The Curious Wavefunction

The NYT has an interesting article on the Warburg Effect and how it can be used to provide a new weapon in the treatment of cancer (the article is part of a larger series on cancer in the weekend magazine). The effect which is named after the Nobel Prize winning German biochemist Otto Warburg pertains to the fact that tumors can grow by disproportionately consuming glucose from their environment. More specifically it deals with anaerobic respiration in tumor cells which allow them to persist even in the absence of oxygen.

This is clearly a mechanism that could be potentially targeted in cancer therapy, for example by blocking glucose transporters. But more generally it speaks to the growing importance of metabolism in cancer treatment. It seems to me that since the 1970s or so, partly because of discoveries regarding oncogenes like Ras and Src and partly because of the explosive growth in sequencing and genomics, genetics has become front and center in cancer research. This is a great thing but it's not without its pitfalls. In the race to decode the genetic basis of cancer, one gets the feeling that the study of cancer metabolism has fallen a bit by the wayside and is now being resurrected. In some sense this almost harkens back to an older period when cancer was conjectured to be caused by environmental factors affecting metabolism.

It's gratifying therefore that things like the Warburg Effect are being recognized. As the article points out, one of the simple reasons is because while many (frighteningly many in fact) genes might be mutated in cancer, a cancer cell usually has only a few ways to get energy from its surroundings: the range of targets is thus potentially fewer when it comes to energy. The recognition of this effect also speaks to the commonsense view that we should have a multipronged approach toward cancer therapy: genetics, metabolism and everything in between. Judah Folkman's idea of starving off a cancer cells's blood supply is another approach, what we may call a 'mechanical' approach (all of cancer surgery is a mechanical approach, in fact).

I could not help but also note the interesting coincidence that this tussle between emphasizing genetics vs metabolism has played out in another area which seems quite far removed from cancer medicine: the origin of life. For the longest time people focused on how DNA and RNA could have been formed on the primordial earth. It's only about 20 years ago or so that "metabolism first" started getting emphasized too: this approach emphasized the all important role that the evolution of life's energy generating apparatus (in the form of proton gradients and ATP) played in getting life jumpstarted. The metabolism first viewpoint really took off with the discovery of deep sea hydrothermal vents which can generate primitive energy-creating biochemical cycles based on proton gradients, alkaline environments and diffusion through tiny pores in the vents. Biochemists like Nick Lane and Mike Russell have been pioneers in this area.

The renewed focus on metabolism in treating cancer as well as in exploring the most primeval characteristics of life seems to me to bring the study of life in both health and disease full circle. Just like you cannot discuss the genetics of life's origins without discussing life's source of energy, so can you also not disrupt cancer's spread by disabling its genes without disabling its source of energy. Both are important, and emphasizing one over the other seems mainly to be a function of research fads and fashions rather than objective scientific reasoning.

As an amusing aside, the father of a very close friend of mine knew Otto Warburg quite well when he worked in Vienna in the 50s. Here's what he had to say about Warburg's scrupulous lab protocols: "One story I've always remembered was that he would clean his own glassware, used in experiments. He didn't trust any low-level dishwasher or junior staff around the lab. He wanted to make sure everything was perfect. I can confirm that even a tiny 'foreign fragment' in glassware can wreck an experiment."

I read this book in one sitting, long after the lights should have been turned off. I felt like not doing so would have been a disservice to Paul Kalanithi. After reading the book I felt stunned and hopeful in equal parts. Stunned because of the realization that someone as prodigiously talented and eloquent as Paul Kalanithi was taken from the world at such an early age. Hopeful because even in his brief life of thirty-six years he showcased what we as human beings are capable of in our best incarnations. His family can rest assured that he will live on through his book.

When Breath Becomes Air details Dr. Kalanithi's life as a neurosurgeon and his fight against advanced lung cancer. Even in his brief life he achieved noteworthy recognition as a scholar, a surgeon, a scientist and now - posthumously - as a writer. The book is a tale of tribulations and frank reflections. Ultimately there's not much triumph in it in the traditional sense of the word, but there is a dogged, quiet resilience and a frank earthiness that endures long after the last word appears. The tribulations occur in both Dr. Kalanithi's stellar career and his refusal to give in to the illness which ultimately consumed him.

The first part of the book could almost stand separately as an outstanding account of the coming of age of a neurosurgeon and writer. Dr. Kalanithi talks about his upbringing as the child of hardworking and inspiring Indian immigrant parents and his tenacious and passionate espousal of medicine and literature. He speaks lovingly of his relationship with his remarkable wife - also a doctor - who he met in medical school and who played an outsized role in supporting him through everything he went through. He had a stunning and multifaceted career, studying biology and literature at Stanford, then history and philosophy of medicine at Cambridge, and finally neurosurgery at Yale.

Along the way he became not just a neurosurgeon who worked grueling hours and tried to glimpse the very soul of his discipline, but also a persuasive writer. The mark of a man of letters is evident everywhere in the book, and quotes from Eliot, Beckett, Pope and Shakespeare make frequent appearances. Accounts of how Dr. Kalanithi wrested with walking the line between objective medicine and compassionate humanity when it came to treating his patients give us an inside view of medicine as practiced at its most intimate level. Metaphors abound and the prose often soars: When describing how important it is to develop good surgical technique, he tells us that "Technical excellence was a moral requirement"; meanwhile, the overwhelming stress of late night shifts, hundred hour weeks and patients with acute trauma made him occasionally feel like he was "trapped in an endless jungle summer, wet with sweat, the rain of tears of the dying pouring down". This is writing that comes not from the brain or from the heart, but from the gut. When we lost Dr. Kalanithi we lost not only a great doctor but a great writer spun from the same cloth as Oliver Sacks and Atul Gawande.

It is in the second part of the book that the devastating tide of disease and death creeps in, even as Dr. Kalanithi is suddenly transformed from a doctor into a patient (Eliot helps him find the right words here: "At my back in a cold blast I hear, The rattle of bones, and a chuckle spread from ear to ear"). It must be slightly bizarre to be on the other side of the mirror and intimately know everything that is happening to your body and Dr. Kalanithi is brutally frank in communicating his disbelief, his hope and his understanding of his fatal disease. It's worth noting that this candid recognition permeates the entire account; almost nothing is sanitized. Science mingles with emotion as compassionate doctors, family and a battery of medications and tests become a mainstay of life. The doctor finds out that difficult past conversations with terminal patients can't really help him when he is one of them.

The painful uncertainty which Dr. Kalanithi documents - in particular the tyranny of statistics which makes it impossible to predict how a specific individual will react to cancer therapy - must sadly be familiar to anyone who has had experience with the disease. As he says, "One has a very different relationship with statistics when one becomes one". There are heartbreaking descriptions of how at one point the cancer seemed to have almost disappeared and how, after Dr. Kalanithi had again cautiously made plans for a hopeful future with his wife, it suddenly returned with a vengeance and became resistant to all drugs. There is no bravado in the story; as he says, the tumor was what it was and you simply experienced the feelings it brought to your mind and heart.

What makes the book so valuable is this ready admission of what terminal disease feels like, especially an admission that is nonetheless infused with wise acceptance, hope and a tenacious desire to live, work and love normally. In spite of the diagnosis Dr. Kalanithi tries very hard - and succeeds admirably - to live a normal life. He returns to his surgery, he spends time with his family and most importantly, he decides to have a child with his wife. In his everyday struggles is seen a chronicle of the struggles that we will all face in some regard, and which thousands of people face on a daily basis. His constant partner in this struggle is his exemplary wife Lucy, whose epilogue is almost as eloquent as his own writing; I really hope that she picks up the baton where he left off.

As Lucy tells us in the epilogue, this is not some simple tale of a man who somehow "beats" a disease by refusing to give up. It's certainly that, but it's much more because it's a very human tale of failure and fear, of uncertainty and despair, of cynicism and anger. And yes, it is also a tale of scientific understanding, of battling a disease even in the face of uncertainty, of poetry and philosophy, of love and family, and of bequeathing a legacy to a two year old daughter who will soon understand the kind of man her father was and the heritage he left behind. It's as good a testament to Dr. Kalanithi's favorite Beckett quote as anything I can think of: "I can't go on. I will go on".

Read this book; it's devastating and heartbreaking, inspiring and edifying. Most importantly, it's real.

Linus Pauling holding enough rope to make sure we can hang ourselves with it if we don't run the right statistically validated experiments

1. A decade ago, MIT biologist Robert Weinberg who has been a contender for the Nobel Prize for his discovery of oncogenes wrote a seminal article in Cell called "The Hallmarks of Cancer". This article which became the highest cited article in Cell ever laid out the myriad ways in which a cell circumvents normal regulatory mechanisms to metamorphose into a monster. Weinberg and co-author Hanahan now follow up with a second "Hallmarks of Cancer" review in Cell to take stock of the ensuing decade's major discoveries and their implications for our understanding of cancer. It's a must read.

Cancer has emerged as a fundamentally genetic disease, where mutations in genes cause cells to go haywire. Yet, finding out exactly which mutations are responsible for a certain type of cancer is a daunting task. A recent report in Nature which details the cataloging of tens of thousands of mutations in tens of thousands of tumors illustrates the merits and dangerous pitfalls of such an approach.

The article talks about the International Cancer Genome Consortium (ICGC), formed in 2008, whose task is to coordinate an international effort spread across different countries, where every country has the responsibility of documenting significant mutations in certain types of cancer. For instance, the US is doing 6 types including brain and lung, China is doing gastric, India is doing oral and Australia is doing pancreatic. The process would involve sequencing tens of thousands of genes from tumors. The goal is to find out all the mutations that separate cancerous cells from normal ones.

Yet this goal immediately runs into David Hume's well-known problem of induction. If a mutation in a gene is observed in, say 5% of tumors, would it be observed in all of them? More importantly, would it be significant as a causative agent? Consider the IDH1 gene which encodes isocitrate dehydrogenase, a key enzyme in the all-important Krebs cycle. As the article notes, IDH1 was not regarded as significant when it initially showed up in a very small subset of certain kinds of tumors. But then it consistently showed up in 12% of brain tumors of a certain kind and 8% of tumors from leukemic patients. Thus, rather than being a chance occurrence, IDH1 now seems like a significant correlative factor for cancer. It is now hot cancer genomic property.

But this is just the beginning, the very beginning. Evolutionary biologists are very well familiar with the problem of determining which mutations- called "drivers"- are causative for a given phenotype, and which ones are just "passengers". One of the biggest mistakes that "adaptionists" can make is to assume that every genotypical change somehow provides a selective advantage, when the change could just be riding on the back of another significant one. Identifying and cataloging thousands of mutant genes says nothing about which of those are truly responsible for the cancer and which ones have just come along for the ride. As a researcher quoted in the article says, "it's going to take good old-fashioned biology to really determine what these mutations are doing".

And I think we can all agree that's its going to take a lot of good old-fashioned biology to accomplish this. Firstly, one has to determine the function of the mutated gene by doing knockout and other experiments, and endeavor fraught with complications. Maybe it codes for a protein, maybe it does not. Even if it does, one then has to identify the function of that protein by finding a suitable system in which it can be expressed and purified. Structure determination may be another hard obstacle on the path to success. Finally, if any kind of therapeutic intervention is going to be attempted, one would have go first find out whether the target is "druggable". And then of course, the long and wildly uncertain road towards finding a small molecule inhibitor only begins.

Even assuming that all this happens, there is no guarantee that hitting the enzyme will produce a therapeutic response. Maybe the enzyme that is mutated is part of a complex pathway of signaling, and maybe one has to really hit something upstream or downstream to actually make a difference. And of course, hitting the target may cause a difference, but it may not be therapeutically significant enough. Thus, it's pretty clear that this project is far from curing any kind of cancer at this stage. What we just described is light years ahead of what is being currently done. Plus, it's worth noting that this is data that is extremely heterogeneous, collated from a variety of populations, potentially subject to the capricious standards of individual agencies and workers. It's nothing if not a statistician's nightmare.

So is the effort worth it? Undoubtedly. Sitting among those haystacks of mutations is the valuable one that may actually be causative. We are never going to identify the culprit if we never line up the suspects. But here, much more than in a police lineup, it is easy to be seduced by statistical significance. The pursuit of the wrong gene could easily mean the loss of millions of dollars and countless hours wasted. The researchers who have descended into this quagmire need to be more careful than Ulysses on their tortuous journey toward the discovery of important cancer-causing mutations. It is all too easy to slip on a stone and chase the wrong rabbit into the wrong rabbit hole. And there are countless number of these at every step.

As Yeats might have rephrased a line from one of his enduring poems, "tread softly, because you tread on my genes".

Ledford, H. (2010). Big science: The cancer genome challenge Nature, 464 (7291), 972-974 DOI: 10.1038/464972a

The New York Times has a rather chilling account of how radiation overdose in the treatment of some cancer patients caused deadly side effects leading to death. The entire sobering article deserves to be read. In one case a man's tongue was going to be selectively irradiated; instead his whole face received a blast of radiation that led to a horrible, slow death. Scott Jerome-Parks's story makes for very painful reading. In another case, misguided radiation beams literally cut out a hole in a woman's chest that gradually killed her. This was Alexandra Jn-Charles. Both Mr. Jerome Parks and Ms. Jn Charles died within a month of each other in 2007.

And all this mainly because of computer errors that were not detected by human beings, errors that caused the radiation to be overdosed or misdirected. Seems like one of those classic "technology is a double-edged sword" kind of scenarios with the whole system just becoming too complex for human understanding. In one instance, a wedge in a linear accelerator delivering the radiation was supposed to focus the beam in the "in" position. But the computer that used Varian software- the same software that I used in grad school for operating the NMR spectrometer built by the same company- made a mistake and instead pivoted the wedge to the "out" position, removing the radiation shielding. The mistake was not detected 27 times, leading to acute radiation overdoses in the wrong parts of the body. In the case of the man whose tongue was supposed to be treated, an error in the software failed to save the critical settings for the accelerator which would have focused the radiation to the right parts. The computer repeatedly crashed, leading to the collimator beams being left wide open, and nobody noticed this.

The statistics unearthed by the Times are startling. From 2001 to 2009, more than 600 cases of improper radiation treatment were reported. Out of those, 255 were related to an overdose, while 284 were related to the wrong parts of the body being exposed to radiation. Even in its idealized form radiation has side-effects, so one would assume that doctors and technicians would be deathly serious about operating these protocols. These statistics were collected for New York State, which is apparently supposed to have some of the strictest radiation standards in the country.

What is even more shocking is the lack of transparency due to "privacy laws". Names of the culprits have been withheld, and some of them seem to have been let off the hook with a simple reprimand. St. Vincent's hospital and University Hospital of Brooklyn, where the two accidents had happened, were simply fined a thousand dollars by the city of New York. Some doctors who have participated in the treatments refused to talk to the journalists. There also does not seem to be a single agency responsible for these radiation safeguards. On top of it all there seem to be scant ways for patients to pick beforehand which hospital they would like to receive radiation treatment in, since records of mistakes are not available to the public. The whole shebang sounds appalling.

Now I understand that 600 cases in 8 years is probably small potatoes compared to the total number of cases in which radiation has worked successfully. Nonetheless, the factors responsible for the lapses and the horrendous consequences deserve scrutiny (seriously, death due to "computer error" sounds like something out of a bad science fiction horror movie). For something as serious as radiation treatment for cancer, one would assume that the same kinds of safeguards, fail-safe mechanisms and backup checks would be in place as are used in nuclear reactor safety. What boggles my mind is that there exist no fail safe mechanisms which would simply shut down the system when they detect an overdose. It simply seems that shoddy training, computer error, and lack of accountability are dealing out death and enormous physical and psychological suffering to patients and their families.

James Watson has an interesting op-ed in the NYT in which he advocates a return to biochemical methods for studying cancer. Watson thinks that while genetic studies of cancer will continue to provide important insights, we need to focus on the basic chemical reactions underlying cancer cell proliferation to come up with new therapies. I find this emphasis on chemistry gratifying, and others have also criticized the undue attention given to genetic studies of the disease. While such studies are and will remain undoubtedly important in elucidating the nature of cancer in individuals, it is only through detailed studies of the biochemical machinery of cancer cells that we can really find out the true nature of future targets for therapeutic intervention.

Watson also advocates emphasizing combinations of drugs instead of the largely single driver paradigm accepted currently. What is a little concerning for me that he does not really talk about toxicity and selectivity; there is usually a good reason why the FDA is loathe to approve combinations of chemotherapeutic agents that might cause lots of side effects. Watson seems to envisage an age when cancer, like heart disease and diabetes, might be able to be managed as a chronic disease. While this is a laudable goal, the nature of cancer compared to other chronic diseases is clearly different; it's far more invasive and involves a far trickier set of fundamental processes to understand and control (although diabetes is also not exactly the simple ailment it was initially thought to be)

Curiously, the example that Watson provides for emphasizing the biochemical basis of cancer seems to me to be potentially replete with selectivity issues. Consider this:

The idea that cancer cells may be united in having a common set of molecules not found in most other cells of our bodies was first proposed by the great German biochemist Otto Warburg. In 1924, he observed that all cancer cells, irrespective of whether they were growing in the presence or absence of oxygen, produce large amounts of lactic acid. Yet it wasn’t until a year ago that the meaning of Warburg’s discovery was revealed: The metabolism of cancer cells, and indeed of all proliferating cells, is largely directed toward the synthesis of cellular building blocks from the breakdown products of glucose. To make this glucose breakdown run even faster in growing cells than in differentiated cells (that is, cells that have stopped growing and taken on their specialized functions in the body), the growth-promoting signal molecules turn up the levels of the “transporter” proteins that move glucose molecules into cells.This discovery indicates that we need bold new efforts to see if drugs that specifically inhibit the key enzymes involved in this glucose breakdown have anti-cancer activity.

While this is definitely an interesting observation, I am not sure how productive in terms of selectivity and toxicity would targeting glucose metabolizing enzymes be. Glucose metabolizing enzymes constitute about as universal and fundamental a set of proteins as you could find in living organisms. Unless there are specific proteins with specific mutations present only in cancer cells, I can see a really big selectivity problem in targeting such proteins. Now of course we have had success in targeting all sorts of proteins that are expressed in both cancer and normal cells (consider kinases like VEGF), but still, it would be very interesting to see whether hitting such a basic part of the cellular machinery can actually provide tangible benefits.

In any case, the goals that Watson expounds on- a return to biochemistry, a balanced focus on pure and applied research, more flexible FDA guidelines for developing combination therapy, and the final goal of making cancer a chronic disease- are all sensible. The dream of winning a "war on cancer" is almost as unrealized today as it was in 1971, but maybe now we can feel confident that we are actually marching toward the front lines.

Stay thin to cut cancer, study says

I am having a fantastic time in London. Details later, but what struck me the most is the incredible friendliness, helpfulness, and most importantly open-mindedness of everyone we met. A large group of people whom we met consisted of doctors and clinicians who are directly involved with cancer patients. I was surprised and very happy to see that these people, with little to no experience with synthesis or modeling, were extremely open to collaboration including both these disciplines.

This is exactly the kind of culture we need to see to fight cancer and other ailments, where everyone from doctors to modelers to synthesists to materials scientists and engineers seamlessly work together and are open to collaboration. Also, nobody but a doctor can truly understand what impact a new treatment can have on a disease. One of the doctors we met had just seen a patient, a young lady not more than 35. He told us that he did not expect her to live much longer. Faced with morbid scenarios like this on a regular basis, it should not be surprising if doctors are willing to try anything and everything to make a new treatment available to patients. And yet it is rare to find people having an untrammeled vision of collaboration, which made our experience a truly pleasant one.

This sort of reminds me in a different sense of that saying which says that strangers are simply family members who we have yet to meet.

O, and kinases were definitely everywhere in the air :)

It says it all.

The article is worth reading (doi:10.1038/442736a)

Came across this neat review by cancer specialist Robert Weinberg from MIT. Six comprehensive and all encompassing checkpoints and regulatory regimes need to be circumvented by cancer cells to become successful cancers, and they still do this. This is much worse law-breaking than any corrupt government in history.



There's only one thing I can say; the cancer cell is one clever, slimy little weasel.