"Personal" Genomics...Part 2

Rather than amend or append my post on "personal genomics" from earlier today, I thought I would provide a new one that expands on the "personal" genomics thread.

But this time, it is not about privacy, confidentiality or other kinds of ethical concerns, per se. Instead it goes right to the heart of the matter of "just how useful will this information be to the average person", average meaning a person at 'average' or 'slightly above average' risk for a disease.

Some details of a very interesting study were released today at the Annual Meeting of the American Association for Cancer Research (AACR) in Chicago (meeting website here), and published simultaneously in the journal Science Translational Medicine. Authored by a team at Johns Hopkins in Baltimore and led by world-famous researcher Dr. Bert Vogelstein, the study, entitled The Predictive Capacity of Personal Genome Sequencing suggests that the information that might be provided could actually be of limited usefulness.

Rather than me trying to paraphrase the whole thing, I refer you to an excellent article by Gina Kolata in the New York Times today (Study Says DNA’s Power to Predict Illness Is Limited) that offers an excellent recap.

For a second viewpoint, but same conclusions, you can check out this column from  Robert Bazell entitled "Gene tests: Your DNA blueprint may disappoint, scientists say" online also today at msnbc.com

Bottom line, it seems to me, is that we really have to be more careful than ever about exposing ourselves to privacy, confidentiality, insurabililty and other legal and ethical dilemmas, especially if the risks might outweigh the gains in many, if not most, cases.

Clearly there is no definitive pronouncement to be made one way or the other yet - it is far too early days for that. But it is good to have these debates with our eyes wide open.

Sure beats the alternative...

More About "Personal" Genomics

No, I didn't make a mistake in the title. I know we talk about genomics and personalized medicine a lot, but in this case I really was referring to "personal genomics". We need more conversations, discussions and debates about how we as a society are going to deal with the inundation of personal gene and DNA information that is coming our way in the brave new world of $1000 genomes.

I have already written some on the subject in a previous post about the promise and the concerns.

I have also provided some links last week to some further information on the subject.

This week saw (at least)  two new entries into this important discussion that I thought were worthy of passing on.

The first of these was a wonderful show on the series "Nova" from WGBH Boston called "Cracking Your Genetic Code".  I thought it was a particularly good treatment of the whole science behind genomics and personalized medicine. If you missed it, or can't get it, for now the show is available online at http://www.pbs.org/wgbh/nova/body/cracking-your-genetic-code.html.

I really encourage you to invest the hour watching this show - it is excellent in my view.

The other is a particularly good article written by Christine S. Moyer of the (American Medical Association) Amednews.com staff. In this piece she writes more about the issues of what are we going to do with all of the information that we might be gleaning very soon. Entitled "Genome sequencing to add new twist to doctor-patient talks", it is written from a health care, ethical and societal point of view - exactly the debate that I have been insisting that we have not been having  nearly enough of.

I am very glad to see that these discussions are expanding and that the issues are starting to come out on the table. We owe it to ourselves to become much better informed and to steer this brave new world or else it will swamp us!

Society, Ethics and Cancer Genomics

In one of my earlier posts (you can read it here), I talked about some of the major societal issues that face us in ethics, health services and health policy arenas (to name but a few), now that we are about to turn the corner on the $1000 genome.

I know that I am not the only one (not by a long shot), who is concerned about these important issues) but it was gratifying today to learn that the US Presidential Commission for the Study of Bioethical Issues is taking up the charge. I will be following this to see what happens....

See a report from Bloomberg News.

Personalized Medicine [Part 2] - Time for a Reality Check?

Despite the enormous promise of personalized or precision medicine coming from the  genomics era, I think we need to collectively take a deep breath and also ponder the reality of just how far this new technology can take us.

Without in any way diminishing the huge potential of the "$1000 genome" era, I think there are at least two important areas where we need to do a reality check.

 The first of these I have already written about - the need for debate in society about how we want to view privacy and confidentiality, and how are we going to deal with the influx of personal, genetic information that could overwhelm and confuse us despite good intentions to the contrary.

The second area stems (no pun intended) from the reality that cancer is, at its heart, a set of diseases marked by tremendous  genetic instability. The reason that so many cancers are hard to treat is because every time you think you have it pinned down, it morphs into something a bit different.

For example, when a number of the first Gleevec patients started to relapse, the sound of people jumping OFF the bandwagon was an audible thud. Skeptics said "see, we knew it couldn't really work so easily!" Subsequent studies showed, however, that Gleevec indeed worked exactly as advertised, but in the interim, the cancers had “evolved” – they developed some secondary mutations that essentially allowed the Gleevec roadblock to be bypassed.  If  you put roadblocks up on the main highways, cancer will find a way to take a side road to get out of town. If you block the side roads, cancer often will find some other route.

So, the advent of an international consortium like ICGC  that is  so very powerful, coupled with the fact that gene sequencing costs are spiralling downward, leads us logically to anticipate a new era of personalized and precision medicine. The idea is out there that if every patient’s tumour could be biopsied and his/her cancer genome sequenced so that we can determine and understand the underlying genetic defects, then we will be able to choose a tailored therapeutic regimen to treat that patient and his/her cancer in a more targeted way than ever before possible.

But that kind of future scenario depends not only on “cheap” sequencing technologies and an enormous database of mutations associated with cancers (both of which are now or will soon be in our reach), but it also depends, at least in part, on one other crucial factor. If we do a biopsy on a patient’s cancer, are we confident that what we will learn will be sufficient to give us the depth and detail of understanding that we need so that we can put this therapeutic precision and personalization to the test?

As is so often the case with cancers, the answer is, maybe…..

Why the hedge? Because we haven’t yet fully accounted for the idea that tumours are undoubtedly NOT homogeneous, that is, they do not have a uniform structure or character. There may well  be many different types of cancer cells even in a single patient’s cancer. We call this “tumour heterogeneity” which in simple terms means that the tumour may be a “dog’s breakfast” of different kinds of cells and different kinds of mutations.

As Dr. Dan Longo wrote in an editorial entitled Tumor Heterogeneity and Personalized Medicine in the March 8, 2012 issue of the New England Journal of Medicine:  

“A new world has been anticipated in which patients will undergo a needle biopsy of a tumor in the outpatient clinic, and a little while later, an active treatment will be devised for each patient on the basis of the distinctive genetic characteristics of the tumor,” he wrote.  “But a serious flaw in the imagined future of oncology is its underestimation of tumor heterogeneity.”

This “complication” came to the fore earlier this month with the publication of a very important study, entitled IntratumorHeterogeneity and Branched Evolution Revealed by Multiregion Sequencing published in the same New England Journal of Medicine issue. 

That’s a very technical title, and indeed a very specialized and technical paper, but the bottom line of it is this: a team of researchers led by Drs. Marco Gerlinger and Charles Swanton from London, UK found that there was an astonishing degree of genetic variation in biopsies from the same tumour from the same patient. In fact, multiple biopsies taken from single patients with kidney cancer (renal carcinoma) showed that there were many different mutations in each biopsy, and that not all of them showed up in all of the biopsies. In fact, the majority (over 60% of the mutations) did NOT show up across all of the biopsies.

Even worse, the researchers found that the mutations and gene “signatures” found in one region of the tumour were consistent with what we would currently have said is a good prognosis, whereas gene “signatures” found in a different part of the very same tumour were consistent with what we would have expected to be a poor prognosis!

This study, if typical for other tumours, suggests that a simple, i.e., non-invasive biopsy of a limited region of a tumour might NOT be at all sufficient to proceed with a very targeted therapeutic regimen. What if we targeted treatment to the wrong cells, cells that maybe by chance only represented 10% of the tumour?  What if we chose not to treat aggressively based on an ostensibly great prognosis from the biopsied material, only to find out later to our detriment that we were fooled by a “sampling error” of lamentable proportions?

So, bottom line, looking at both sides of the coin of "personalized medicine" (e.g., this post and the previous post), what does this all mean?

Are genomics, DNA sequencing and the building of mutation databases of enormous proportion tantamount going to lead us single-handedly to the Holy Grail of cancer treatments? Hardly.

Does the Swanton et al. study on genetic variation in kidney cancers mean that we are wasting our time with  the pursuit of genomics and precision cancer therapies? Again, hardly.

Like all things cancer, black and white approaches are simply not the way to go. This may be a bump in the road, as some have alluded, but if it is, it is not the end of the road by any means. We will learn some breathtaking insights from genomics, but it will be only one powerful tool in the arsenal, not the whole answer.

As one blogger eloquently put it in describing the kidney cancer study (Jessica Wapner, March 9, 2012, in a PublicLibrary of Science blog)

“It’s for this reason that the idea of personalized medicine—and here we are talking specifically about drugs targeted against the genetic make-up of an individual cancer, not about a whole-person regimen for life based on your personal DNA quirks—is one that has to be held with a long-view. It took decades for the first useful chemotherapy drug to be discovered. If we absorb the notion that targeted therapy is still in its nascent stage, then this new study isn’t a bump in the road, but rather another description of the scenery.”

Personalized Medicine [Part 1] – The PROMISE...

Whether you call it personalized medicine, or precision medicine, or whatever, the promise of the $1000 (or less) genome has captured the imaginations and aspirations of the public and the research community alike.

This excitement is not ill-considered. One can assume that there are going to be vast improvements in our ability to prevent, diagnose, treat and cure cancers as we learn more and more about the mutations that drive the diseases.

As  Colin Hill contributed to Forbes on Feb 9, 2012 in his post “Beyond the $1000 Genome on the Forbes website.

“Larger availability of complete genomic data will have a profound near-term impact on cancer research. The ability to rapidly and economically sequence individual patient tumours will help us to better understand the biological mechanisms of cancer and will facilitate data-driven patient stratification. This, in turn, will facilitate more effective clinical trials and speed the development of new therapies.

The significant near-term growth of rich genomic data will impact the patient care side too. Companies ... will use this data to perform molecular analysis of tumours that will assist in pinpointing the optimal treatment strategies for individuals with cancer.”

But of course, no matter how cheaply it can be done, sequencing a single patient’s genome is not going to tell us much if we don't know what we are looking for. How will we know a “bad” mutation from a “neutral” mutation? As we saw with Craig Venter’s genome, his natural amount of genetic variability, and presumably yours and mine as well, is very high, and yet Craig Venter is by all accounts a healthy man.

Well, the supposition is that if we look at enough DNA sequences of enough cancer patients then a pattern will start to emerge and we will start to see certain mutations showing up over and over. How many will there be? Will some mutations be more directly linked to actual “causation” of the cancer (so called “driver” mutations) or will some be there as a consequence of the cancer and not actually involved in the origin or progression (so-called “passenger” mutations). Will we be able to tell the difference?

Answers to these crucial kinds of questions require a lot more data than we currently have. And that is where and how the International Cancer Genome Consortium (or ICGC) was formed.

Inaugural Meeting of Genome Scientists in Toronto 2007

Much like the Herculean world-wide effort to collaborate in determining the very first human reference genome sequence, the ICGC is also a massive consortium (website at http://icgc.org/) . The ICGC is a consortium not so much of scientists but of whole countries. The consortium was formed in 2008 after an inaugural meeting (Toronto) and report in 2007, to bring a global effort to bear in sequencing enough genomes for each of perhaps 50 or more types of important cancers so that we could start to answer some of the questions posed above. It is estimated that perhaps several hundred genome sequences derived from patients with any individual type of cancer may needed in order to be able to have statistical confidence of which mutations may indeed be the “drivers” vs. those that may simply be the “passengers”. If you consider the effort, and cost, of sequencing hundreds of genomes for each of perhaps 50 types of cancer, you start to see the enormity of the task, and why a consortium of countries in needed.

The ICGC is therefore funded in the main by governments and government agencies (federal and provincial here in Canada) of countries, along with some notable cancer charities and other funders. Each participating member country of the consortium is expected to invest at least $20 Million overall to that country’s activities. Furthermore, a commitment to fully, openly and quickly share ALL data with other qualified researchers world-wide is an absolute requirement for membership.

The secretariat of the ICGC is in Toronto, at the Ontario Institute for Cancer Research (OICR; http://oicr.on.ca), and Dr. Tom Hudson, an internationally renowned genomics researcher who is President and Scientific Director of the OICR heads the Executive.

OICR also operates the main data coordination centre for the consortium. Tom took me on a tour of the OICR server room about a year ago and I can tell you it is like something out of the movies :) The air conditioning costs alone for  just keeping the server room(s) cool must be enormous!

The goal of all of this of course is to have an international database of “signatures” of dozens of types of cancers, with enough confidence that we can start to use that data to better understand cancers at the gene and molecular levels, and be better able to determine predisposition to cancers (leading to better prevention strategies); to determine better and more pin-point diagnostic and marker mutations (leading to earlier diagnosis and better interventions), and to determine many new therapeutic targets for treating and curing more and more cancers.

In Canada, we have taken a leadership role for three different types of cancer – Pancreatic Cancer (ductal adenocarcinoma of the pancreas; collaborating and funding organizations can be found here; Brain Cancer (pediatric medulloblastoma; collaborating and funding organizations can be found here; and Prostate Cancer (adenocarcinoma of the prostate; collaborating and funding organizations can be found here.

 

Whether the ICGC actually achieves all of its lofty goals is of course yet to be fully seen. What is clear is that a major undertaking like this brings out what I consider to be the very best in science and scientists: the desire and willingness to not compete but instead to openly collaborate, to share data, and to work for the common good in ways that no single researcher or even a single country could manage.

This is so-called “big science” at its best and we should all be pleased that it is being undertaken in the international arena, and in the collegial and cooperative manner that it is.

Welcome to the World of Genomics... [Part Three]

In the last post [World of Genomics Part 2] I tried to give you a flavor of just how far and how fast the science of genomics has progressed in the last decade. We are truly getting to a point where an individual human DNA sequence will be available for $1000 or less.

There is also increasing prospect of what is called “direct to consumer" products where you will be able to order your genome from a company on the Internet without any intervention by your physician. In fact, I suspect this is already happening in limited ways but will pick up steam very soon as the affordability continues to drop.

As much as the technology will afford us an unprecedented technological advance into our understanding of human diseases such as cancer, it is my belief that this era of “cheap” genomes is also ushering in some unprecedented questions of ethics and law that we are not yet facing head on, and need to start debating and discussing as a society ASAP.

Top of the list perhaps are issues of privacy and confidentiality. 

Where is your genome sequence going to be stored? I could imagine an app on your smart phone in the not so distant future! Do we really want to have our genomes floating around in cyberspace? Do we trust some central database (e.g. a government database) to house this information? I will wager that many of you already feel uncomfortable about the fact that the CRA in Canada or the IRS in the United States holds so much informational power over you by having your detailed tax records and related files in their databases. I cannot imagine a piece of information more personal or more confidential than my own detailed DNA sequence; will I really trust that it will be kept secure on the Internet or in someone's file cabinet?

The privacy and confidentiality issues lead us then to questions such as insurability. Suppose an individual is carrying seven particular mutations that might, and I stress might, predispose them to a particular disease. And suppose that information is now made available to an insurance company, and as a result life insurance or mortgage insurance or some other form of insurance is denied because the risk is deemed to be unacceptably high? What happens then?

What, in fact, does “predisposition to disease" really mean anyway? In the vast majority of cases this is not a clarion signal that the disease will develop. It merely says that you MIGHT need to take different levels of precaution than your neighbour in order to prevent or avoid that disease from occurring in the first place.

And if your doctor is able to determine from your mutational status that you have a predisposition to some particular disease, what about your “need to know” vs. your “right to know”? In some jurisdictions, such as France, the obligation of a physician to disclose this information is enshrined in law, as I understand it. In the US and in Canada there are no such regulations yet. Who is going to make the decision about when your health care professional should, or must, advise you of your mutational status, especially if it doesn't actually mean anything finite in the immediate sense of the word? If there is nothing you can do, then how important is it for you to know? Is it your right to know?

And even if it is your right to know, is it possible that we will end up creating so much anxiety and stress in individuals who learn of a particular mutational status that we will in effect “stress” them into the very diseases we are trying to prevent? The notion of creating so many self-fulfilling prophecies is very real in my view .

And then there are issues of economics and policy. The better able we are to define specific sets of mutations and to tailor treatments to those sets of mutations, it could be imagined that we will need more and more targeted drugs. While targeting and specificity are a good thing, most of these drugs are not cheap! One could rightly ask why would we be developing more and more expensive drugs when we can't even afford the ones that we have now.... 

And how will decisions be made about who has access to which drugs? We already see significant differences in Canada from province to province about cancer drugs that are paid for by the public health system in one province but are not available to patients in a neighboring province.

And from a policy maker's point of view, it could be fair to ask "how much is X months of someone's life worth?" If an expensive drug can prolong a cancer patient's life by six months, for example, who makes the decision about "at what cost"? I can easily see that if the patient in question is your mother, or your son, or your sister etc. then you might justifiably argue that ANY cost is worth it - you are prolonging the life of a loved one.

But if you are the Minister of Health and you have to look at this in terms of benefit vs. cost to society at large, you no doubt will need to look at this more objectively and dispassionately.

The answers to these kinds of questions will come from new kinds of cancer research, but it won’t be in the usual laboratory settings. Instead, we need to accelerate our efforts into research in:

  

•  health economics of cancer
• how will money be best spent?
• health services research
• how will services be best organized?)
• health policy research
• how will information be provided to policy makers for best use?)
• ethics research
• how will resources and access to service be maintained in the fairest way for all patients? 
• how will we protect vital personal and confidential information? 
• who owns the data? 
• who defines a patient's “need to know” vs. "right to know”?)  

The point is, that we are at a stage in the development of very powerful technologies that are going to create opportunities but also some very fundamental ethical issues that I do not believe we are ready to deal with at the societal level.

There have been a few other technological “tsunamis” that have broken on society and changed our world irrevocably in the past. One of these was of course the advent of nuclear technology and all of the good and ill that brought with it. 

Another was the development of recombinant DNA technologies that brought with it the modern era of molecular biology, of which these genome science opportunities are the latest wave. I am not old enough to know what sort of public consultations, if any, accompanied our ushering in of the nuclear era, but I do very much remember some of the public debates that happened in the early 70’s around the advent of the new molecular biology.

Without in any way suggesting that the outcomes of those debates and consultations were appropriate or not, at least an attempt was made to engage the public and to inform people of what was coming, and to attempt to assess it from both a benefit and risk perspective. I don't see the same level of engagement happening now with the new genome technologies and I think it is overdue. 

These issues are too important and the ramifications are too far-reaching to not have these debates and discussions right now…

Welcome to the World of Genomics... [Part Two]

In an earlier post [World of Genomics, Part 1], I began a discussion of the powerful new world of genomics, and how this kind of technology has the potential to turn cancer research on its head. The publication in February, 2001 of a complete sequence of a full human genome was indeed a watershed event. But as I indicated, this was what might be termed a "reference sequence" in that it was not the full sequence of an individual person, but rather a compilation of sequences from around the world that were pieced together to indicate what a "typical" human genome would look like.

In 2007 another major leap forward occurred with the publication of the full genome sequence of an actual living individual human being. The individual who contributed his DNA for this purpose was a familiar name to those who were following the world of genomics: Dr. Craig Venter.  

Craig Venter's Chromosomes

Dr. Venter has been one of the pioneers in this field, and was one of the principal architects behind the sequencing of the first human genome. Since I don't know Dr. Venter personally, I cannot comment on whether the contribution of his DNA to science was an act of supreme selflessness, or one tinged with egotism, or both, but it did help to pave the way for another major chapter in the unfolding world of human genomics.

 

By sequencing Dr. Venter's genome we learned many, many important things. First of all, we learned that he has 23,224 genes to be precise!

Far more importantly for our basic understanding of human genomes was the fact that almost half of his genes had variations or mutations of some sort. The genetic diversity that was shown was several-fold higher than anyone would have imagined prior to seeing the actual sequences.

Indeed, the day after Dr. Venter's sequence was published, Carolyn Abraham wrote in the Globe and Mail newspaper (September 3, 2007) that 

"the full human DNA sequence of one healthy middle-aged man is a boggling array of genetic quirks, burps and hiccups".

She then quipped, perhaps whimsically, that "there are 7 billion more humans to go".

I can't say whether or not her tongue was planted firmly in her cheek when she wrote that last comment, but I can tell you that it may have been more prophetic than she knew at the time. Consider that the original human genome program that culminated in the 2001 publication of the reference sequence was a truly international effort that probably took over 10 years to accomplish at an estimated cost of perhaps as much as 1-3 $Billion.

Contrast that with the fact that the determination of the Venter genome took far less time and far less money, perhaps in the order of $10 million. Of course, that is still a huge amount of money but compared to the original project, a significant improvement.

Where can we expect the future costs to be?

Genome scientists have been 100% correct in their assertion that the costs will continue to go down dramatically. Will they ever get to a point where we can see genome sequencing on a much more widespread basis? One look at the graph below suggests that this indeed will be the case, and probably very soon! 

The graph is courtesy of the National Human Genome Research Institute in the United States, and it shows how the cost per genome has been steadily going down over the last number of years. You will see a line on the graph called "Moore's Law". You may be familiar with Moore's Law from the world of computers, where the principal is that the number of transistors per square inch on integrated circuits had doubled every year since the integrated circuit was invented. In other words, computing power approximately doubles every two years.

On this graph, you see an inverse variation of that general concept, because in this case the cost of determining a genome is going down by approximately half every two years. Notice however, that right around the time of the determination of Craig Venter's genome there is a huge downward shift in the curve and the cost per genome has been plummeting ever since (note the log scale - this is an exponential decline!). This is due in the main to new technologies for automated sequencing that have truly revolutionized the field.

To emphasize the point, a company called Life Technologies based in Carlsbad California announced in January of this year that they will be debuting, later this year, an automated sequencing machine called the Ion Proton that will be capable of determining the entire sequence of a complete human genome in less than one day for a cost of less than $1000!

While $1000 is not exactly pocket change for most of us, it does put this into the realm of many other medical tests that might be done today. In other words, is not out of the question that your own doctor may one day be ordering a test for you that will see the complete determination of your genome as part of your doctor's diagnostic regimen.

So, what is the significance of all of this, aside from it being an astounding technological achievement? What it promises is an unprecedented understanding of human genetic variation, human disease (including cancer) that will also teach us much about predisposition to disease, including cancer.

This is where the idea of personalized cancer diagnosis and treatment comes truly to the fore. Instead of a "one-size-fits-all" approach with a cocktail or treatment "off-the-shelf", imagine instead the opportunity to treat your cancer taking into account your genetics and your specific underlying mutations. This idea of much better tailoring your treatment to your specific cancer mutations is the basis of "personalized" medicine that you have no doubt been hearing more and more about in the popular press lately.

Does this truly mean that every single person will be treated differently than every other person? Although one might actually think so based on some of the hyperbole that has accompanied this technological breakthrough, this is in fact not a reasonable extrapolation, in my opinion. Instead, what will be done is to better group individuals to ensure that the treatment that they are getting will actually benefit them.

We already know that many cancers that might appear to be the same to a classical pathologist under a microscope are not actually the same to a molecular pathologist once the genetics and specific gene mutations are better understood. And we also know that based on those specific sets of mutations, that some patients will benefit from certain therapies while others will not benefit at all. Rather than treat everyone the same we will increasingly be placing patients into subgroups to make sure that the treatments they are getting are actually going to produce positive outcomes. Perhaps this is why there is a growing trend away from the term "personalized" medicine and a growing adoption of the word "precision “medicine instead.

I think that there is also a huge significance in terms of the way it is going to impact society, and that is not necessarily all positive. More on that in the next post...

Welcome to the World of Genomics... [Part One]

Although chronic myelogenous leukemia (CML) which is the main target of Gleevec, would not be considered one of the "major" cancers, I consider Gleevec to be the "poster child" for rational cancer drug design. I think that its importance goes far beyond CML but really creates a "proof of principle" that this kind of approach really will pay huge dividends in the future.

But as I stressed in the last post, approaches like this can only work when we understand more and more at the gene and molecular levels exactly what are the nature of the mutations that underlie particular cancer diagnoses. Which brings us to the brave new world of genomics…

With the success of drugs like Gleevec, combined with huge advances in technology, the field of cancer genomics is exploding and researchers around the globe are trying to catalogue as many cancer-causing mutations as we possibly can. So, what exactly is the study of genomics, and why should we care?

To understand cancer genomics we need to step back and understand what exactly is meant by the "human genome". Simply put, the human genome is the full collection of genetic material in each one of us.

You will recall that normal human beings have 23 pairs of chromosomes, and these chromosomes are comprised of long strands of DNA. If you remember your high school biology you will remember that DNA is comprised of four different chemical building blocks which we abbreviate as "A", "T","C", and "G". In each of our genomes there are about 3 billion(yes, that's billion with a 'B') of these building blocks arranged along each of the 23 chromosomes, but in a very particular order for each unique individual. It is this unique sequence of your DNA that defines the genes that make you an individual, different from me as an individual, different from your friend, different from your siblings etc. So, genomics is simply the study of the genome, and our attempts to understand how differences in the sequences of DNA contribute to human life and to individual variation.

So why is this important for cancer? Simply put, cancer is a disease of genes and mutations, i.e., mistakes in this “DNA alphabet”. The more and more we understand the genome alphabet and the more we learn about the different mutations that are associated with cancer, the better able we will be to understand, prevent, diagnose, treat and even cure cancers.

Now we have known about some fundamentals of DNA for a long time. The famous paper in the journal Nature by Jim Watson and Francis Crick was, after all, published on April 25, 1953! But knowing about some of the fundamentals of DNA is not nearly enough until we developed some tools to really study this in detail. Fast-forward from the famous publication by Watson and Crick about 25 years and you find me, as a postdoctoral fellow at the University of Calgary, doing some sequencing of DNA genes. In those days, in the late 70’s, I would have been able to routinely analyze a few dozen base pairs of DNA at a time, and that would have typically taken me several days to perhaps a week in order to accomplish. When you're dealing with 3 billion base pairs, this is very slow progress indeed.

Let's put the genome challenge in perspective in a different way. The human genome is comprised of about 3 billion base pairs. If your job was to read aloud your own genome starting from one end of chromosome number 1 and going all the way to the tip of chromosome 23, how long would it take you to read your own DNA sequence? Let's assume that you can read at the rate of about five bases per second, and that you work eight hours a day straight, five days per week (I'll give you your weekends off!), and you do this 50 weeks per year. How long would it take you to read your own DNA sequence?

The answer is something in the order of 84 years!! More than a lifetime for many of us…

So when I tell you that on February 15, 2001, the same prestigious scientific journal Nature (the one that published the original Watson and Crick paper in 1953, published a paper from an international consortium of scientists that reported, for the first time in history, the entire DNA sequence of a human genome, I think it's more than fair to say that this was a truly monumental accomplishment.

In fairness, this was not the full DNA sequence of a particular individual - that would come later - but rather what could be termed to be a “typical" sequence or a "reference" sequence. It was created via a precedent-setting, historic worldwide scientific effort, combining the efforts of many, many researchers and laboratories around the world, and stitching together bits and pieces of human DNA sequence to form this prototypical reference sequence.

While I personally don’t consider this accomplishment to be the absolute holy Grail of molecular biology,  I cannot over stress how pivotal, historic and important this accomplishment was. It lays the very groundwork for an unprecedented understanding of human life, genetic variation, and even human disease. And it will have a profound impact on how we view cancers, and how we deal with cancers.

In a future post, I will show you just how far we've come even since 2001 when this first reference human genome was published, and by doing so, give you a glimpse into a future filled with optimism and excitement, yet one that we may not be quite ready for…

The era of rational drug design begins…

In a previous post I talked about barn doors and picking locks: how we need to get far more specific and selective in recognizing how to kill only cancer cells and leaving normal cells intact. Let me continue the lock and key analogy just a little bit further.

Suppose you found an old trunk in the basement or in the attic and it was secured by a huge padlock and you had no idea where to find the key. You could search through every key in your pocket or on your key ring, you could look in that little junk drawer in the kitchen that we all have or you could ask all of your neighbours to bring their keys to see if any of them might fit the lock. But that would be like kissing thousands of frogs in the hope of finding one Prince!

That might be great for children's fairy tales, but it isn't what a logical, thinking person would do. I’ll bet you’d call a locksmith who would be able to design a new key for the lock and get you into your trunk. (Actually, you might be prone to get a pair of large bolt-cutters and destroy the lock, but play along with me for the sake of the mind experiment!)

A few years ago anew drug called Gleevec hit the market and was the embodiment of this lock and key analogy. Gleevec was a drug that was targeted at a particular kind of cancer, a leukemia called chronic myelogenous leukemia or CML.

We had known for a long time that CML was characterized by an abnormal chromosome fusion. A small piece of chromosome 9 gets fused to a piece of chromosome 22 and creates a new DNA sequence at the point of fusion that does not exist in normal cells. It just so happens that this new DNA sequence encodes a new protein that is comprised of two pieces of two proteins that normally never see one another. A small part of a gene called BCR from chromosome 22 gets fused with a gene called ABL on chromosome 9. It is the over-expression of this new hybrid protein, not surprisingly called BCR-ABL, that creates the cancerous condition.

If you think of this new hybrid protein as a lock, then think of Gleevec as a specific key that fits into this lock and actually shuts the activity of the protein off. The abnormal protein is effectively stuck in the “on” position, and Gleevec interacts with a critical part of the protein and basically turns it into more of an “off” position. When the new abnormal proteins is no longer abundantly produced, the cancer effectively goes away…

The diagram below shows a schematic of this process. The green “ribbon” is a 2-dimensional approximation of what the CML abnormal protein looks like and the small molecule in red(Gleevec) is shown in the critical pocket of the protein where it interacts to turn it from “on” to “off”.

From a patient’s perspective, what is even more remarkable is that this new drug, that works so specifically, actually comes in a simple capsule. Take a pill, cure a cancer. How elegant is that?

That all sound good in theory. Does it really work?

Well there are countless patients alive today who will tell you that it does. Take Mr. Jason Blake, for example. Many of you will remember Jason Blake as a star hockey player for the Toronto Maple Leafs. Blake was diagnosed with CML a few years ago and was treated with Gleevec. By most accounts of the day, he barely missed any games and continues to play today, now with the Anaheim Mighty Ducks. In January 2010 when he was traded from Toronto to Anaheim, he was naturally asked about his cancer. According to an article in the L.A. Times on January 31, 2010, he said “"It's basically forgotten about now. I take a pill as someone would a vitamin every day...   At the end of the day, I never think about it. It doesn't affect me.“

Pretty hard to ask for a better outcome than that!

But realize that this kind of success of so called “rational drug design” or designing a key to fit a lock, ONLY can happen if you know what the lock looks like in the first place. No more kissing thousand of frogs, but you HAVE to understand at the molecular level what is the specific mutation or mutations that are the root cause of the cancer, and then isolate or design a specific drug that targets that/those mutation(s).

This is why we are beginning an era of trying to catalogue as many cancer-causing mutations as we can, in as exquisite and fine detail as possible, and why the era of “precision medicine” or more “personalized medicine” is firmly upon us.

More about that to come...

Picking The Lock…

Most everyone has heard the old adage that the three most important things in real estate are "location, location, location".  If you were to use a similar approach for cancer therapeutics it might be "specificity, specificity, specificity".  To my mind, 'specificity' may be the single most important attribute for any cancer therapeutic to be maximally effective, and therefore the search for absolute specificity is in many ways the Holy Grail of cancer research.

Why do I say this?  To start with, there is a myth in the public's mind that it is difficult to kill cancer cells.  Frankly, this is nonsense.  Generally speaking, it is very easy to kill cancer cells.  What is difficult is killing ONLY cancer cells and leaving normal cells unscathed. This is where, by and large, cancer treatments of the past have failed us. 

But aren’t anti-cancer drugs, by their very name and nature anti-“cancer” drugs? There is where a second misconception enters the fray: that most chemotherapeutic agents have been specific anticancer drugs.  Actually, for the most part, most of the “classical" chemotherapy agents have in fact been drugs that interfere with cell division as opposed to being anticancer drugs per se. In fact, most of these drugs of the last generation target rapidly dividing cells, not necessarily only cancer cells. 

While it is very true that most cancers are comprised of rapidly growing cells, unfortunately they are not the only cells in the body that divide rapidly. For example, for those unlike myself were not follicularly challenged <smile>, your hair cells divide rapidly and replenish quickly. The cells in your digestive system and your gut are being replaced at a very fast pace.  And the cells that populate your blood system are also dividing quickly and on a constant basis to provide a (usually) never-ending supply of blood cells of all sorts.

By now, you can probably see where I'm going with this.  What are the major side effects at we usually associate with chemotherapy?  Your hair falls out, you get sick to your stomach, and more often than not you get anemic.  That's because the normally rapidly-dividing cells in your hair, your gut and your bloodstream are also under attack. The chemotherapeutic agents interfere with their rapid division in much the same ways they interfere with the rapid cell division of cancer cells.

So the trick is to discover and develop treatments that recognize truly unique properties of cancer cells, i.e., properties that are not shared with non-cancer cells. Simply targeting rapidly dividing cells is no longer be adequate (not that it ever was...).  We need to discover better signposts that define and identify cancer cells as opposed to normal cells.  We need to find new ways to make cancer cells stand out from the crowd, ways that make cancer cells scream out at us "I am the cancer cell.  Don't waste your time with those other normal cells. Take me!"
 
Look at the two accompanying pictures: I like to think of this as the old barn door analogy.  No longer is it acceptable to do a scatter-shot at the side of the barn in the hopes of hitting the barn door.  Now we want to go in and pick the lock...

I doubt that very many of my cancer research colleagues would appreciate being called the next generation of lock-pickers, but in one very real sense that's exactly what they are! The more and more specific, the more and more targeted and the more and more selective we can make our future cancer therapeutics, the better will be the treatment, the better will be the outcome for patients and the better will be the quality of life for patients during and after treatment.

This notion of targeting and specificity will be a constant thread throughout many of the posts to follow. You've all heard by now, I am sure, of the notion of "personalized medicine" or a related term "precision medicine".  This is a very important part of the whole notion of attaining maximum specificity in the treatment of cancers of all types.