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.”

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...