Image of healthy tissue on the lower right (notice the orderly ring structure - in this case it's a healthy gland within the breast), while the large image is one of breast cancer. The image illustrates the chaotic nature of cancer - disorder where there was once order. Courtesy Vincent Cryns, MD at Northwestern

An interesting article appeared on NYTimes.com today that deals with “new” old approaches to the cancer thought and research paradigm. In essence, the article points to research that indicates cancer is more than just a group of genetic mutations – it’s also caused by the tiny interactions of proteins and other parts of the cell that are sometimes not genetically based.  Physical entities inside cells like proteins and other environmental aspects clearly play an important role in cancer, its prognosis and will eventually inform its treatments and cures.  At an even higher level that means that cancer is even more of a multifactorial disease – it’s far more complex than we ever thought.

The implications are that research will have to focus not only on genetics, but proteomics and cellular metabolism and physics.  An interdisciplinary approach.  However, one of the biggest problems here is that often each of these areas tend to be researched in silos – there’s not much overlap or intercommunications between research groups.  This has to change.

Thought about another way, often research can focus on specific areas for years while neglecting other important areas of research that are simply not as trendy (yes, even researchers can be petty at times).  For example, antibiotic research took a backseat to HIV/AIDS research starting in the mid 90′s, which extended up until a couple years ago.  The result is that we now have fewer new antibiotics to treat drug resistant bacteria.  We neglected one area in order to make advances in another – it’s a classic resource allotment problem as well.  Where do you place scare resources?  In this case, specifically, what research do you fund?

For cancer it’s my sincere hope that none of the individual disciplines are neglected – they all need to grow in unison and in turn inform and help each other to advance.  For example – one genetic mutation could in turn affect many different cellular processes on a metabolic level.  Understanding not only what the individual metabolic disturbances do, but how they link back to mutations and other cellular processes will be absolutely critical in understanding the disease.  These seemingly disparate areas of research will have to collaborate in order to make more breakthroughs.

Romanesco - a cross between broccoli and cauliflower. The result is a pattern that is a naturally occurring fractal - a pattern that repeats itself as you look closer and closer.

What makes it difficult now is the chaotic nature of all those cellular processes.  The cellular processes, while seeming complex today, may seem relatively simple once we gain the ‘right’ perspective, which may be many many years in the future.  It reminds me of fractals – chaos on top of chaos but from a certain perspective a pattern emerges.  And, as you go deeper you discover more and more previously unknown patterns.  If you look too closely you only see one aspect of the fractal.   If you look from too far away you might see the overall large pattern,  you’ll miss the intricacy of the smaller, repeating pattern.  An approach from both perspectives is necessary to understand the fractal.  I think the same can be said for not only cancer research, but all biological research in general.

An up close perspective of romanesco. Pretty amazing pattern if you ask me.

For biology the deeper perspective will be gained through not only new technologies but collaborations between disparate fields within biology (and potentially other sciences) that bring novel perspectives to these findings.  Tools like whole genome sequencing, biophysics modeling and the interplay between all of the fields will help transform how we view biology, which in turn will yield new insights.  Not only that, but if these currently disparate or silo’ed fields begin to collaborate my bet is that we will continue to not only make new discoveries, but continue to make them faster and faster.  And it’s not only the hard core, more quantifiable aspects of scientific research – qualitative field like clinical medicine and information from medical informatics systems will need to be included as well. But, as we know from the fractal example, the closer we look, the more we find, the more we have to discover.

Beautiful artful image of chaos - reminds me a bit of DNA. Courtesy David Nightingale @ Chromasia - http://www.chromasia.com

To get to this type of collaboration we’ll need not only advanced technologies, but collaboration tools and a willingness between researchers, corporations and other players to begin to cooperate and collaborate.  That might actually be the bigger challenge and require a whole blog post to itself (or many many posts!).  There are many perspectives in the fight against cancer and in the push to eliminate other diseases they should work harder to influence each other and promote novel ideas and create new discoveries.  I bet that approach would radically accelerate the pace of new discoveries and breakthroughs.

The bottom line for me is that I’m happy to see that these ‘old’ ideas in cancer research continue to stick around and that we have researchers and experts who continue to push the field along despite the nay-sayers.  I’m looking forward to more and more collaboration between disciplines and research groups.  And that’s no small feat.

Composite image of some of the iconic images from Apple's "Think Different" campaign.

How we frame and think about subjects clearly has an impact on how we approach and attempt to solve problems.  The first image, right or wrong, that comes to my mind is Apple’s “Think Different” campaign back in the mid 1990s. But I’m talking about the importance of perspective in a much bigger sense – we’ve defined and approached some of our biggest problems using techniques and perspectives that were modern 50 years ago.  Specifically, I’m thinking about how we diagnose, treat and research cancer.

Today we diagnose a patient’s cancer based on the tissue of origin (i.e. breast cancer, colon cancer, leukemia, etc), what it looks like to the naked eye and under the microscope, and where it has spread in the body.  The American Cancer Society has a great description of how cancer is “staged.”  Once our doctors have diagnosed the cancer, the treatment is based off of that diagnosis – most often it’s either chemotherapy, radiation, surgery or some combination of the three.  The treatment was based on how we diagnosed the cancer, which was defined on the technology we had available to better understand cancer.  But, for anyone who’s had experience with a loved one with cancer knows that the current therapies and techniques are certainly lacking – we need to do better. As a side note, the history of cancer chemotherapy is pretty fascinating and also reason for moving beyond current therapies.

The molecular structure of the origin of modern cancer chemotherapy - developed by German scientists for war in 1917 - but identified by American scientists as a treatment for cancer. It's time to advance our cancer therapies past this brutal approach.

Today we finally have better tools that enable us to better understand the core of cancer and will help us get to the root of the disease.  Genomics and informatics – the sciences of decoding DNA and then comparing different DNA sequences – are helping to transform not only how we research cancer, but in how we diagnose and ultimately treat cancer.  In theory this will lead to better outcomes for cancer patients.  If you understand the root of a disease – in the case of cancer, the genetic mutations and internal cellular processes that have gone haywire – you’ll better understand and better treat the disease.

For example, instead of diagnosing breast cancer based on exams, images and pathology slides, we’ll begin to take a sample of the tumor itself, analyze its genome and compare that to cancer genome to your healthy genome (taken from a healthy cell).  This is where the recent advances in genomics and informatics come in to play.  As we gain the ability to sequence vast amounts of DNA, we’ll greatly increase our knowledge of the genetic make up of cancers.

Specifically, genes today can tell us why the cancer has grown out of control, whether it will metastasize, and we now know it may even help predict where it will metastasize to.  But, that technology isn’t ready for clinical medicine just yet – much more research needs to be done to help us better understand the disease process.  In the future, though, instead of defining cancer by the staging system or its pathological features, we’ll diagnose a cancer based on its genetic profile.  In turn this will help us better understand the best course of treatment, the prognosis and how to prevent the disease from spreading.  My guess is that it will even help us be predictive of whether the cancer will metastasize, how fast and to where in the body.

This is a microscopic image of breast cancer (click to enlarge) - it looks pretty standard for a pathology slide, but it's also indicative of new research - the dark brown spots are cell nuclei that contain a marker that has helped to redefine how we treat breast cancer. Taken from the National Institutes of Health. Courtesy of Ronald S. Weinstein, M.D., University of Arizona.

By better understanding the genetic mechanics behind the cancer, we’ll be able to more accurately target our therapies and medications to the specific cancer.  This will drastically cut down on unnecessary side effects and ineffective therapies, and potentially lead to better and faster outcomes.  We’ll discover new therapies and drugs based upon what we discover through this genomic research. In other words, instead of using cytotoxic agents, like today’s modern chemotherapies, we’ll have drugs that are targeted to the specific genetic make-up of a cancer.  This will lead to many fewer side effects, and better patient outcomes.

Taken to the next step, we may even be able to better predict what type of cancers a person may develop based on their genetic make-up.   This knowledge will be essential in our fight against cancer.  We may even begin to better understand how to harness the power of our own immune system to target cancers.  At the foundation of all this knowledge will be genomics and our understandings of the basis of the disease.  If we have a better understanding of the genetic mechanics, then we can better define, diagnose and treat the disease.  All this advance comes from a shift in how we define and therefore understand the disease in its most basic elements.  Maybe it’ll lead to a cure, or maybe improvements in cancer therapy. It’s an exciting time in cancer research.

In PEHub yesterday an article about 23&Me and the financial issues it’s been having.  As an entrepreneur and having had plenty of great ideas poo-poo’ed by investors and industry folks alike, it’s really hard for me to understand why anyone would have invested in 23&Me as a company.  What I don’t understand is why highly skeptical VCs have invested in a business who’s central premise, while certainly desirable, is so far from reality at this point that it’s amazing anyone would invest. It’s certainly an important idea – scanning our individual genetic make-up to discern health risks and prevent them. Who wouldn’t want to understand what preventable diseases they’re prone to? I certainly would (well, to an extent – but that’s for another post).

For the uninitiated, 23&Me is a personalized genomics company that will take a couple drops of your saliva, extract your DNA and screen it for hundreds if not thousands of genetic disease markers.  The company name is derived from the 23 chromosomes humans contain – 23 from mom and 23 matching from dad. But the company over promises and under delivers.  At the end of the day, the fact is that biomedical science isn’t advanced enough yet for us to make meaningful predictions off of the information screened by 23&Me. And, to boot, there are other companies like Navigenics that have a little better model of screening, but they’re still pretty far off mark – as of yet. That said, Navigenics’ science and results are much better than 23&Me, but that’s like saying Peet’s is better than Starbucks – Peet’s may have better beans, but the coffee’s still not all that good.

A gene chip by the company Affymetrix. That little square on the chip can yield information on 500,000 different genetic variations.

Let’s dive right to the core of the issue – the biomedical science behind 23&Me. 23&Me (and Navigenics) use “gene chip” technology , which can screen thousands of genes at once and tell you where you have variation (mutations)  that are known to be correlated to disease.  In other words, if the gene chip picks up that you have a variation in a gene that has been correlated to a heart illness, 23&Me argues that you have a higher chance of developing heart disease. While that certainly seems logical – “I have a gene that shows a higher risk of heart disease, I better do something about it” – it remains somewhat misleading.

A closer look at that square on the gene chip - this is what the chip looks like under magnification when it's read by a computer. The different colors indicate different gene results.

We have to dive a little deeper here to understand why the findings from these tests don’t correlate to real disease risk. When researchers do genetic studies (the type of studies 23&Me base their tests on), most of the time they find correlations between gene variations and a disease. And I want to stress – these are correlations – and are not purely 100% causative like the genetic testing companies would like you to believe.  Put another way, these genes are found in these diseases, however they are not the root cause of the disease.  Most diseases are due to multiple genetic mutations, which means the underlying causes for these diseases are much more complicated than just one genetic mutation.

We now know of 20 genes that correlate to height, but they only explain 3% of variation in height between people. Only 3% of the difference in height between these two men! What about the other 97% of difference? More research!

For example, a study came out in the New England Journal of Medicine that detailed just how little we know about how our genes and how they become translated in to real world physical traits and disease. This review study illustrated that we know of 20 genes that correlate to the differences in height between people.  While that sounds impressive, turns out that those 20 variations explain only about 3% of the true variations in height. I’m 6’5″ – those 20 genes explain only about 1/3 of an inch of the variation in height between my 5’6″ wife and I! 20 genes!! Why then do we then think that 1 gene will detail risk for heart disease or cancer?  The bottom line is that before we can accurately correlate and make meaningful disease predictions based on genomics, much much more research needs to be done.

So, let’s come back up to the surface. I’ve detailed why genetic research to date isn’t as complete as these companies would have you believe. The personal genetic variations they uncover, while using the most advanced technology and knowledge we have, isn’t sufficient to fully explain disease risks. The companies are selling a service based on scientific misconceptions – people are accepting 23&Me’s marketing, rather than good science. And that lack of scientific and clinical substance is why the medical community hasn’t embraced these tests.

I’m going to get in trouble with these companies because they don’t directly make these claims – but I think it’s implied based on their marketing and how they discuss their product. Doing these tests even just for curiosity’s sake is even a waste of money – they don’t truly tell you anything useful.

As one caveat, Navigenics does have a much better platform than 23&Me and how they correlate gene changes to disease risk is much better than 23&Me. They do take a look at diseases more holistically – let’s say they’re screening for heart disease and for argument’s sake that they screen for 25 different genes correlated to heart disease. They take that information and integrate all the risk factors to give you a more accurate risk analysis based on population statistics. It’s a little better, but I wouldn’t spend the money for it yet.

Don’t get me wrong, these types of products and services are the future of medicine. Maybe not in this direct way, but we will be screening people for disease risk.  No, not for insurance reasons, but rather to attempt to prevent diseases before they take hold. It’s just too early for this type of genomic analysis to be accurate enough to truly act upon. Although I’d like to be an optimist, the technology isn’t there, medical practice hasn’t accepted these tests (and they shouldn’t) and the businesses like 23&Me are floundering as a result. All of this to say, as a consumer patient hold on to your money for now, the scientific community has a long way to go before we really have the information necessary to make strong clinical correlations and to make valid disease predictions.

One of the most harrowing experiences of medical school was during a surgery for a gynecologic oncology patient.  Prior to the operation we had absolutely no idea that this woman’s ovarian cancer had spread – we had only detected a spot on her left ovary.  However, during surgery we discovered that her cancer had metastasized to the lining of her abdomen (something that couldn’t be detected via MRI or CT scan).

Although experience told the surgeon this finding was evidence for a terminal diagnosis, we waited a couple days to inform the patient and her husband of 45 years because the surgeon wanted the pathology report to 100% confirm his suspicion.  After 3 days we finally informed the patient and her husband of the news.  There was really nothing we could do.  It was an absolutely heartbreaking experience.

From my personal perspective this experience, while a harsh reality of medical training, also made me want to learn more and to help save lives.  I spent time at Memorial Sloan Kettering when I could.  During my surgical rotations I usually opted for the cancer operations and office visits.  I’ve posted in the past about the US’s ongoing War on Cancer, but I think the thing that intrigues me about this disease is that there remains so much that we don’t know despite our vast experience with patients and disease.  I get this sense that there remains so much knowledge about the disease locked up in the cancer genome that with newly created DNA technology it’s finally time that we begin to unlock the mysteries of this disease. (Picture above is an electron microscope image of brain cancer cells invading healthy tissues.)

Electron microscope image of a breast cancer cell spreading "pseudopods" as it seeks out its next direction.

Indeed, this is one of the main reasons I’m so very excited about the prospect of genomic science – its crossover with cancer research and the promise that holds for better therapies and eventually a cure. Looking specifically at the genomics of cancer, a review article was published in the New England Journal of Medicine last year that summarized the details of what we currently know about cancer.  Just 20 years ago the Nobel Prize was given to two doctors from UCSF for the discovery of what we now call oncogenes.  Think about it this way – all of the cells in our body need signals that tell them when to grow and then signals telling them when to stop growing.  In cancer, the genes that typically tell the cell to grow a little bit faster are completely up-regulated (they cause too much growth) and the genes that typically put the brakes on growth stop working (effectively shutting off the brakes to growth ).  That disease dynamic makes a lot of sense since cancer is essentially the uncontrolled growth of cells.

But since that time much research has happened, and with it has come advances in cancer knowledge.  For instance, we have discovered that there are genes that actually tell cells when to die – to apoptose.  Think of that as the Control-Alt-Delete function of the body.  If something goes completely haywire, then a cell needs to be able to remove itself from the system.  However, if there’s something wrong with the apoptosis gene, then a cell is more likely to grow out of control and become cancer.

The same is true of genes that typically anchor cells to where they are – when haywire, these genes allow the cancer to detach – to metastasize.  Other genes convey an advantage to survive in other specific tissues, thus some cancers display similar traits – always metastasizing to similar, specific organs.  There are several other types of genes also thought to contribute to a cell becoming cancerous.  In a brief time period scientific and medical research went from a very limited knowledge base about  cancer to a very full and greater understanding of how this disease comes in to being.

One of the more interesting aspects is that cancer is now understood to be a disease with multiple genetic mutations.  Before, we would have looked for one or two “cancer genes.”  Today our reality is that cancer is much more complicated than the model of one gene-one cancer.  And this is a good thing.  We now understand that multiple genetic mutations are needed before a cell turns cancerous.  Growth needs to go out of control, the cell needs to split and grow like crazy, and it needs to travel from its home site. Not to mention it also has to elude the immune system!  Healthy individuals get cancerous cells every day – the difference between these people and cancer is an unfortunate set of mutations that leads to full blown cancer.

The cell at center is a cancer cell that is being attacked by the immune system (purplish cells). You can see one cell in the lower left being a "kamakazi" cell - sacrificing itself against the invading cancer. Understanding how the immune system helps to fight cancer will be a key understanding in the war on cancer.

Ultimately, what this understanding does is help us to discover that which we don’t know – we can better identify areas we didn’t know we needed to know.  As our genetic model for cancer becomes more complicated we’ll begin to better understand the disease and most importantly, make improvements in treatments and save lives. As I’ve said before, all of this research has shown us just how much we don’t know.  We need to take solace in the fact that the more complicated the true cancer genomics model becomes, the closer to savings lives we’ll be.  But there’s a lot of work and research until we make more major breakthroughs.  Fortunately for us, with the improvement in genetic and cellular research we’re closer than we’ve ever been in the past.