (You can  guess this one)

Pretty obviously, you want your test to have as few FPs and FNs as possible.  Medical researchers calculate several  useful ratios from these statistics, viz

PPV (Positive Predictive Value).  PPV = TP/(TP  + FP)

SE (Sensitivity).  SE = TP/(TP + FN)

SP (Specificity).  SP = TN/(TN + FP)

The meaning of these things is fairly obvious.  SE tells you how likely you are to have the condition if you test positive. SP, on the other hand, tells you how likely you are to be free of the condition if you get a negative test.  Obviously, a good test would have SE and SP values close to 1.  PPV measures how ultimately useful the test will be:   you want PPV to be as close to 1 as possible. 

There:  wasn’t that fun!

I am writing this blog because I have run on some articles that report that the symptom index (SI) for ovarian cancer – which I have been pushing for nearly a year – doesn’t work.   For instance,  the PPV (for a particular study) was only .006 to .011 – meaning roughly that out of every 1000 women who tested positive using the SI, only about 10 would actually have ovarian cancer.  Thus SE and SP would both be near zero.  So: don’t use the test.

Well, nuts to that, say I.  First:  nobody intends that the SI be used unsupported by additional lines of evidence.  For instance, the studies I am familiar with merely use the SI as a trigger for more medical attention: go see your doctor, maybe get an ultrasound, etc.  Second: who cares?  Maybe it would lower overall national medical expenses if women having the symptoms ignored them instead of bothering a doctor.  From my perspective, saving (or prolonging) the lives of those ten women  is worth far more than any costs associated with those  990 unneeded visits to a doc.  Hell, the doctors probably feel good about telling someone they are healthy!  And they get paid for doing it.

One other thing comes forth from these papers: when the SI does work, the cancer probably is fairly far advanced.  What is needed, everyone agrees, is a test that will catch it when its first ugly little cell begins to divide.  That is what my group at the Hutch is working on.



Profiles in Research Excellence: DR. BRIGITTE THERIAULT

Even windblown she was beautiful

 

Eureka, 2008

As promised, from time to time I am going to “profile” a young cancer researcher; specifically, those that have received a grant from the Marsha Rivkin Center for Ovarian Cancer Research.  To kick off the series we consider Dr. Brigitte Theriault, Ph.D. 

Dr. Theriault currently works for the University Health Network, in Ontario, Canada.  She earned her Ph.D. from Dalhousie University, Nova Scotia, in 2007 at – judging from her recent youthful photo –  about the age of 16.    She later Post Doc’d at the University of Toronto.  She has published 13 papers on ovarian cancer in the last few years, received several awards (including ours – MRC) and helped organize  an important conference on ovarian cancer.  It should give us confidence in the eventual extinction of ovarian cancer that people like Brigitte Theriault are on the job. 

I would like to give you the biochemical lowdown on Dr. Theriault’s work, but – quite frankly – I don’t understand it.  Instead, I will quote from two documents describing her research – documents that quite  obviously are not meant for the likes of me.

Her efforts focused on studying how differential regulation of autocrine transforming growth factor beta (TGFβ)/bone morphogenetic protein (BMP) superfamily signalling between ovarian cancer and normal ovarian surface epithelial cells regulates cellular processes such as proliferation, adhesion and migration.  This from her Ph,.D. work in Halifax.

And this, from the MRC citation:

Brigitte Thériault, PhD

Ontario Cancer Institute

Modulation of KIF14 overexpression in ovarian cancer

Dr. Thériault's lab had previously discovered that the gene KIF14 is present in high amounts in the majority of ovarian cancers, and that patients with high KIF14 have much worse survival than patients with low KIF14. KIF14 is normally found in cells that are growing and dividing and is usually not found in adult human tissues. Her prior research in cell cultures and in animal models has shown that accumulation of KIF14 leads to tumor spread and blocking KIF14 causes tumor cell death. Dr. Thériault's goal in this project is to understand how tumors accumulate such high amounts of KIF14 so that she can find ways to block KIF14 production, stop tumor cell growth, and improve the survival of ovarian cancer patients.

All I can say is that, although I may not understand what she’s doing I can tell she’s dedicated, smart, young and energetic – and I wish her Godspeed.

 

 

 



MRC RESEARCH GRANTS

Why I married here: she could do anything.  1967
Most likely a car load of college boys came by 12 seconds later.
I know I would have stopped

Encouraged by the Comment of my granddaughter Amanda, from time to time I am going to “profile” one or another of the cancer researchers we at the Marsha Rivkin Center help support.  We (MRC) offer support in three categories, but it is clear that each emphasizes innovation.  We try to identify people who may have spied an incipient crack in the armour (of ovarian cancer), and  then  help them pry it open.  Once they are inside, we leave it to the far deeper pockets of the NIH to fight the war.  To me – I had no part in the design of any of our programs – this seems to be a remarkably promising approach.  I wish I were 30 again and a biochemist; I’d rather be one of those smart young people than simply an old guy  writing about them.  But, you do what you can with what you’ve got.

Rather than jumping right in, I will describe the kinds of grants we award.  In ascending order of dollars available, and – probably – difficulty in getting funded:   we award Scientific Scholar Awards, Pilot Study Grants, and Challenge Grants.   

 Scientific Scholar Awards:  These go to young, bright, early-career scientists.  The purpose is to enable them to try out new ideas (which the young have in profusion, I am told – I can't  remember.)  Needless to say, the ideas chosen have relevance to ovarian cancer.  A grant amounts to $60,000 for one year, which isn’t much these days but may make the difference between trying out an idea and shrugging it off.  This year (2012, actually) we gave out three of these, to young women in England, Canada, and the United States.

 Pilot Studies:  These are worth $75,000 for one year.  In 2012 we awarded ten of them.  I gather that the successful applicants tend to be better established in their field, but need help and encouragement in developing some novel approach to ovarian cancer.  One of these awards went to a scientist in Helsinki.

 Challenge Grants:  I don’t precisely understand the nature of this award, so I will simply quote what is said in the MRC Website:  “Challenge grants in scientific research revolve around posing a grand scientific question to the research community and asking researchers to submit their best ideas for meeting the challenge with creative solutions. With help from our Scientific Advisory Board, the Rivkin Center will identify areas in ovarian cancer research in which the greatest strides can be made today and offer a 2-year, $150,000 Challenge Grant to the research group that proposes the best solution.”

 The 2011-2013 MRC  Challenge Grant was awarded to Dr. David Bowtell, who works in Melbourne, Australia.  Dr. Bowtell is testing the hypothesis that ovarian tumors, especially of the most lethal type – serous – leak pieces of DNA into the blood-stream  in quantities sufficient to serve as an early marker of the disease.  Specifically, he is looking at a mutated version of the gene TP53, which apparently is associated with numerous kinds of cancer.  Incidentally, it appears that serous “ovarian” cancer originates in the fallopian tubes.

 Regarding  Dr. Bowtell’s very important  work:   as an Aussie friend of mine was fond of saying, “Goodonyah”!



ANOTHER EXCUSE TO POST A PICTURE - AND LAY A TRAP

Posing on a bridge in Inverness, Scotland, 1999

I was sick as a dog.  She went shopping.

Driving my new Jeep Wrangler in the desert is lots of fun.

This lead sentence is an experiment.  I suspect that someone or some thing (organization) is trolling through the blogosphere looking for references to something that can be sold.  At least that is the only plausible explanation I can see for the fact that my innocent little blog of October 21^st has had about five times the average number of “hits”.  It wasn’t particularly clever, or particularly important, but I did mention my nw jeep.  We will see – I will report in a “comment” in a few days.

I am taking a botany certification course, thinking about studying to become a “field master” for the paleo people, hiking in the desert whenever I can to build up some stamina, helping to re-write the geology section of the paleo  certification course, cooking my own meals, and cleaning the house every month or so.  This leaves me darned little time to pursue my principal long-term goal: to win the Nobel Prize in Medicine for curing ovarian cancer.  Besides, Dick Ingwall has been under the weather (or the NYTimes is tired of writing about medicine), and the NCI Cancer Bulletin has ceased publication. This means that I will have to do my own research!  I have some plans:  I am thinking about profiling the work of each of the young investigators that the Rivkin Center has supported in recent years.  As there are upwards of 50 of them, I can keep busy.  Soon.

But, in formulating this idea I ran onto some interesting facts.  (1) The Fred Hutch program I attempt to help has been awarded research grants of $36 million over the past 15 years (eat your hearts out, geologists!);  (2) the Research Department of the U. Michigan Department of Surgery consists of 56 people at the Ph.D. or M.D. level, which together represent well over 300 – more like 450 - person-years of post-graduate education.  We haven’t cured cancer yet, but nobody can say we’re not trying.