Just shuffling chairs about the Titanic

Figured that Golden Gate Mornings deserved its own space.
So, if you look to the right of the screen before you, there within "Pages" and under "Home" is "Golden Gate Mornings" where you will find the Golden Gate Mornings updates. Thanks for stopping by!

July 23, 2014: Further update. Realized that the Golden Gate Mornings page is getting way too long. So i broke it up into monthly chunks. Figure that might make it easier to read.

Sunday, April 23, 2006

Threshold

When cancer is treated with radiation or chemo, or even the up and coming antibody therapeutics, some cancer cells may survive. These surviving cancer cells contribute to the much more malignant and harder to manage recurrent disease that results in death. The reason why certain cells survive anti-cancer treatments is thus far unknown, the best that science and biotechnology can provide is that tumor cells are heterogeneous, and because of that heterogeneity, certain cells in the tumor are resistant to anti-cancer treatments. The reason for the inability for science to investigate the biology behind drug resistance lies in two places. One, the inability, thus far, for science to obtain true "cancer" cells suitable for in vitro experimentation. Second, the inability to correctly reproduce the selective pressures exerted upon the tumor cells in vivo.

The first of the two problems, the concern of the true "cancer" cell, is currently being pursued by numerous academic and industry concerns. Central to this is obscures the push for stem cell research, the hope of deriving a truly "normal" human cell "line" that can be instigated to become cancerous and allow for the study of the mechanism of tumorgenesis de novo.

The second problem, the problem of exerting the correct selective pressure, is related to the first concern. However, there is a deeper theoretical question attached to it. Were a correct cell line to be derived, what is the correct selective pressure? In that, a drug, used at a higher and higher dose, will eventually wiped out all cells exposed to it. It is a numbers game. At a small dose, the cell can adapt by changing the rate of molecule movement and the rate of metabolism to overcome a stressed or minimally inhibited process. At a moderate dose, the cell can further tax it's trafficking mechanics or alternatively, toggle it's metabolite dependence to escape the handicap dealt by an altered or inhibited process. When the dose becomes overwhelming, however, the processes sensitive to the selective pressure can no longer be ignored or by-passed, resulting in death. This dose sensitivity is called the threshold.

As we are constantly astride the threshold to cancer therapies, the threshold stares back and mocks us.

Tuesday, April 18, 2006

Chat persona

Who am i on chat? Am i the same person as i am in real life? This question came up today as i chatted away while my samples thawed slowly from deep freeze.

i think it is safe to say that i am a different person in chat than in real life. Though the difference is entirely in the outward persona. The inner self, that which contains the moral balance, the sence of right and wrong, that is not changed between real life and chat. The outward me, the me that interacts and speaks, however, is very different.

i think i am a lot less cautious in chat. i think less over what i am about to say and am less worried about my statement's effects on the recipient.

i am more flirtatious in chat. That is for certain. However, i can honestly state that the flirtation ends as soon as the keys are tapped.

i probably appear more perverted and lascivious in chat than in real life, but that is a very fine difference i think. What can i say, i am just a pervert at heart.

i think those are the major differences between the real life i and the on-line i.

Tuesday, April 11, 2006

Magic Bullet

From F. Gabor et al., Adv. Drug Delivery Rev., 56 (2004) pp459-480

At the beginning of the previous century, Paul Ehrlich attended C.M. von Weber's opera "Der Freischutz" and he was greatly impressed by the magic bullets. Max, a huntsman, fired these magic bullets in any direction an they yet reached their goal. Subsequently, Paul Ehrlich hit the idea of magic bullets as ideal drug delivery systems, which preferably recognize the affected tissue and release the drug at the intended site of action similar to guided missiles ... In the opera, the magic bullets were targeted by the devil. In reality, fortunately, the drug delivery system is decorated with biorecognitive ligands, which possess high affinity to receptors at or close to the desired site of action.

The magic bullet, the holy grail to drug discovery. Sometimes one wonders if it is just as unattainable as that mythical chalice. You see, cancer is a funny thing. Were cancer a human, Cancer would be described by it's neighbor as "quiet, kept to him/her self. Polite, you know, an average guy/gal". The police report for Cancer would be "male/female, medium height, average weight, fair coloured hair, average coloured eyes, no distinguishing features in plain view. Unassuming". Cancer would be just like any other person in all of humanity, silent, drifting quietly through the days, until such a time when Cancer awakes and goes on an axe murdering frenzy reminiscent of some of Mr. Wes Craven's finer horror films. Like some of Mr. Craven's finest, Cancer is often stopped, only for the world to realize, there is the Seed of Cancer, and the Seed is somewhere, out there, feeding like you and i, living, laughing, crying like you and i, waiting and biding for that time of activation and awakening.

True, i might just be a tad over dramatic. But i am not wrong.

So you ask, how does one find the magic bullet?Is it out there? Will it come and save us all? i certainly hope so. The more we study Cancer, the more we understand it's subtle differences from you and i. Cancer is like T-1000 (as played excellently by Robert Patrick), outwardly, it can look just like anyone of us, inwardly, there are extreme differences in various processes. The key to the magic bullet lies in discovering and uncovering of these inward differences between Cancer and us average folks. Discovering these differences will finally allow us the edge to distinguish Cancer from the background of us average folks, and allow us to isolate, nay, terminate Cancer before it's ugly awakening.

A few posts ago i rambled about my motivation for science. This is my motivation for science. This is why there is even joy in failure. Failure simply removes variables and, in its small failed kind of way, thin out the field of scientifically viable possibilities.

Monday, April 10, 2006

Guilty Pleasures

Tonight, leaving work a little early as the wife was tired after a late night out last night, we tackled our nightly question. "So... what do you want for dinner?". From the way she had asked the question, i kinda got a drift that she had a certain craving she wants satisfied. So i gave a modified version of my typical non-commital answer, "still full from lunch dear, what do you want? you crave something don't you?". Heh, if a voice can blush with embarrasement, her replie certainly did. In her wee small voice, which, when first used, gripped my heart strings and never had let go, she said, "don't judge me, i feel embarrased to say, but i have a guilty pleasure to confess... microwaved frozen bean burritos". Oh, how i laughed.

We both have guilty food pleasures really. When we are not both being slighly snobby foodies and eating our monthly pay cheque away at our favourite resturants. Her guilty food pleasure is Panda Express and frozen bean burritos. Mine resides in the realm of Burger King, Carl's Jr., and Taco H(B)ell.

Some days, some days we just crave. There is no logic or reason to it. Your mouth just crave a certain taste, and were you not satisfied... oh, the humanity indeed, were you not satisfied! Today was one such day for the wife. Started at lunch with the need for rocky road ice cream (almonds, not walnuts thank you very much!) and culminated tonight with the desire for microwavable frozen burrito (2 for a dollar at the local Safeway market, the bank account loves it too!). For her, the guilty pleasures represented the college days, when making ends meet can come down to that last dollar. The guilty pleasures represented the mall where she hung out during high school and have loved ever since. Ah! how i am most pleased that i can help her satisfy her guilty pleasures.

Though her cravings are not always for the guilty pleasures! After all, it was also that same craving, though this time for that delectable hearty southern French loveliness that is cassoulet, that allowed us to discover our favourite French bistro.

Friday, April 07, 2006

Unintelligent Design

The article

and i quote, from the article:

Dr. Behe described the results as "piddling." He wondered whether the receptors with the intermediate mutations would be harmful to the survival of the organisms and said a two-component hormone-receptor pair was too simple to be considered irreducibly complex. He said such a system would require at least three pieces and perform some specific function to fit his notion of irreducibly complex.

Dr. Behe, the "
main advocate of intelligent design", in dismissing the work reported in the article as "piddling" has made my day. i've not had such a hearty geek laugh for so long! Sigh.

The article describes the following paper published in the journal Science. The paper describe the evolutionary derivation of two hormone receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Both receptors arose from a gene duplication event deep in the vertebrae lineage.

In most vertebrates, GR is used to regulate metabolisms, immunity and inflammation while MR is used by the kidney to regulate electrolyte homeostasis. GR is uniquely specific to the stress hormone cortisol, and is regulated through the binding of cortisol. MR, on the other hand, can interact with both cortisol and another hormone, aldosterone. However, in most MR expressing tissues, a cortisol scavenging mechanism exists to render MR an uniquely aldosterone responsive receptor. The expression of GR and MR is also found in lower vertebrates, such as the skate. In more primitive animals, such as the jawless fish lamprey and hagfish, only a single corticoid receptor (CR) is present. In turn, these animals only produce cortisol, and not aldosterone. All of these receptors are responsive to the intermediary hormone, 11-Deoxycorticosterone (DOC).

The authors of the Science paper, by piecing together the genetic information from the GR and MR isolated from skates and the CR from lamprey and hagfish, "resurrected" the ancestral corticoid receptor (AncCR). The AncCR, surprisingly, is responsive to cortisol and aldosterone, and DOC, much like the vertebrate MR. The authors were able to express AncCR in vitro for ease of study. From working with all three receptor types, the authors were able to conclude that, from the AncCR, two separate single amino acid point mutations must take place to derive the two distinct receptors MR and GR. One of these mutations transformed the AncCR, normally responsive to aldosterone and cortisol, to become insensitive to both hormones but remain responsive to DOC. With this first point mutation in place, the second point mutation resurrects the cortisol binding capabilities of AncCR, transforming it into the vertebrate GR.

Cool huh? It gets better. Aldosterone is only found in vertebrates. However, cortisol and DOC are found in both invertebrates and vertebrates. Aldosterone, however, is only found in vertebrates, yet both aldosterone and cortisol are end point product to progesterone, sharing DOC as an intermediary. So, along with the change in the receptors, a transformation was also happening with hormone regulation and bioavailability. What has not been demonstrated is which came first, the change and transformation of the hormone or the evolution of the receptor.

This gets us back to why i had a good geek laugh today. Perhaps the change of two "piddling" amino acids (each with a 1 in 20 chance of being the correct change) in a 984 amino acid protein isn't "irreducibly complex" in the eyes of Dr. Behe (note: numbers used chosen by author due to laziness in calculating the probability of the occurrence if one were to look at the nucleotide sequence). It certainly is complex enough for a mere bench jockey of my limited capacities. Yes, perhaps a two component system like hormone and receptor interaction is "piddling" in the eyes of mighty Dr. Behe, but for a mere mortal like i, who understands the myriads of different intracellular signaling pathways a single hormone can alter, it is "irreducibly complex" enough. Well, let me take that back. "Irreducibly complex" enough to get my geek w00d up and pit my life and intellect into understanding it, but not "irreducibly complex" enough for me to throw up my hand heavenward and say "ummm... that person did it".

Somewhere in the evolution of the species, a hormone evolutionary step and a receptor evolutionary step took place. This change was but one piece of the whole that led to the divergence between vetebrate and invertebrate species. Enclosed in this story of evolution lies the extreme flexibility and adaptability of biology.

Thursday, April 06, 2006

Dickens

"It was the best of times, it was the worst of times"

"It was drug discovery" quipped S.

It really won't be funny if it isn't true.

Drug discovery, may as well have said military intelligence. Our understanding of human biology is pathetically poor. Ever little step we make while fumbling in the dark opens up a myriad of possible resolutions that ends up leaving one in a state of utter despair.

True, i might have been a tad pessimistic there, but only just so.

Biology, it is my second love. i enjoy every second that i spend studying it. i enjoy every bittersweet second of it. Because of that, i realize, all too bluntly, that we understand next to nothing about the human biology. The science of biology has been built on highly contrived and controlled models of limited interactions. Pathways and effects elucidated in such models becomes woefully inadequate when inserted into the background of a human being, a multi-cellular, multi-organ'd, multi-multi'ed model with no fine controls or contrivances. In the human, biological understanding elucidated in the ivory towers of academia and industry comes crumbling down. Yet we struggle on, and from the struggle we derive the joys of minute success and the bittersweet delight of failure.

It is hard to explain to someone who has never wetted their hands on a bench how much joy one derives from research. The hardest part to explain is the joy one finds in the pain of failure.

Tuesday, April 04, 2006

Reflections

It is amazing how quick three days can come and go. It was as if my wife and i had just picked CL and M up from the airport, and this morning we are ready to deliver them to C in the city and bid them a farewell. In reflection, it was time well spent. True, we indulged them, perhaps a bit too much for their and our own good. True, we played tourists and really didn't do anything "educational" or "culturally gratifying". We simply enjoyed ourselves for three days.

It was, i think, an interesting experience for my wife and i. We've never spent time with ones so young before. No, not for an extended period of time. This truth was ever more evident when CL mentioned that she was born in 1990, the year that my wife and i graduated from high school. Yes, CL could've been a biological daughter of our's. Scary, but true! M, without saying, could also then be a daughter of our's as well. The challenging part of this weekend was to strike a balance between what my wife and i were willing and comfortable to do and what CL and M wanted to do. CL and M came to our city with certain impressions of what this city was supposed to be. These impressions are collages of images taken from their friends' travels and/or their family friends' fragmented recollections. We took it upon ourself to show them a balanced view of what this city is, from a tourist's view point, and what this city has to offer, from a resident's and our biased interpretation. i think we did a banged up job!

It was also our intent to challenge them to new experiences. Be it in the form of different foods or in the form of different enviroments. i belive we achieved this goal as well, though i don't believe the message we had intended to deliver was driven home so well. What was the message? you might ask. The message simply is, for them to realize, at thier young age and limited life experiences, that an open mind will serve them better than a closed one, that the world is greater and more complicated than one's immediate contacts.

At the end of these three days, my wife and i have concluded that we would like to spend more time with CL, and show her more of our world. This is not due to any arrogance on our part, i don't think. The place we live is simply a different place from where CL is residing. Our interpretations of life is certainly very different from CL's family's interpretation of life, stemming from cultural backgrounds and life experiences. For CL to experience a change in enviroment and a change in the lens through which life is viewed will further her understanding of the world, and more importantly, herself. CL is an amazing kid, looking at her accomplishments and talking to her about her life and aspirations makes me realize how far ahead of the curve she is. i certainly was no where near as accomplished or mature back when i was 16 as CL is now in her 16th year.

Sunday, April 02, 2006

Teenagers

Preface: My mentors are C and A.

So last night my wife and i were at the airport picking up my mentor C's two teen age daughters,CL and M. It was something that my wife and i have looked forward to for a while. My wife has not seen CL and M for two years, and dearly misses interacting with them, and i simply adore spending time with the two of them. i have known CL since she was 4 years old, and have known M since she was 1 or 2. They were the first children that i have seen grow up before me, traversing from being carefree innocent children to become multi-faceted, individual and thoughtful teenagers they are today. Through that time, i must say that i've grown rather attached to both of them, and view them as blood relations, not just daughters to a very dear friend. Then again, since i view C as my surrogate father, is it a surprise that i view CL and M as younger sisters that i've never had?

Of the two of them, i have a stronger attachment to CL. We interacted meaninfully earlier on, as she is older than M, and interacted readily when i first met her.

At the time C and i were still working in the northeast, and we were, and are still, avid fishermen (well, it was because of C that i became an avid fisherman). The two of us would work full days in lab (7am to 7/8pm), head over to C's home, have a quick bite, load the fishing tackles onto the 14 foot "Ranger" that C had, and headed out into the harbor at around 10/11pm. We would fish all night for striped bass, C using lead line and flies while i was jigging away on a spinning reel. The sun rise over the city skyline would signal an end to the fishing excursion, and home we would go, to shower, breakfast, and head back to work. Because of this rather fanatical (in hind sight) fishing schedule we had, i had many opportunities to be one of the persons tucking CL into bed or reading her the bed time stories. At the age of 4, CL was already capable of reading rather intricate books by herself, so i took the habit of telling her stories from chinese mythology as bed time stories. i had figured that these stories were ones that she will most likely not read about or hear about as she grows up. They were stories i grew up with that had shaped some of my moral and ethical bearings, and in some naive way i was hoping that they will do the same for her. These bedtime interactions, and the morning "time to get out of bed you sleepy head" confrontations, allowed me and her to learn about each other quite well.

From that early point onwards, it has just been sheer joy to watch her grow up. To be able to see the changes she goes through as the world around her, the enviroment around her, and the new interactions around her grow and change has been one of my greates honor and pleasures in life. It is indeed something that is deeply personal and rewarding, even though C and i are now at the opposite ends of the country.

Needless to say, i am looking forward to spending a few days with CL and with M.

Saturday, April 01, 2006

Mentors

So my mentors are in town for a conference. Got to spend some time with them, over dinner, over drinks, and caught up on all that has happened in the time spent apart. They are two of the most important persons in my adult life, my second father and my second mother. The evening of looking back and chatting about the present was one of the most enjoyable evenings i've had in a long time.

i've known the two of them for almost 12 years now. They were the first bosses i've ever had coming out of a rather staid and unimpressive college career. In more ways than one, they gave me a focus and direction during a time in my life where my only thought was on making ends meet for the next month.


i had been doing bench research for a year or so by the time i wandered into my mentors' lab for a first interview. Though i loved what i did, the research i was doing was remarkable for it's lack of progress and insight. This was due to the fact that i had very little understanding of what bench research really was, and a complete lack of direction and a lack of knowledge. i was floundering with the best of them. When i first saw the want ad on the cummings street memo board, i had only two thoughts in mind. One, i loved research and science, and i really did want to explore what more there was out there. Two, i needed a job, i was graduating from college soon, had no future plans in mind, no career goals in mind, and three years to kill while my then girl friend finished medical school.

i interviewed in my dark navy, white pinstripped three piece suit with a red tie. Yeah, it was the 90's.

When i got the job and showed up for the first day of work, there was absolutely no expectations. i was begining a career as a lab tech. i was simply looking forward to direction, protocols, and colour by numbers work. Two weeks into the job, i knew things were about to get a lot better than i had ever hoped. My mentors are two of the most passionate researchers i have ever met in my career. They encouraged the curiosity that i had within me, but more importantly, they guided me through the first rocky weeks of the learning curve. They patiently explained to me the scope and goal of the experiment, pointed out the caveats to the experiment planning, and showed me the paper trail behind the science. With each experiment, they also made sure i understood the science behind what it was that i did. When we reviewed results and experiments, they tested and questioned me regarding why the results are interesting, significant, or even relevant.

To this day, the lessons i learned in the early days of working with my mentors stay with me. Those exercises we went through to design experiments are still used daily when i work on my current projects. They gave to me the mental tools and the analytical mental eye that allowed me to progress to where i am today. They are my mentors. To them i owe more than a king's ransom in gold and jewels.