The First Cell

by Azra Raza

  HOW MANY OMARS AND ANDREWS WILL IT TAKE?

  Why did we only diagnose Harvey when his lymphoma was widespread throughout the body? Or Omar when his sarcoma was already spilling cells into blood vessels, invading surrounding muscles, settling in lungs and limbs, or Andrew’s tumor only when it had grown to a nine-centimeter mass, threatening to choke the spinal cord, making him quadriplegic within days of the initial symptoms? Why are we not doing more to detect the earliest sign of cancer instead of chasing after the last cell with draconian treatment options? This leads to the question of why would anyone be looking for cancer in a twenty-two- or a thirty-eight-year-old man? Of course, no one is immune to cancer at any age. Every individual has to be monitored for it on a regular basis. The science and technology must be developed to make this happen. Cancer must be prevented at a precancer level. I am not the only one saying this.

  It is universally acknowledged that early detection is the key to the cancer problem. This is why screening procedures were set into motion decades ago and early detection has reduced mortality by at least 25 percent. Now we need to trace our way to even an earlier detection of cancer cells, prior to their appearance on scans. So why is it that only 5.7 percent of the total budget of the National Cancer Institute is allocated toward this critical area of research? Why is 70 percent of the budget funding research that concentrates on advanced malignancies conducted on animals and tissue culture cells that will lead to clinical trials with a failure rate of practically 90 percent? Why isn’t it just the opposite, with the majority of support going to detect cancer at its inception?

  How many Omars, how many Andrews, will it take?

  What would it have taken to cure Harvey? There are many cancers curable by surgery, chemotherapy, radiation therapy, and stem cell transplants. Which cancers are curable hasn’t changed much in recent years. Most advances in cancer treatment have been incremental and have focused largely on better identification of the patients who are likely to benefit from each. Of the cancers resistant to these approaches, little progress has occurred in the past five decades. Targeted therapies and individualized precision medicine approaches benefit a small percentage of patients by adding a few months to their survival while costing enormous physical and financial burdens. Immune therapies have been in trials since 1910 in various forms and sporadically help subsets of patients.

  I have already argued that a major part of the problem is the reliance on unreliable preclinical testing platforms and animals for preclinical research. I am not against the use of animal models across the board. In biologic research using these same models, great progress has occurred in understanding cancer at the molecular level. Most of these advances have occurred through careful study of tissue culture cell lines and animal models, be they the fruit fly, zebra fish, worms, rodents, or apes. But they have been useless as preclinical drug-development platforms. If we continue in the same direction, spending precious resources to improve the same models, it will take us another few hundred years to arrive at a meaningful solution for cancer.

  Contrast the putative scientific gold standard of a reproducible animal model with the known fact that every patient’s cancer is a unique disease, and within each patient, cancer cells that settle in different sites are unique. When a malignant cell divides into two, it can produce daughter cells with the same or radically different characteristics because during the process of DNA replication, fresh copying errors constantly occur. Even if two cancer cells have identical genetics, much like identical twins, their behavior can differ depending on genes expressed or silenced according to the demands of a thousand variables, such as the microenvironment where they land, the blood supply available to them, and the local reaction of immune cells. The resulting expansive variety of tumor cells that exist within tumors are unique within unique sites of the body. Multiply this complexity further by adding the host’s immune response to each new clone and you get a confounding, perplexing, impenetrable situation in perpetual flux.

  Disease complexity is not restricted to cancer. Jon Cohen reported in Science on the failure of an anti-inflammatory antibody in having any benefit for human HIV after a study demonstrated cures in monkeys intentionally infected with the simian form of the AIDS virus. Attempts by an independent team to replicate the results in a second set of diseased primates also failed. The conclusion by the head of the National Institute of Allergy and Infectious Diseases, and a coauthor on the study, was that the original monkey results “might be a fluke.” While such an unusually candid admission is laudable, the question I have relates to the path forward. What steps has the agency taken to shut down animal studies of this nature susceptible to unpredictable happenchance? Despite these findings, why are we continuing to invest hundreds of millions of dollars into animal studies with the delusion that the next one will provide clinical guidance for humans? Why are we, the public, not demanding more accountability about the way our resources are being allocated? Who are the beneficiaries of these resources, and why? The patients certainly are not.

  The ultimate aim of all cancer research is to find better therapies, yet the means we have employed for the study of human tumors are grossly inadequate, especially the drug-testing platforms. We remove a few cancer cells extracted from a minute sliver of the tumor, plate them in dishes or inject them in mice, and expect them to recapitulate the vast heterogeneity of the evolving, expanding, transforming, invading, regressing, recovering, transmuting population of malignant cells in vivo. Whatever grows out cannot be representative of even that small sliver because upon removal from their normal habitat, cells change characteristics as they adapt to new environments. There is more than ample evidence to show that cell lines growing in vitro resemble each other more than the tissue of origin (liver, lung, pancreas) from which they were derived. They manifest a uniform “transcriptomic drift” in that the majority of genes expressed by all cell lines are ones needed for survival ex vivo. How can scientists, who demand great precision in everything they do, simply turn their eyes away from such fundamental fallacies?

  So what is the solution? The first step is to descend from our high horses and humbly admit that cancer is far too complex a problem to be solved with the simplistic preclinical testing platforms we have devised to develop therapies. Little has happened in the past fifty years, and little will happen in another fifty if we insist on the same old same old. The only way to deal with the cancer problem in the fastest, cheapest, and, above all, most universally applicable and compassionate way is to shift our focus away from exclusively developing treatments for end-stage disease and concentrate on diagnosing cancer at its inception and developing the science to prevent its further expansion. From chasing after the last cell to identifying the footprints of the first.

  BY THE TIME of diagnosis, one centimeter of the tumor contains roughly three billion cells. This is far too many cells needing elimination. A millimeter of tumor carries three million cells, and a 0.1 millimeter tumor approximately three hundred thousand malignant cells. The future lies in developing technologies to detect the presence of very few cancer cells through telltale footprints. What are these footprints?

  The science of surrogate marker detection is in its infancy. Cancer cells die at a rapid rate, jettisoning revelatory biologic markers. Pieces of DNA, RNA, and proteins shed in a drop of blood, traces of cancer, can be detected as molecules exhaled in the breath. Or through recording changes in magnetic fields caused by the presence of very few cancer cells, or using antibodies that bind and reveal femtomoles of proteins (a billionth of a millionth mole, or very minute fractions of a gram).

  As seen repeatedly so far, a major problem with cancer is its silent, surreptitious nature. Tumors can replace a large portion of the organ in which they are growing without causing any symptoms. It is exactly what happened in the case of Suketu Mehta, Omar, and Andrew. Suketu lucked out by being diagnosed with lung cancer serendipitously, but by the time cancer in the other two was detected, the game was a
lready over. I had been working with deadly cases of AML for many years until I realized the hopelessness of chasing after so devious an enemy and turned my focus to early detection. I have been studying preleukemia for this purpose for thirty years, but since MDS can also kill with the vengeance of AML without ever becoming AML, I have also been committed to screening normal, seemingly healthy individuals for the earliest sign of MDS, AML, or cancer in general.

  Efforts to diagnose cancer early are as old as the declaration of war on cancer. Unfortunately, population-based, conventional screening programs costing astronomical sums of money have not yielded the dramatic success that was expected. Moreover, the assumption that early detection and therapeutic intervention would lead to cures has also been challenged through cautionary tales associated with these attempts.

  For one thing, screening can result in overdiagnosis and overtreatment, and this could harm patients and be an added financial burden on the health care system. Cancer begins in a single cell, but given the variability in growth rates, it can take decades to become clinically apparent, one study suggesting that the journey for breast cancer could be starting in utero. With the time line spreading over decades for some common tumors, the contention that finding a tumor and eliminating it urgently at some point in its natural history is the only way to cure it is clearly misplaced. It is therefore no surprise that many cancers detected early—say, through imaging or tumor-specific antigen tests—have proved to be of nonlethal varieties that would have responded to treatment even if detected at a later stage once they became clinically apparent.

  Of the aggressive cancers detected early, the news was also less than encouraging: the majority had already disseminated anyway, offering no advantage for early diagnosis. In breast cancer, for example, early detection of tumors with favorable molecular signatures was not helpful because the tumors would have grown so slowly as to be inconsequential within the life span of the patient, and even if they progressed to a clinically detectable state, they would be amenable to standard available treatments. Early detection of more aggressive breast cancer was not helpful because by the time the tumor appeared on a mammogram, it had already spread and was incurable. A review of multiple large population-based studies from several European countries examining the role of mammography as a screening tool led to a depressing conclusion by P. Autier and M. Boniol: “The epidemiological data point to a marginal contribution of mammography screening in the decline in breast cancer mortality. Moreover, the more effective the treatments, the less favourable are the harm-benefit balance of screening mammography. New, effective methods for breast screening are needed, as well as research on risk-based screening strategies.” The US Preventive Services Task Force recommends biennial screening mammography for women aged fifty through seventy-four, the current evidence being insufficient to assess the benefits and harms of screening mammography in the other age groups.

  As far as affecting mortality of prostate cancer, a meta-analysis of multiple studies also failed to show substantial improvement through PSA screening, D. Ilic and colleagues concluding that “at best, screening for prostate cancer leads to a small reduction in disease-specific mortality over 10 years but does not affect overall mortality. Clinicians and patients considering PSA based screening need to weigh these benefits against the potential short and long term harms of screening, including complications from biopsies and subsequent treatment, as well as the risk of over-diagnosis and overtreatment.”

  If there is one situation where early detection markers are urgently needed, it is ovarian cancer; notorious for being a killer of fourteen thousand women annually in the United States, the disease is generally diagnosed when it is already beyond the grasp of curative therapies. Cancer antigen 125 (CA-125) produced by as many as 80 percent of epithelial ovarian cancers, detectable in the blood with a simple test, was hailed as a welcome advance. Screening studies, however, revealed fundamental problems with the test, calling its use as a screening tool into question. First, the amount produced by early, small tumors is undetectable in the blood, and by the time blood levels increase, the tumor is already far advanced. Its levels seem related more to the tumor burden since 90 percent of women with stage II ovarian cancer tested positive as opposed to only one-third to one-half with stage I disease. Second, CA-125 is not always a harbinger of malignancy, present in rare cases of benign, inflammatory situations. This may be why a Swedish study found only 6 cases of ovarian cancer (with 2 out of the 6 at the targeted early treatable stage) from 175 exploratory surgeries following random screening of 5,500 women. CA-125 measurement is more suited to monitoring the efficacy of a given treatment in established cases of cancer since diminishing levels relate to regressing tumor burden. Clifton Leaf, in his excellent book The Truth in Small Doses, concludes about CA-125: “The point of diagnostic screening is to alter the outlook for many individuals while keeping the cost of unnecessary intervention low. This biomarker, as with hundreds of other well-touted candidates, managed neither.”

  Based on minor successes compared to the enormous investment of resources since 1980 in population-based, conventional screening measures, Hans-Olov Adami and colleagues have called for an end to such studies altogether since “population-based early detection screening for cancer has not fulfilled our expectations, and indeed induced considerable harm to a large population of healthy individuals.” They propose saving early detection screening measures for populations at high risk of developing cancer, either because of genetic susceptibility or through lifestyle risks and exposures.

  On the other hand, screening has helped save lives of colorectal cancer patients. These cancers start out as benign adenomas and progress in a stepwise manner from stage I through IV so that early detection is helpful. Similarly, screening for cervical cancer, which also progresses through distinct stages from dysplasia to stages I through IV, worked dramatically, as deaths from cervical cancer declined substantially when the Pap test became common practice. Despite the many pitfalls in screening measures, the 25 percent decrease in overall cancer mortality between 1990 and 2015 is largely due to high-quality screening for breast (down by 39 percent) and colorectal cancers (down by 47 percent in men and 44 percent in women). Of note, most of this screening is preventive screening and not early detection of an established, bona fide cancer.

  To summarize, early detection screening tools available thus far are helpful in preventing cancers that evolve in well-defined stages but fail to benefit cancers of unpredictable potency. The latter would include thyroid, prostate, and some breast cancers, where size may not correspond directly to metastatic potential—a small tumor potentially capable of shedding cells early in its development, while larger ones may follow a less aggressive natural course. The challenge is how to improve detection of precancers through minimally invasive tests before they become cancer.

  Improved cancer treatments have helped only a fraction of the 1.7 million patients diagnosed annually, resulting in 600,000 deaths in the United States. Through early detection and preventive measures, we can save the lives of 120 million, one-third of the population slated to get cancer in their lifetime.

  IMAGINE A MACHINE that automatically images your entire body while you are in your morning shower. Or a smart bra that has two hundred tiny biosensors built in to monitor micro-alterations in temperature and texture; worn for an hour a week, it generates sufficient data on an accompanying app to show distortions created by the presence of very few cancer cells. Or taking a pill whose contents are absorbed preferentially by cancer cells, excreted in the urine, and detected by a Fit Loo. Or receiving a cocktail of reporter genes whose protein products can be imaged with handheld devices to pinpoint cancer cells anywhere in the body. How about yelling at a cancer using ultrasound, compelling it to reveal its presence and its lethal potential as the tumor is forced to shed more markers into the blood when hit by waves at the right frequency? Or exhale deeply into a device that accurately recognizes the earliest footprints of c
ancer. Or simply prick your finger periodically to provide a drop of blood to a magneto-nano-sensor that identifies surrogate markers of malignancy instantly.

  The above are not scenes from Fantastic Voyage. These are real-life technologies in various stages of development today, heralding the dawn of a new era in cancer research. Sanjiv Sam Gambhir at the Canary Center at Stanford University is at the forefront of this revolution in early detection of cancer from blood, urine, stool, saliva, breath, and tears, using a host of genetic, sonic, and imaging methods. The emergence of these groundbreaking technologies is a direct result of collaboration between experts coming from many disciplines—geneticists, biomedical engineers, radiologists, oncologists, molecular biologists, nanotechnologists, AI experts, computer scientists, and bioinformatics wizards. Even in sports, teamwork and cooperation win the day, so why not in cancer?

  Here is one scenario for the future. Everyone from birth to death is regularly screened for the first appearance of cancer cells in the body. Once detected, protein markers would be identified, providing a zip code for the cancer cells. A tube of blood from the individual would be obtained, and T cells would be isolated, activated, and armed with the address for the cancer based upon the unique protein bar code and the RNA signature it expressed. These CAR-Ts can be injected back into the individual to seek out and kill every cell with that address. None of the toxic effects seen with the present CAR-T therapies would be an issue because the tumor mass would be minuscule compared to what we target now. Eventually, we should not even have to draw blood for screening. Rather, every infant would be fitted with an implantable tiny device at birth that would constantly monitor for such a mishap, send signals in a timely manner so that confirmation, validation, and treatment could swiftly follow. The ideal is to find every cancer at the precancerous stage through perturbations in disease-prone networks detected via dynamic monitoring by implanted devices. Of course, this is the dream scenario and far from current practices. There are a thousand slips betwixt this cup and lip, but we will never get there if we don’t start. Besides, I have great faith in the ability of humans to step up and innovate rapidly as long as they have a goal and are financially incentivized to do so. The goal now should be spelled out in no uncertain terms. We are to stop developing minimally effective therapies and go for nothing less than a humane cure that will be applicable globally. The best cure will be prevention.