Spontaneous Regression of Cancer

Cancer is one of the scariest words in the English language and when we are afraid we tend to become irrational – even otherwise intelligent people. That is why there are more quackery around cancer treatments than any other disease.  Cancer is likely second only to death itself in terms of stuff that frighten people. And just like there are myths and charlatans exploiting our fear of death, there is an entire voodoo industry to exploit the fear of patients with cancer.

While complimentary and alternative therapy for cancer is a universal phenomenon (I often see patients who also take some form of alternative medicine for cancer here in USA too), it is of a completely different and dangerous magnitude in India. I have seen this first hand as I frequently get medical records of cancer patients for second opinion from India, and it is very troubling to see the number of poor patients who continues to be exploited by peddlers of alternative medicine in India.

As a recent example, from my visit to Kerala in November 2017, one of the patients who came to see me for a second opinion was someone I knew all the way from my childhood days who was unfortunately diagnosed with bladder cancer around 6 months ago. He saw an Oncologist and a Urologist at a highly reputed hospital in Kozhikode, who both appropriately advised immediate surgery to take care of his early stage bladder cancer, which could have been curative. Instead he decided to forego Modern Medicine and sought treatment from an alternative medicine provider who claimed he could cure this cancer with some “lehyam” and other quackery. As symptoms continued to worsen patient went back to his original doctors, who repeated a CT scan. He brought with him his CT scans, and I reviewed his old and new scans, and unfortunately his disease had now progressed significantly and had become inoperable. And sadly, patient also had gone in to renal failure due to the enlarging tumor blocking his ureters. While we are constantly bombarded in social media on the extremely rare instances of advanced cancers “being cured” with alternative medicine, one never sees the much common occurrences like the case above, where relying on alternative medicine and delaying modern medical treatment become deadly.

The number of claims of medical miracles and magic diets for cancer is astounding. As discussed above, the more frightening an issue is, the more willing people will be to believe in fairy tales and subscribe to magical thinking. What is unfortunate is that, unlike in the past, effective cancer treatments are now widely available and cancer death rate down. However, the key to a good out come still remains early treatment. And many a time as in the case above, the delay in early treatment while patient tries out various unproven alternative medicines could change an early treatable disease to an advanced and incurable death sentence.

Quacks and promoters of alternative medicine comes in various forms. Some are “professional peddlers” who promote their wares with benign sounding words (like “organic”, “plant derived” and so on. A brief note here - just because some thing is derived from plant does not make it automatically healthy – nicotine, the commonest cancer-causing agent in the world, is an “absolutely organic and plant derived” product!) These professional peddlers are very adept at marketing and experts at using social media. Unfortunately, people are much keener on reading and disseminating extra ordinary claims and conspiracy theories than what is truly scientific and rational, so these charlatans have become very successful with the wide spread use of social media.

Another and even more effective form of peddlers are those who have been the very fortunate quacks who happened to come across a case of spontaneous regression of cancer. These quacks have other people, often cancer patients or relatives, vouching for their remarkable recovery. Many of these are again totally fabricated stories, but some time these could be real patients and real stories. So how would one explain those remarkable stories, assuming the story is real? Can a patient with advanced cancer who have failed all therapies can suddenly become cancer free?

Here is how to explain this – as briefly noted, there is a well-known entity in cancer biology called “spontaneous regression of cancer”. This is the disappearance of cancer without a satisfactory explanation. There is an entire body of literature on this rare but well described topic. And with a better understanding of cancer biology, especially with advances in cancer immunology, this is no longer a “mysterious” or “miraculous” subject but come totally within the realm of known cancer biology.

The patron saint of cancer patients is St Peregrine, OSM (1265-1345), a 14th century priest whose cancerous leg became ulcerated and festered for years and was, according to Christian legend, healed by Divine intervention the night before he was scheduled to undergo amputation.^1,2 Case reports like this fits the general rubric of “spontaneous regression.”³

Discounting these unique events may be the easiest course of action but it is unscientific, as medical historian and hematologist Dr Jocalyn Duffin noted in an analysis of Vatican archives in her book, “Medical Miracles: Doctors, Saints, and Healing in the Modern World”.⁴ Her interest in this subject started when Dr Duffin was sent pathology slides for interpretation from the Vatican regarding a patient diagnosed with acute myeloblastic leukemia, who was supposed to have been cured “miraculously”. The source of the slides was unknown to her at first, though more than 30 years later the patient is alive after initially failing standard therapy.^4,5

Critical analysis of cases of spontaneous regression by sober and scientific observers dates back more than a century to physicians like Dr William Coley, Dr G.L. Rohdenburg in 1918, landmark studies by Drs J.J. and J.H. Morton in 1953, and the widely cited review by Drs T. Everson and W. Cole in 1956.^6-8 The latter study defined the modern version of spontaneous regression of cancer as: “the partial or complete disappearance of a malignant tumor in the absence of all treatment, or in the presence of therapy which is considered inadequate to exert a significant influence on neoplastic disease.”

Medical literature is now filled with observations of biopsy-confirmed malignancies with computerized tomography (CT) scans or magnetic resonance images (MRIs) showing widespread disease that spontaneously regresses, which encompasses nearly every cancer type and histology. Examples include: acute myelocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, breast cancer, non–small cell and small cell lung cancer, testicular cancer, prostate cancer, cervical cancer, hepatocellular cancer, colon cancer, Merkel cell carcinoma, sarcoma, melanoma, neuroblastoma, astrocytoma, and renal cell carcinoma.^9-26

The mechanisms most-often implicated in driving the spontaneous regression of cancer are thought to be mediated by immune system activation (or reactivation). Sometimes the driving force is an acute intercurrent bacterial or viral infection. Initiated by the work of Dr Lloyd Old, the founder of modern cancer immunology, the US Food and Drug Administration (FDA) in 1990 approved the first bacterial immunotherapy, Bacillus Calmette-Guerin (BCG), for in situ bladder cancer. More recently the FDA approved T-Vec [talimogene laherparepvec], a viral vaccine used to evoke an immune response in patients with advanced melanoma.^27-29

The development of other viral and bacterial vectors is an active area of new drug development, with further success anticipated.^30,31 The recent approval of checkpoint inhibitors against an array of cancers and chimeric antigen receptor (CAR)-Tcell therapy are testimonies to the power of the immune system, when it awakes from its slumber, to simulate a process historically regarded as “miraculous.”^32,33

The immuno-editing theory proposed by Drs Robert Schreiber, Mark Smyth, and Lloyd Old has helped to refine medical understanding of spontaneous regression, which may be seen as the interplay of cancer undergoing incomplete elimination, equilibrium, and escape.³⁴ Under ideal conditions the innate and adaptive elements of the immune system work in concert to eliminate the cancer (often imperfectly) with regulatory (CD4+) and cytotoxic (CD8+) T cells, dendritic (or antigen presenting cells), natural killer (NK) cells, and macrophages along with a host of immune-activating secreted proteins such as interferon gamma, interleukin 12, and tumor necrosis factor (TNF) all working in harmony. Spontaneous regression may in some cases be a manifestation of this dynamic process, and immunoediting fits well into observations that some cancers that undergo spontaneous regression recur, sometimes years later.

Another example of this phenomenon can be seen with the so-called abscopal (or out-of-field) effects of radiation therapy, which causes the immune system to mount a systemic response to distant metastases.³⁵

I expect that in the future, as our understanding of cancer immunity matures, the fascinating phenomenon of spontaneous regression will help guide us towards developing safer and even more effective drugs. What is remarkable is that, these rare cases of “spontaneous regression of cancer”, once ascribed to miraculous intervention or unproven “herbal” and other remedies, now have a very scientific explanation. Unfortunately, how this plays out in the real world currently is however different; a patient with an advanced malignancy who was fortunate to have such a case of spontaneous remission may end up with a lucky quack, who claims full credit for this rare natural phenomenon; and the news spread like wild fire in the social media jungle; prompting a deluge of desperate patients flocking to get this “magical herb”, while the herb had nothing to do with the spontaneous remission. And while a sole case of spontaneous remission is broadcast through out the world, millions of more lives are cut short trying these voodoo "treatments" from alternative medicine practitioners. And with the Indian Government's proposed recent legislation that could allow a back door entry for alternative medical practitioners to practice Modern Medicine, public will have even more trouble in the future to distinguish between real Medicine and quackery in India.   

References:

1.       Pack GT. St. Peregrine, O.S.M.--the patron saint of cancer patients. CA Cancer J Clin. 1967;17(4):181-2.

2.       Jackson R. Saint Peregrine, O.S.M.--the patron saint of cancer patients. Can Med Assoc J. 1974; 111(8):824-7.

3.       Krone B, Kölmel KF, Grange JM. The biography of immune system and the control of cancer: from St Peregrine to contemporary vaccination strategies. BMC Cancer. 2014;14:595. doi: 10.1186/1471-2407-14-595

4.       Duffin J. Medical Miracles: Doctors, Saints, and Healing in the Modern World. Oxford: 2008.

5.       Pukel C. Immunotherapy in the twentieth century: William Coley and Lloyd J. Old. Cancer Therapy Advisor website. Published March 15, 2017.

6.       Rohdenburg GL. Fluctuations of the growth energy of malignant tumors in man with especial reference to spontaneous reference. Cancer Res. 1918;(3)2:193-225.

7.       Morton JJ, Morton JH. Cancer as a chronic disease. Ann Surg. 1953;(137):683.

8.       Everson TC, Cole WH. Spontaneous regression of cancer: preliminary report. Ann Surg. 1956;144(3):366-80.

9.       Barrett R, Morash B, Roback D, et al. FISH identifies a KAT6A/CREBBP fusion caused by a cryptic insertional t(8;16) in a case of a spontaneously remitting congenital acute myeloid leukemia with normal karyotype. Pediatr Blood Cancer. 2017;64(8). doi: 10.1002/pbc.26450

10.   D'Arena G, Guariglia R, Pietrantuono G, et al. More on spontaneous regression of chronic lymphocytic leukemia: two new cases and potential role of lamivudine in a further patient with advanced disease and hepatitis B virus infection. Leuk Lymphoma. 2014:55(8):1955-7. doi: 10.3109/10428194.2013.858151

11.   Udupa K, Philip A, Rajendranath R, Sagar T, Majhi U. Spontaneous regression of primary progressive Hodgkin's lymphoma in a pediatric patient: a case report and review of literature. Hematol Oncol Stem Cell Ther. 2013;6(3-4):112-6. doi: 10.1016/j.hermonc.2013.06.004

12.   Takahashi T, Ikejiri F, Takami S, et al. Spontaneous regression of intravascular large b-cell lymphoma and apoptosis of lymphoma cells: a case report. J Clin Exp Hematop. 2015;55(3):151-6. doi: 10.3960/jstrt.55.151

13.   Ito E, Nakano S, Otsuka M, et al. Spontaneous breast cancer remission: a case report. Int J Surg Case Rep. 2016;25:132-6. doi: 10.1016/j.ijscr.2016.06.017

14.   Nakamura Y, Noguchi Y, Satoh, E et al. Spontaneous remission of a non-small cell lung cancer possibly caused by anti-NY-ESO-1 immunity. Lung Cancer. 2009:65(1):119-22. doi: 10.1016/j.lungcan.2008.12.020

15.   Kitai H, Sakakibara-Konishi J, Oizumi S, et al. Spontaneous regression of small cell lung cancer combined with cancer associated retinopathy. Lung Cancer. 2015;87(1):73-6. doi: 10.1016/j.lung ca.2014.10.015

16.   Balzer BL, Ulbright TM. Spontaneous regression of testicular germ cell tumors: an analysis of 42 cases. Am J Surg Path. 2006;30(7):858-65.

17.   Lee T, Guo Y, Vij S, Bansal R, Wong NC, Shayegan B. Case: spontaneous regression of post-radical prostatectomy prostate-specific antigen elevation without adjuvant therapy in a patient with lymph node metastasis. Can Urol Assoc J. 2017;11(7):E315-7. http://dx.doi.org/10.5489/cuaj.4324

18.   Katano A, Takenaka R, Okuma K, Yamashita H, Nakagawa K. Repeated episodes of spontaneous regression/progression of cervical adenocarcinoma after adjuvant chemoradiation therapy: a case report. J Med Case Rep. 2015;9:114.

19.   Parks AL, McWhirter RM, Evason K, Kelley RK. Cases of spontaneous tumor regression in hepatobiliary cancers: implications for immunotherapy? J Gastrointest Cancer. 2015;46(2):161-5. doi: 10.1007/s12029-015-9690-7

20.   Chida K, Nakanishi K, Shomura H, et al. Spontaneous regression of transverse colon cancer: a case report. Surg Case Rep. 2017;3:65. doi: 10.1186/s40792-017-0341-z

21.   Pang C, Sharma D, Sankar T. Spontaneous regression of Merkel cell carcinoma: a case report and review of the literature. Int J Surg Case Rep. 2015;7C104-8. doi: 10.1016/j.ijscr.2014.11.027

22.   Bonvalot S, Ternes N, Fiore M, et al. Spontaneous regression of primary abdominal wall desmoid tumors: more common than previously thought. Ann Surg Oncol. 2013;20(13);4096-102. doi: 10.1245/s10434-013-3197-x

23.   Miller CV, Cook IS, Jayaramachandran R, Tyers AG. Spontaneous regression of a conjunctival malignant melanoma. Orbit. 2014;33(2);139-41. doi: 10. 3109/01676830.2013.851708.

24.   Diede SJ. Spontaneous regression of metastatic cancer: learning from neuroblastoma. Nat Rev Cancer. 2014;14(2):71-2 doi: 10.1038/nrc3656

25.   Buder T, Deutsch A, Klink B, Voss-Bohme A. Model-based evaluation of spontaneous tumor regression in pilocytic astrocytoma. PLoS Comput Biol. 2015;11(12):e1004662. doi: 10.1371/journal.pcbi.1004662

26.   Murphy KA, James BR, Guan Y, Torry DS, Wilber A, Griffith TS. Exploiting natural anti-tumor immunity for metastatic renal cell carcinoma. Hum Vaccin Immunother. 2015;11(7):1612–16.

27.   Kucerova P, Cervinkova M. Spontaneous regression of tumour and the role of microbial infection – possibilities for cancer treatment. Anticancer Drugs. 2016;27(4):269-277.

28.   Jhawar SR, Thandoni A, Bommareddy PK, et al. Oncolytic viruses-natural and genetically engineered cancer immunotherapies. Front Oncol. 2017;7:202. doi: 10.3389/fonc.2017.00202

29.   Corrigan PA, Beaulieu C, Patel RB, Lowe DK. Talimogene laherparepvec: an oncolytic virus therapy for melanoma. Ann Pharmacother. 2017:51(6):675-81. doi: 10.1177/1060028017702654

30.   Lee CH. Engineering bacteria toward tumor targeting for cancer treatment: current state and perspectives. Appl Microbiol Biotechnol. 2012;93(2):517-23. doi: 10. 1007/s00253-011-3695-3

31.   Howells A, Marelli G, Lemoine NR, Wang Y. Oncolytic viruses-interaction of virus and tumor cells in the battle to eliminate cancer. Front Oncol. 2017;7:195. doi: 10.3389/fonc.2017.00195

32.   Geng Q, Jiao P, Jin P, Su G, Dong J, Yan B. PD-1/PD-L1 inhibitors for immuno-oncology: from antibodies to small molecules. Curr Pharm Des. 2017 Oct 4. doi: 10.2174/1381612823666171004120152 [Epub ahead of print]

33.   Wilkins O, Keeler AM, Flotte TR. CAR T-cell therapy: progress and prospects. Hum Gene Ther Methods. 2017;28(2):61-6. doi: 10.1089/hgtb.2016.153

34.   Schreiber RD, Old LJ, Smyth MJ. Cancer Immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011;331(6024):1565-70. doi: 10.1126/science.1203486

35.   Cong Y, Shen G, Wu S, Hao R. Abscopal regression following SABR for non-small-cell-lung cancer: a case report. Cancer Biol Ther. 2017;18(1):1-3. doi: 10.1080/15384047.2016.1264541

Death and Dying - Some Reflections

Read the deeply affecting "When Breath Becomes Air" by the late Dr. Paul Kalanithi recently; it is a small yet powerful book, not just because the book appears like a deeply thoughtful and smart man talking to you from beyond the grave, but the contents are especially affecting for us doctors who has to deal with death and dying on a daily basis. As an Oncologist I could empathize with his Oncologist, whom he trusts and adores, but could see through her at times - times when the relationship is no longer just a bland and emotionless "Doctor-Patient relationship", but as he wrote beautifully "it is the relationship of two people huddled together, with one of them facing the abyss" and how he forgives his Oncologist's sunny - and eventually wrong - prognostications with the saying "some time Doctors needs hope too". 

With his deep and vast knowledge including a PhD in English Literature, formal training in Philosophy, a stint at History of Medicine, Neuroscience and of course as a promising Neurosurgeon, all at some of the world’s best institutions, even without his untimely death and this book, it is fairly certain he would have become famous, a future Oliver Sachs. Or may be like many doctors, his profession would have swallowed him whole and the wider world would never have heard of him. Medicine is indeed like a possessive wife, often causing other passions to die. So in one way, even though he died at age 37, he has become now immortalized by his book, which I suspect could become a "required reading material" for many future students of Medicine. I often tell patients with terminal cancers "to live one day at a time" which is really a cop-out - as Dr. Paul Kalanithi writes "I would like to know; because if I have only few months I want to write a book; if I have few years I want to pursue Neuroscience". But nothing is harder than prognostication, especially with newer treatments for previously incurable cancers. It is easier in some cases, but often it is not. Anyway I would strongly recommend this remarkable book; short book which can be finished in one sitting yet powerful. 

So the book, an examination of death, reminded me of something I read couple of years back and wanted to share this with readers. This is a remarkable idea on death and afterlife that most people have not heard of. The two traditional and competing theories of afterlife are 1) An Eternal Heaven/Hell 2) Nothingness. But there is a third alternative: The term for this is "Near Death Experience leading to Never Ending Dream" or NDE to NED. NDEs are well documented phenomenon and reported across various cultures. In many NDEs, individuals describe intense dreams of being drawn through a tunnel toward a bright light into a celestial realm and of feeling wonder, love, and contentment.  The NED theory of heaven suggests that NDEs provide evidence of a “natural afterlife” and thus perhaps a heaven which exist in the person's mind; etched forever in the brain of the dying person. The NED theory suggests those describing NDE are indeed experiencing "heaven". But then they awake and return to consciousness. That is, the NDE doesn’t become their NED and natural afterlife, though it very well could have.

To better grasp this, imagine what it’s like to never wake up from a dream, something none of us have experienced. You’re having your NDE. Effectively, you’re in heaven. But then you die, and so you never become consciously aware that your dream ends. It’s not like the dream screen displays "The End" or even goes blank! Thus, as far as you know, you’re in heaven forever. And reality is what ever our brain makes of this world. So to an out side observer you are dead; but as far as the dead person is concerned, his last experience is the vivid dreams of a Near Death Experience - which thus becoming a Never Ending Dream as the person never wakes up from this dream. 

Most people would find it hard to swallow, as we are chained by our ideas of time. So the first question when some one hears of NED is "what happens when the person dies"? This question forgets the intensively subjective nature of time as well as consciousness and sense of self. But what is time anyway? Time may be only a human illusion. It’s relative to perceived events and when we begin to perceive none—e.g., when falling into a dreamless sleep or passing out under general anesthesia (or in dying!)—our self, or our spirit (or soul?), doesn’t cease but time ceases and we simply enter a timeless state. The universe itself may be fundamentally timeless as Einstein himself believed.

The concept of time here is like that which we have “experienced” before-life, i.e., before we were born. Timeless! Billions of years pass by in no time at all, literally. The big difference, however, is that our “afterlife” begins at death enjoyably immersed in a glorious dream. While this dream physically ends, from our mind’s perspective it is now an NED. After a billion years have passed by, for instance, we are still unaware that we are dead.

Why this third way, the so called “Never Ending Dream” could be true? Because of the following three features 

1) Our ability to dream—specifically, to have an NDE, there are so many well documented evidence of this across varying cultures; there is an excellent book written by Neurosurgeon Dr. Eben Alexander who almost died from a severe case of meningitis (“Proof of Heaven”); All these NDEs are very similar, and some as in Dr. Eben Alexander’s case could be extremely elaborate 

2) Our perception of time as a perceived ordering of events is illusory 

3) Our inability to realize the moment of death, i.e., our imperceptible death.

Based on research, some scientists believe that common NDE features may be induced, possibly as a defense mechanism, by psychological and physiological processes occurring in the brain as it senses doom or shuts down. For instance, chemicals are released as a protective mechanism when the brain is traumatized. These chemicals have been shown to trigger intense hallucinations with features like those of NDEs. While such science is used to explain NDEs as just natural phenomena mistaken for a supernatural heaven, it also shows the natural ability and propensity of the brain to trigger vivid NEDs.

More support for the NED theory comes from our dreaming experiences. I for one believe that despite numerous studies and publications about dreaming, it hasn’t been given the prominence it deserves. When inside our dreams, we can’t distinguish them from real-life. Also, when dreams are pleasant, real-life worries are left behind, as in heaven. Our dreams are truly another dimension of being, like another universe.

And why do we possess this amazing ability to dream? Some scientists believe that dreaming evolved to better prepare us to face life’s crises, though this theory seems to apply only to nightmares and doesn’t seem to explain most of my dreams. The NED theory provides another purpose: a potentially satisfying, evolved and/or God-given, afterlife experience.

And who or what controls our dreams? I certainly don’t control mine. Some scientists speculate they’re brain-controlled processes that assimilate and store recently accrued knowledge. However, many of my dreams are weird, unrelated to recent experience, and so don’t appear to fit this explanation at all. Dreaming seems a realm within our universe yet out of this universe.

The NED theory facilitates a distributive heaven rather than a centralized one. So, heaven could be whatever one believes and dreams. Suppose one doesn’t believe in heaven? Then maybe there’s no NED and one’s afterlife will be just like one’s before-life.

Can an NED be "hell"? Studies based on NDE reports vary much but show that on average about 15% of NDEs are reported as hellish experiences. So yes, I guess NED could be like a nightmare that never ends.

Will someone be denied an NED if they are “blown to bits” in an instant? As indicated before, the brain can likely paint a heavenly landscape almost instantaneously. Also, if the brain can, as reported, make life flash before one’s eyes in the moments before pending disaster, maybe it can execute an NED in nanoseconds before shutting down.

Why this is important? Whether one agrees with the idea of NED or not, as far as I know, this idea of “Never Ending Dream” ties together lots of loose ends, and could answer one of the most fundamental questions humanity ever faced. I would even go on to say that, if there is even a tiny possibility of NED, then we should develop techniques and medications (like endogenous hallucinogen dimethyltryptamine) to help dying patients to have vivid and happy dreams; which would become his/her “Never Ending Dream”. While waiting for such technology to evolve, I guess the next best thing is to live a good life; from Dr. Kalanithi’s book, and the description of how he died surrounded by so much love, it is quite possible that Paul is now in a heavenly state of Never Ending Dream. Research also shows that what we dream can be influenced somewhat by heavy concentration on a topic just before falling asleep. So what is one’s final dream after fixating the mind on death and its meaning? A life well lived without too many regrets could indeed be the way to heaven; so one's Near Death Experience is a pleasant and even heavenly one. and if it indeed ends up as death, then one has the possibility of entering an eternal world of heavenly "Never Ending Dream" state.

The Paradigm of Cancer Care in the Era of Genomics, Proteomics and Immuno-oncology

The word “paradigm shift” is used fairly loosely in many contexts, but in the field of Oncology there has truly been a paradigm shift in both the understanding of cancer biology as well therapeutics in the last decade and the pace of change has accelerated even more so in the last couple of years. Those outside the fields of oncology and related fields are unaware of many of these seismic shifts taking place, and this blog is an attempt at briefly updating the reader on what is happening in the field of oncology.

Let me start by illustrating by the example of a current patient of mine; she is a 56 year old patient, non smoker, with stage IV adenocarcinoma of the lung with brain metastasis, diagnosed over 2 years ago. If some one asked me how to treat a patient like this when I was doing my Hematology-Oncology fellowship over 12 years ago, the appropriate answer would have been “any doublet chemotherapy containing a platinum compound”, along with brain radiation. Basically, it didn’t matter what kind of mutations the tumor itself possessed as we not only knew little about mutations withing lung cancer, we also had no specific or targeted therapy for individual mutations even if we found them then. So all lung cancers were treated as a single group, and given a pretty similar type of chemotherapy regimen. Some of the patients responded to this, and those who did not and those who progressed, there were few, if any viable options apart from palliative care.

What has changed in over 12 years? So many things. For once, we have now so many different sub types of lung cancers, based not just on histology but also based on molecular and genetic profiling. My particular patient was found to have a lung adenocarcinoma with a so called EGFR exon 19 mutation, which is very sensitive to an oral kinase inhibitor called Afatnib. My patient initially underwent so called “Cyber knife Radiation” for her brain metastasis – which is a highly focused form of radiation targeting the metastasis while sparing normal brain. After this she was started on afatinib. This is a pill taken once daily while she continued to work. A PET scan done after 3 months of this therapy showed she was in a PET negative remission. She continued the same medication for another 18 months but unfortunately progressed with a new bone lesion. At the time of progression, a new test which can test mutational status of any circulating tumor cells became available and was performed, and this showed she had now circulating tumor cells positive for a mutation called T790M. This is a classic mutation which makes the EGFR clones resistant to drugs like afatinib. These mutant cells are actually a bit less robust than cells without the T790M mutation, but in the presence of drugs like Afatnib the cells with the T790M mutation have a specific survival advantage.

At this point she was enrolled in a clinical trial looking at a so called third generation EGFR kinase inhibitors which works around the T790M mutation, being developed by Astra Zeneca. She responded nicely for about 5 months on this yet to be approved drug; then around 1 month ago she progressed again. A repeat cell free DNA testing now showed she has developed cells expressing so called BRAF V600E mutation, which was not present in the original tumor or on first progression – one of her cancer cells have now mutated to be now the “fittest” clone. We have now obtained a BRAF inhibitor and a MEK inhibitor on a compassionate use protocol (as these drugs are not yet approved for lung cancer but only for melanoma). We and the patient and her family are all keeping our fingers crossed to see what would happen. My guess is she will respond for few months, and then her cancer cells will find a way around that pathway also and then progress, but hopefully we will find another mutation which we can target by then, or she could get conventional chemotherapy which is yet to receive nearly 2 years after diagnosis. And during these nearly 2 years of ongoing therapy, patient continued to work and enjoy a fair quality of life allowing her to pursue her work and hobbies. 

The above case illustrates how from randomly treating all lung cancer patients with a generic “platinum doublet” 10 years ago, cancer treatment now involves sub dividing the cancers in to very specific molecular sub types and treating with appropriate medications. The case also illustrates how dynamic is the process of cancer; we spoke about targets in the past as if they were fixed (like "estrogen receptor positive breast cancer"). We still do so, but is realizing these targets change and mutates and cancers evolve over time. While vast majority of cancers still do not have "targetable mutations " like the patent's case above, we are at the cusp of some exciting new fronts in cancer care. What follows is a very short summary of cancer biology as well as how this is changing how cancer is treated now a days, along with a brief overview of future potentials and challenges.  

Cancer as an Evolutionary Process:

What we have learned is that the best way to look at the cancer is through a Darwinian lens. This so called micro evolution – or evolution at cellular levels and happening at warp speed can explain a whole lot of once mysterious things about cancer biology. In the past we used to look at cancer as a “monoclonal process”, a set of uniform cells competing against normal cells. This appears to be a very simplistic way to look at cancer – cancer is unfortunately a way more complex disease process than that.


What is meant by looking at cancer through Darwinian lens? Here is how: A body can be considered as an entire eco system –whose individual members are cells. These cells have ecological and classic Darwinian features like cell births, deaths, habitats, territorial limitations, and maintenance of population sizes. The one Darwinian rule that does not apply is however “natural selection” – there is no competition among somatic cells. The rules of somatic cells are instead self-sacrifice—as opposed to survival of the fittest. Ultimately, all somatic cells are committed to die; they dedicate their existence to support of the germ cells, which alone have a chance of survival and propagation. One could think of germ cells like the “queen bee” of an ant colony. There is no mystery in this, as the body is a clone, and the genome of the somatic cells is the same as that of the germ cells. By their self-sacrifice for the sake of the germ cells, the somatic cells help to propagate copies of their own genes.

To coordinate their highly cooperative behavior, cells send, receive, and interpret an elaborate set of signals that serve as social controls, telling each of them how to act, when to divide, when to die. As a result, each cell behaves in socially responsible manner, resting, dividing, differentiating, or dying as needed for the good of the organism. Molecular disturbances that upset this harmony mean trouble for a multi cellular society like our body. In a human body with more than 10^14 (or 100 Trillion) cells, billions of cells experience mutations every day, potentially disrupting the social controls. And an occasional mutation can give one cell a selective advantage, allowing it to divide more vigorously than its neighbors and to become a founder of a growing mutant clone, a “selfish” clone. Once cells learn to be “selfish” then the typical Darwinian “survival of fittest” rule applies within that clone– each subsequent cancer cell population gets “better” at resource utilization. And since mutational rates are higher among cancer cells, purely from random chance one of these cells would develop a special property (like more efficient anaerobic metabolism) - this cell then have a survival advantage over other normal and cancer cells. Note that by this time cancer cells are competing among themselves, and not against normal cells. Because cancer cells are way so advanced in their ability to divide and utilize resources, competing with normal cells is like Michael Jordan playing against a school kid. Their competition is mostly with other cancer cells.  Such repeated rounds of mutation, competition, and natural selection operating within the population of cancer cells cause matters to go from bad to worse, see the diagram below. 


For example: when a critical size is reached, the cancer cells may not get enough oxygen, then one of these cancer cells – who are all competing with each other like it is the great African Serengeti plains – would develop a mutation that allows it to utilize anaerobic pathways better, or attract blood vessels to grow in to it, or develop an ability to pump out chemotherapy drugs etc.  Several more cell divisions later another cell would find a way to get out of the resource poor primary site and goes and thrive in another, healthier and "less competitive" environment - what we call metastasis. See the diagram below to show how clonal evolution works:








This is why recurrent cancers are harder to treat and cure. Thus cancer is a disease in which individual mutant clones of cells begin by prospering at the expense of their neighbors, but soon their competition is among cancer cells themselves, each “out mutating” each other, eventually becoming such a remarkable , and almost immortal, dividing cells, who only dies in the end when they destroy the whole body. If those cells can be taken out and given perpetual nourishment, these cells can literally live forever (portrayed in the wonderful book “The Immortal Life of Henrietta Lacks). These advanced cancer cells have actually mastered what humans have been searching for all of history - immortality.

As noted a single mutation alone can rarely causes cancer. Genesis of a cancer typically requires that several independent, rare accidents occur in the lineage of one cell. If a single mutation were responsible, occurring with a fixed probability per year, the chance of developing cancer in any given year should be independent of age. In fact, for most types of cancer the incidence rises steeply with age—as would be expected if cancer is caused by a slow accumulation of numerous random mutations in a single line of cells. In fact if one lives long enough, it is almost a given that some type of cancer is bound to happen. A recent study from Sweden looked at whole genome sequencing of healthy adults, and found that over 12% of general population over age 65 had what we now call as ARCH (Age Related Clonal Hematopoiesis) in their blood – and they had 15 times risk for developing subsequent blood diseases like AML and MDS. (Interestingly those with ARCH in their blood also had higher cardio vascular and endocrine morbidity and mortality suggesting a possible common inflammatory pathway to both cancers and other common diseases)

Why are so many mutations needed for cancer? Because think of cell as a car; but instead of a single accelerator and a single break, cells have many many breaks and accelerators. A critical number of breaks have to be gone and a critical number of accelerators pressed before a cell truly becomes “cancerous”. (By the way those with familial cancer syndrome like Li Freumani already are born with some major breaks - like p53 - already gone, so it takes less mutation for them to get a cancer). Moreover, not all cancers are the same in terms of how "fast" they are. In fact we now routinely use a test called “Mammaprint” to decide which of the early stage breast cancer patients need treatment, and who does not. I explain to patients this test differentiates whether their cancer is an old car or a brand new Ferrari. And if they are lucky and if their cancer is a like an old car, we don’t give them chemo these days and treat them just with hormonal therapy.


Just to add some subtlety to this story – mutations alone can’t cause cancer – often many mutations are needed unless it is one of the “driver” mutations like 9-22 translocations in CML. An estimated 10^16 cell (100,00 Trillion) cell divisions take place in a normal human body in the course of a lifetime. (By the way these are truly cosmic numbers. For example an average human have 1000 times the number of stars in the Milky Way galaxy!)  Even in an environment that is free of mutagens, mutations will occur spontaneously at an estimated rate of about 1 in a million mutations per gene per cell divisions.—a value set by fundamental limitations on the accuracy of DNA replication and repair. Doing the math one can see that in a lifetime, every single gene is likely to have undergone mutation on about 10^10 (or 10 billion) separate occasions in any individual human being. Among the resulting mutant cells one might expect that there would be many that have disturbances in genes that regulate cell division and that consequently disobey the normal restrictions on cell proliferation. From this point of view, the problem of cancer seems to be not why it occurs but why it occurs so infrequently. I routinely get asked by patients – often who have done all the right things from their diet to exercise who gets cancer – why they got cancer. (Without elaborating the numbers what I tell them is this: That it is a miracle of our immune system that we don’t get a new cancer every day!) 

What is a Driver Mutations versus “Passenger” mutations:

Countless studies have shown that sequential acquisition of mutations results in gains in evolutionary fitness. Furthermore, tumor initiator clones (also often referred to as cancer stem cells) have been identified in a subset of cancers and highlight the potential for a genetically “simple” tumor cell progenitor to propagate disease relapse. There is perhaps no disease with greater evidence of this than CML.

The introduction of imatinib, a small molecule inhibitor of ABL family kinases including the BCR-ABL fusion gene, revolutionized the way that CML is managed and dramatically improved outcomes for these patients. An important factor contributing to the unusual success of imatinib is that it targets the initiating event in the clonal evolution of CML. This means that all daughter cells that evolve following this initial event (ie, every cell in the clonal pool) also carry the BCR-ABL trans location and are susceptible to the effects of imatinib. . The terms “driver mutation” and “passenger mutation” were coined to discriminate between (1) those mutations that play an active role in disease pathogenesis (ie, driver mutations) and (2) those mutations that do not contribute to disease pathogenesis but undergo clonal expansion alongside one that does (ie, passenger mutations). Also note that not all driver mutations are created equal but rather are acquired in an ordered hierarchy. That is, some driver mutations occur as early events during clonal evolution and play a role in disease genesis (early drivers), whereas others occur as later events during clonal evolution and play a role in disease progression (late drivers/accelerators). Early driver mutations that have a role in disease genesis, such as the BCR-ABL trans location, will therefore be present in every tumor cell, whereas late driver mutations may only be present within a subset of tumor cells (ie, in a subclone).


To further complicate understanding and measurement of the clonal origin of mutations, each driver mutation will confer a variable boost in evolutionary fitness, which will cause them to overtake less-fit clones at different rates. This means that some driver mutations, despite occurring as late events in disease evolution, may appear to be present in the majority of tumor cells because they provide a significant boost to clonal fitness.


Currently, we do have “actionable” mutations (mutations that are matched to targeted therapies) for a number of cancer types, but as of this writing we know of many more “mutations” than there are “actionable mutations”. However, the future of precision medicine is one in which we will have a much wider array of actionable mutations matched to suggested therapeutics or clinical trials. Understanding the hierarchical order in which somatic mutations are acquired in each cancer will become an important consideration in ranking therapeutic targets for drug development, but this is a complex scientific undertaking, to say the least, and would require significant computing and clinical resources. A future format of molecular genetic results should incorporate a measure of not just the presence or absence of a mutation, but also the clonal representation or allelic frequency for each mutation, so that oncologists can be more informed about the biology of the tumor they are treating.While cancer is primarily a disease of the genes and result from acquired mutations within somatic cells, there are additional layers of complexity involved in actual cancer. We have to consider many host factors affecting the development and propagation of cancer (like familial predisposition, immunologic factors and metabolic factors). Add to this fact that cancer cells are intimately linked to the host in multiple ways, briefly as shown in the diagram below; unlike in experimental models, cancer in vivo has complex interactions between various host factors as represented below:

The initiating event in CML is acquisition of the t(9;22)(q34;q11) translocation, which creates a fusion between the BCR and ABL1 genes. Secondary genetic alterations, such as mutations of TP53, RB1, and CDKN2A, can be acquired after the BCR-ABL translocation and may play a role in progression of CML from an early chronic phase to a more aggressive blast phase.

We also have to consider that not all genetic changes will lead to protein production, so will need to interrogate cancer cells at not only genomic level but also at the proteomic levels. But once we start looking at cancer in such a comprehensive way, oncology care wil change from one that relies primarily on trial-and-error treatment strategies based on the anatomy of the tumor to one that is more precisely based on the tumor’s molecular, proteomic, metabolic level and appropriate for the particular host, thus enabling many cancers to be turned into manageable chronic disease, and providing patients with long-term high quality of life.

Dr. Patrick Soon-Shiong, MD is one of the leaders of this new push for a paradigm shift in how to address cancer given all these current understanding in to the biology of cancer. He is the inventor of nab-paclitaxel (Abraxane), the first U.S. Food and Drug Administration (FDA)-approved nanotechnology-based chemotherapeutic agent. He is also the Founder and CEO of NantWorks and its subsidiary NantHealth, a cloud-based biomolecular medicine and bioinformatics company that uses high-frequency, high-throughput tumor genome sequencing to analyze the DNA, RNA, and protein levels of an individual patient’s cancer cells. Proud to say the our practice is one of the select few from the US South Central region who is collaborating with Dr. Soon-Shiong’s company in developing a global consortium of cancer providers and patients to advance this field of precision medicine.

A GPS for the Oncologist:

How do you navigate this “maze” of molecular genetics, protoemics and other data to come up with the best suited treatment for a particular patient? I think Dr. Soon-Shiong is a true visionary in this regard, as his aptly named GPS (genome/proteome sequencing) involves a next-generation sequencing technology to analyze genomic (DNA) and transcriptomic (RNA) sequencing data. This identify variants between somatic and germ line DNA. What was interesting, though not unexpected was that, after analyzing a cohort of 3,784 patients (on 19 anatomic tumor types), it was found that genetic mutations in gene panels do not always result in protein expression. Thus even the informed clinician who is up to date with the latest molecular genetic data could miss or over read these reports – as what truly matters is downstream protein expression and not just DNA alterations alone. And this signatures change with time. Luckily however this entire GPS Cancer can be run now on circulating tumor cells, avoiding the need for repeat biopsies, capturing cancer as it evolves, rather than considering cancer as a static process as was the orthodox - and flawed - view in the past.

Advancing the Next Paradigm of Cancer Care

As detailed above, cancer is no longer considered as a single clonal disease nor static in it's genetic make up. Cancer cells also show enormous inter- and intra patient tumor heterogeneity and cancer progression is driven not just by one genetic mutation, but in many instances driven by tens and even hundreds and perhaps thousands of mutations, rearrangements, and structural changes in the genome, dynamically changing across time and space.

What is the downside of this approach of interrogating cancer at a much deeper level? Basically from being a “common disease” cancer becomes a set of rare diseases. Each patient’s mutational, proteomic, immunologic signature is going to be unique, and hence treatment should be tailored to that individual patient. Even large institutions will not have enough patients of a “specific GPS signatures” so Dr.  Dr. Patrick Soon-Shiong is spearheading a large collaborative “omics” network—a muscularly sophisticated network of oncologists to share outcome data and create an “adaptive learning system.”  This will require an infrastructure for sharing of outcomes in real time as well as an infrastructure to receive an in-depth whole-genome, RNA, and proteome sequence analysis in a timely manner to take advantage of real-time knowledge that may better inform a clinical decision.

Cancer care in the not distant future:

How do we effectively attack this multi clonal disease that changes its gene expression over time and space? The best way is to explore ubiquitous pathways driving proliferation and metabolism of the cancer cell, to attack both the stem and metastatic cancer cells, to recognize that the biology and evolution of these two cell types differ, and to use multiple drugs focused on multiple points of attack, targeting the cell’s nucleus, DNA, cell signal pathways, and metabolism and micro environment all simultaneously while also enhancing host immune system. The field of immunotherapy for cancer is worth it’s own blog, but briefly this has been one of the most exciting areas in all of oncology in the year 2015, with several new medications approved across a variety of cancer types where the treatment work by stimulating patient’s own immune cells or by enhancing the anti tumor immunogenecity.

Is there going to be a “magic pill” for cancer:

If you are still asking this question after reading the above blog, I would strongly recommend reading it again! Cancer is an extremely heterogeneous disease, so unlikely we will have a “magic pill” that will work across cancer types. However by “intelligently and selectively” blocking the various metabolic and survival pathways of cancer cells, by going after the cancer stem cells as well as the metastatic cells, and by enhancing the patient’s immune system we have a chance of changing the paradigm of how we manage cancer patients. Eventually, by more deeply understanding the biology of the cancer stem cell, we will provide long-lasting remission and get closer to a functional cure for cancer.

Buddha, Bohr and Einstein

What I needed, according to a dear friend, was some spirituality to uplift my mid life blues, and I was kindly provided with a copy of the book “Universe in an Atom” written by none other than His Holiness, the Dalai Lama himself. As most impartial observers would appreciate, Dalai Lama has become a global symbol of what a spiritually enlightened being looks like. In comparative terms, if the picture of Einstein immediately conjures up the image of super human genius, the picture of the Dalai Lama conjures up the image of a fully enlightened being while still fully human. Though I had been fascinated by him, and actually had the privilege of listening to him in person when he visited Birmingham last year, I never had the privilege of reading a book by him. While I expected what he would be writing – the importance of spirituality and the Buddhist ideals of “Ahimsa” or “non violence”, I was very pleasantly surprised after reading this book on the depth of understanding the Dalai Lama shows in the modern sciences, especially in the fields of quantum mechanics, relativistic cosmology and consciousness research, and provide valuable pointers to places where Buddhist (and ancient Indian) philosophy can meet modern science, and at times even fill the gaps in our understanding of issues on the borders of physics and metaphysics. This is a humble review and summary of the book. For anyone interested in a deeper understanding I strongly recommend to read the full book, which can be finished in 2-3 hours but is full of useful information as well profound insights.

Many religious leaders and scholars have written books claiming to connect their particular faith with modern ideas of science. Almost all of them are written to prove the author’s particular theology has pre-dated or even predicted all or part of modern science. However this book offers something much wiser and more humble; this book is written by a compassionate and well read religious leader who not only respects science but, for the most part, embraces it. "If scientific analysis were conclusively to demonstrate certain claims in Buddhism to be false, then we must accept the findings of science and abandon those claims," he writes. No one who wants to understand the world "can ignore the basic insights of theories as key as evolution, relativity and quantum mechanics."

That is an extraordinary concession compared with other religious leaders who conducts seminars and conferences devoted to “reconciling” science and their particular faith. These “dialogues", some of which I had attended or watched online, implicitly begin with the non negotiable like  “Jesus was born of virgin mother, and after death on the cross He was bodily resurrected into heaven. . ."  then seek scientific justification for what is already assumed to be true.

The story of how someone so open-minded became the Tibetan Buddhist equivalent of the Pope reads like a fairy tale. When the 13th Dalai Lama died in 1933 he was facing northeast, so a spiritual search team was sent in that direction to find his reincarnation. The quest narrowed further when a Lama had a vision pointing to a certain house. The little boy in that house, considered the re incarnation of the previous Dalai Lama, was then taken to the official residence of the Dalai Lama, the Potala Palace. The Buddhist elders soon realized they have indeed selected a very special child, as the little boy showed a wide ranging curiosity and sharp mind, learning not only the ancient traditions and scholarly work, but in his lonely childhood found solace in the very few technological marvels in the ‘otala palace, like a clock and a brass telescope. When he focused it one evening on what Tibetans call "the rabbit on the moon," he saw that it consisted of shadows cast by craters. Although he knew nothing yet about astronomy, he inferred that the moon, like the earth, must be lighted by the sun. He had experienced the thrill of discovery of himself and it appears he continues this tradition of discovery – spiritual and scientific – even today. When I saw him speak at Birmingham, what impressed me most was, despite his age and wise looks, he acted, spoke and most importantly laughed with the innocence of a child. In this book also one can see the insatiable curiosity of a child trying to grasp some of the deepest questions humans have ever faced.

What is remarkable is, despite absolutely no formal training in the fields of mathematics, biology or physics, his childish curiosity would serve him well to have a perfectly adequate understanding of the basic concepts in these fields. In no small part this was helped by his association with some of the greatest scientists and philosophers of the latter half of 20^th century. These scientists and philosophers included American Physicist David Bohm, German Physicist Carl von Weizsäcker (a student of quantum mechanical pioneer Werner Heisenberg) and British philosopher (and a friend of Albert Einstein himself), Sir. Karl Popper. In his humble way he praise these and other scientists and philosophers as “my respected teachers” – he treat them with the same regard he holds for his spiritual masters who taught him while he was a young monk at the Potala palace.

His interest in the intersection of science and spirituality and his willingness to embrace science with an open mind endeared him to spiritually inclined scientists all over the world. He has been conducting the so called "Mind and Life" conferences which have brought physicists, cosmologists, biologists and psychologists to Dharamsala, India, where he now lives in exile from the Chinese occupation of Tibet. He and his guests discuss things like the neuroscientific basis of Buddhist meditation and the similarities between Eastern concepts like the "philosophy of emptiness" and modern field theory. In fact when he visited Birmingham he was the distinguished guest speaker at a seminar organized by UAB Department of Neuroscience on the topic of Neuroplasticity and Healing. 

Dalai Lama is very open when it comes to admitting where scientific reasoning far exceeds the traditional “concrete logic” as used in Buddhist and ancient Indian philosophy. He explains it by describing how Buddhism and science differ in the role of deduction. While in science reason uses highly developed use of profoundly complex mathematical reasoning, Buddhism, like all other classical Indian philosophies, has a very concrete use of logic, whereby reasoning is never divorced from a particular context. In contrast, the mathematical reasoning of science allows a tremendous level of abstraction, so that the validity or invalidity of an argument can be determined purely on the basis of the correctness of an equation. Thus the generalization achievable through mathematics is at a much higher level than is possible in traditional forms of logic.

Dalai Lama explores this further by stating that “given the astounding success of mathematics, it is no wonder some people believe that the laws of mathematics are absolute and that mathematics is the true language of reality, intrinsic to nature herself”.

While accepting the superiority of science in general, Dalai Lama argues against scientists and some non scientists, who appear to believe that all aspects of reality must and will fall within the scope of science, the view also shared by “hard atheists” as well as by Marxist dialectical materialists. He argues against this view, in which science is perceived as having disproved many of the claims of religion, such as the existence of God and the eternal soul. Per him “Such views are effectively philosophical assumptions that reflect their holders’ metaphysical prejudices” which to him sounds very similar to theistic presumptions. He argues that the scientific cannot exhaust all aspects of reality, in particular the nature of human existence, the subjective world of feelings, emotions, thoughts, and the values and spiritual aspirations based on them. One finds it hard to argue with his point that “if we treat this realm of spirit as though it had no constitutive role in our understanding of reality, we lose the richness of our own existence”. Below I have summarized his book in to the following three sub headings. 1) Buddhism and Quantum Mechanics 2) Buddhism and Relativity / Cosmology 3) Buddhism and Life/Consciousness.

Quantum mechanics and the Philosophy of Emptiness:

One of the most important philosophical insights in Buddhism comes from what is known as the "theory of emptiness". Briefly from what I understood, this argues against a “separate self”. Though our every day experience makes us want to think of us (and other sentient beings as well as non sentient matter) appear as discrete particles, the theory of emptiness argues this is just an illusion. Per the theory of emptiness, our individual identity and “separateness” is a persistent but false delusion of the mind. This delusion of separateness leads to our “discrete ego” which in turn leads to many of the ills at individual and societal levels including attachment, loneliness, and development of our numerous prejudices. This theory of emptiness was first systematically expounded by the great Buddhist philosopher Nagarjuna (c. second century C.E.); though little is known of his personal life other than that he came from Southern India, he was—after the Buddha himself—the single most important figure for the formulation of Buddhism. Historians credit him with the emergence of the Middle Way school of Mahayana Buddhism, which remains the predominant school among Tibetan Buddhists to this day. 


Dalai Lama argues the ideas of quantum mechanics leads to very similar conclusions. It is fairly well known even among those who are not very scientifically literate that the microscopic world of quantum mechanics challenges our commonsense understanding. Examples abound, including facts like light can be seen as either a particle or a wave (In fact, the man who won the Nobel Prize for showing that the electron is a wave, George Thomson, was the son of the man who won the same prize for showing that the electron is a particle, J. J. Thomson.), and that the uncertainty principle tells us we can never know at the same time what an electron does and where it is, and the quantum notion of superposition all suggest an entirely different way of understanding the world from that of classical physics, in which objects behave in a deterministic and predictable manner. For instance, in the well-known example of Schrodinger's cat, in which a cat is placed inside a box containing a radioactive source that has a 50 percent chance of releasing a deadly toxin, we are forced to accept that, until the lid is opened, this cat is both dead and alive, seemingly defying the law of contradiction. Dalai Lama argues that to a Mahayana Buddhist exposed to Nagarjuna’s thought, there is an unmistakable resonance between the notion of emptiness and the new physics. If on the quantum level, matter is revealed to be less solid and definable than it appears, it is like science is coming closer to the Buddhist contemplative insights of emptiness and interdependence.

Dalai Lama, quoting Nagarjuna, suggests that the theory of emptiness is not a question of the mere conceptual understanding of reality. It has profound psychological and ethical implications. He then recollects a conversation he had with American physicist David Bohm: “From the perspective of modern science, what is wrong with the belief in the independent existence of things?” Bohm responds that “if we examine the various ideologies that tend to divide humanity, such as racism, extreme nationalism, and the Marxist class struggle, one of the key factors of their origin is the tendency to perceive things as inherently divided and disconnected. From this misconception springs the belief that each of these divisions is essentially independent and self-existent”. Bohm’s response, grounded in his work in quantum physics, echoes the ethical concern about harboring such beliefs that had worried Nagarjuna, who wrote nearly two thousand years before. Similarly the “observer effect”, where reality depends on the observer (collapse of the wave function in quantum mechanical language, where a “cat could be alive and dead at the same time as in the Schrödinger’s thought experiment) suggest that we must abolish as a matter of principle the separability of subject and object, the observed and the observer.

Relativity of time in Buddhist philosophy:

Einstein’s theory of relativity showed conclusively that time is “relative” to the speed of the observer. This leads to many of the interesting paradoxes, like the twin’s paradox, time dilation, or the contraction of objects at high velocity. (For those interested to read Einstein's ideas in more depth, click on the link to these blogs What time is it? and How fast does Brahma moves?). Dalai Lama quotes the story from Buddhist mythology of how Asanga was taken to Maitreya’s Heavenly Realm, where he received the five scriptures of Maitreya, a significant set of Mahayana texts, all in the time frame of a few minutes. Thus it appears, according to Buddhist and Ancient Indian principles, the concept of time as relative is not new. Dividing the temporal process into the past, present, and future, the Sautrantikas demonstrated the interdependence of the three and argued for the untenability of any notion of independently real past, present, and future.

EPR Paradox and Buddhism: Named after its creators, Albert Einstein, Boris Podolsky, and Nathan Rosen—which was originally formulated to challenge quantum mechanics, the EPR paper is a famous thought experiment in the early days of quantum mechanics, and was suggested to explain why quantum mechanics can’t be true. Briefly the EPR paradox is this: Assume a pair of particles is created and then separates, moving away from each other in opposite directions. One of the properties of this pair of particles is that their spin must be in opposite directions—so that one is measured as “up” and the other will be found to be “down.” According to quantum mechanics, the correlation of measurements (for example, when one is up, then the other is down) must exist even though the individual attributes are not determined until the experimenters measure one of the particles. Such an entangled particle pair could be at great distances from each other, say at either ends of the visible universe; but a “measurement” of one particle could cause a simultaneous change in the paired particle, even if that particle is at a great distance. Einstein’s relativity conclusively showed nothing can travel faster the speed of light. So how is it possible for this paired particles to communicate instantly across vast cosmic distances? Stranger is the fact that this EPR paradox has now been proved experimentally to actually exist in reality. While the authors of the original EPR paper wrote it to discredit quantum mechanics, it appears EPR phenomenon actually happens. Einstein called the EPR phenomenon “spooky action at a distance”. And it appears nature is spooky after all!

Dalai Lama gets in to this argument as follows: He quotes the so called "Vaisheshika atomism", which substituted a plurality of indivisible “atoms” as the basic units of reality for a single underlying reality. So what appear to be events separated by great distances are in fact connected through this underlying substratum of reality, one that is not obvious to us.

Cosmic origins:

It appears there are two main traditions of cosmology in Buddhism. One is the Abhidharma system, and the Mahayana Buddhism, especially the version of Indian Buddhism known as the Nalanda tradition. The primary work on the Abhidharma system of cosmology that made its way into Tibet was Vasubandhu’s Treasury of Higher Knowledge (Abhidharmakosha). Buddhist writing in the fourth century describes cosmic origin in terms of the theory of “dependent origination”. This theory states that all things arise and come to an end in dependence upon causes and conditions.

The second cosmological tradition in both classical Indian philosophy and Buddhism is called “Kalachakra” or the wheel of time. Both the Abhidharma and Kalachakra suggest ours is one among countless world systems. Evolution of a particular world system is understood in terms of four stages 1) Emptiness 2) Formation 3) Abiding and 4) Destruction. Each of these stages is thought to last a tremendously long time. At the heart of this idea is that there are not only multiple world systems but they are in a constant state of coming in to being and passing away. According to Dalai Lama, the idea of a single beginning, a singular big bang, is inaccurate – because such a singular beginning could suggest one of two things 1) Theism which suggest a universe created by an intelligent designer 2) Universe came in to being with no cause at all as hard atheism suggests. Surprisingly (for me), it appears Buddhism, like science, share a fundamental reluctance to postulate an intelligent designer. Buddhism in turn proposes the following origin story; In the beginning was the vast void; out of which (“emptiness”) a new universe if formed; this universe go through immense period of expansion, and is finally destroyed or turn back to pure emptiness. And the cycle continues. What is remarkable is how closely this indeed resembles our best understanding on the structure and life cycles of the cosmos.

A Mahayana text titled “The flower ornament” describes with precision about the large number of “worlds” and the limits of human knowledge. A section titled “incalculable” contains numbers named “the measureless”, the “boundless”, the incomparable” and “square untold” which is “unspeakable” multiplied by itself! Amazing that they were at least thinking of really huge quantities at a time when our everyday experiences did not require use of such large quantities. As any one familiar with modern cosmology must have read, the currently accepted "pre big bang" cosmology mandates vast amount of "parallel universes". And famous Physicist Lawrence Krauss discuss in explicit details in his fascinating book A Universe From Nothing how an entire universe could form literally from "nothing" - where "nothing" is described as unstable quantum form from which, statistically at least, an entire cosmos could arise.

Evolution, life and consciousness in Buddhist traditions:

For a brief overview of the modern ideas on consciousness, please click on the link (Some Random Thoughts on Consciousness) The Buddhist realm consists of three realms of existence – the desire realm, the form realm and the formless realm, each progressively subtler and higher levels of existence. The formless realm transcends physical sensations and lives in a purely mental realm. Human evolution in Buddhist philosophy is somewhat “anti Darwinian” – it suggests humans have “descended” from a higher level of life; from “formless celestial beings”.  This is of course very different from the “upwardly mobile” ideas accepted in science where humans have evolved from apes. Dalia Lama readily accepts the modern Darwinian rules of evolution, though he believes in some of the ancient ideas of Karma and the permeation of energy and consciousness throughout the cosmos, something that cannot be contained in a vessel or within a single body. He argues for additional forces other than “survival of the fittest” should have shaped evolution to explain emotions like love and altruism. At least in this section, His Holiness appear to wobble a bit, as clearly defined Darwinian rules of group selection and even anatomic features (like Mirror neurons) appear to explain these puzzles clearly. Unfortunately even Dalai Lama confuses Darwinian Theory with the much maligned social Darwinism, which has nothing to do with the scientific theory of evolution.

With regards to consciousness and the study of “qualia” or that indescribable “inner feelings”, Dalia Lama gives an excellent over view the Eastern ideas on this most elusive of subjects. He describe that the Tibetan word “Namshe” or Sanskrit “Vijnana” encompasses a much broader range of conscious experiences. Buddhist philosophy describes consciousness as “luminosity” and “cognizance” as the two features of consciousness. As the primary feature of light is to illuminate, so consciousness illuminate the objects. Buddhism suggest three fundamental aspects of the world – 1) Matter consisting of physical objects and energy 2) Mind – subjective experiences 3) Abstract composites or mental formations  like a theorem in Mathematics. Consciousness transcends both the realm of Mind as well as Abstract composites. This is surprisingly similar to the ideas of Karl Popper. 

He asks a very valid question on the nature of consciousness – that while we have known the levels of certain neuro transmitters like serotonin can affect our emotions, could it be also true that the “emotions” came first and changed the level of the neuro transmitter? He briefly also dwells in the controversial topic of quantum mechanics as an explanation of consciousness, including the “non locality” as described above in the EPR paradox and how the observer and observed could be part of a larger quantum system. He talks about the ideas of Buddhist thinker Dharmakirti, who argues that the rational basis of rebirth (that the consciousness comes from a prior instance of cognition, so the consciousness of the new born also must have existed prior to being born). Then he explores how meditative practices could change our consciousness (this is a well researched field with empirical evidence supporting the notion that meditative practice could indeed change our brain’s “wiring” as is shown in several experiments using functional MRI). He quotes the work of Nagarjuna “Praise to the Ultimate Expanse” which argues that essential nature of the mind is pure and the mind can undergo meditative purification from impure thoughts. The modern ideas of neuro plasticity (that new connections between neurons can be formed and brain is highly malleable even in adults) support many of these traditional Buddhist arguments.

In short, this is an unusual book written by an unusual and charismatic Religious leader. Even though the category of "science and spirituality" is a subject matter of many books, this book shines through for it's simplicity, humility and deeply spiritual writing, just as the author Himself. His Holiness, who appears to possess the inquisitiveness of a child while also deeply well read not only about classical Indian and Buddhist philosophy but also well versed in the language of modern science, shows science and spirituality can not only co exist but inform and strengthens each other. A must read for anyone interested in these timeless questions.