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Musings of a Cancer Doctor

Wide-ranging views and perspective from George W. Sledge, Jr., MD

Wednesday, April 14, 2021

By George W. Sledge, Jr., MD​

Lately, COVID-trapped and bored with my surroundings, I've become captivated by a select few YouTube pursuits. One of them is mudlarking, and the other metal detecting. Go to YouTube, put either into the search function, and you will be introduced to a world of enthusiasts, some odd, some interesting, and all determined.

Both mudlarking and metal detecting involve a search for small treasures. Of the two, mudlarking is the more focused pursuit. Mudlarkers walk along the banks of a tidal river at low tide, picking through the flotsam and jetsam released from the river's banks. London's Thames River is the home of mudlarking, and mudlarkers there actually obtain a license for the opportunity to harvest the banks of the Thames.

For those who are interested in mudlarking, I would recommend either Nicola White's YouTube vlogs, or alternatively (for a deep dive) Lara Maiklem's book on the subject, Mudlark: In Search of London's Past Along the River Thames. Maiklem also has a nice Facebook page which appears to serve as a sort of clearinghouse for the Thames mudlarking community. Both of these women are passionate and amusing guides to the pleasures of pulling old things out of mud.

The old things, if one lives in London as opposed, say, to Palo Alto, can be quite interesting: ancient coins, both Roman and medieval, are regular finds. There seems to be an amazing abundance of clay pipes as well, many dating from the 17th century and adorned with unusual decorations. Mudlarkers, at least the ones I see online, also appear to have a soft spot for broken pottery. Nicola White's house appears to be filled with pipes and shards of pottery.

Mudlarking is, by and large, a solitary pursuit, and one requiring hours of careful perusal of small stretches of the landscape. Nature is said to abhor a vacuum, but mudlarkers know that river banks abhor straight lines and perfect circles. They develop an eye for straight lines and perfect circles.

Mudlarking is not a high-tech proposition, and most mudlarkers appear to use no tools other than pattern recognition and a small trowel. For a more high-tech pursuit, one turns to metal detectorists. If you have ever walked down a beach, you have probably chanced upon a metal detectorist swinging a device slowly back and forth, waiting for a beep that indicated the presence of metal.

Metal detecting requires a real investment of time and at least modest expense. Looking at metal detectors on Amazon, I find equipment ranging from $89 to $365, well within reach of most hobbyists. These apparently vary in their sensitivity and specificity, though having never used one I have no way of judging.

When I watch metal detectorists extol the virtues of their hobby on YouTube, they routinely speak of spending hours searching all types of land and water for hidden treasures. The return on investment cannot be very high. If my review of YouTube excursions is at all representative, a big haul for a metal detectorist frequently involves a miscellany of 20th century dimes and quarters. Given the time devoted, what they find represents a sub-minimum wage payout. But hobbies have rarely been about money. We fall in love with a subject and pursue it past all reason, a crime that many of us have been guilty of during our lives.

There are exceptions. British metal detectorists are in it for the big score. Their great white whale involves discovering an ancient hoard of gold or silver objects. These hoards reflect the nasty history of the British Isles, with the Roman conquest, the subsequent Roman withdrawal three and a half centuries later, the barbarian invasions of the Angles, Saxons and Jutes, Dark Age kingdoms struggling for power, Viking looters and the eventual Norman Conquest. Whenever something bad happened, you buried your important stuff hoping the raiders would move on. Then, apparently, you died, probably horribly, before you could retrieve your riches. Your riches then awaited some middle-aged guy with a big gut, too much time on his hands, and a Garrett Ace 300 Metal Detector 15 centuries later.

The great recent example of how this can pay off is the Staffordshire hoard, the largest hoard of Anglo-Saxon gold ever found. Metal detectorist Terry Herbert, searching in a farmer's field in 2009, discovered a hoard consisting of over 3,500 items, consisting of 5.1 kg of gold, 1.4 kg of silver, and 3,500 pieces of garnet cloisonné jewelry. The hoard is absolutely gorgeous. You can see it online at www.staffordshirehoard.org.uk.

Because of strict national laws, the Staffordshire hoard was declared a national treasure. The metal detectorist and the farmer shared a 3.285 million pound reward, the archeologists got to examine it in situ, and the hoard stayed in the hands of a British museum. The British take these national treasure laws seriously: a more recent hoard, discovered by metal detectorists and initially hidden from the authorities, resulted in jail time for the miscreants.

Again, unlikely that I will find anything similar in Palo Alto, unless some computer mogul buried the code for the next Google or Facebook in my backyard. You have to have had plundering hordes of barbarians to hide and find a hoard, and so far that hasn't happened around here. Still, I can dream, or at least watch dreaming metal detectorists.

What I find interesting about all this is how the British have dealt with their mudlarkers and metal detectorists. Leaving aside the national treasure angle, a distinct minority of the finds, the vast majority of finds are small, not financially very valuable one-offs. But collectively they amount to a vast national experiment, in which citizens collect enormous quantities of potentially interesting historical material that paints the story of an evolving population over time. The British Museum, realizing this, created the Portable Antiquities Scheme, in which the mudlarker or metal detectorist can go online and enter a find. To date 1,520,563 objects have been entered.

The objects are entered into a searchable database, which in turn can be used by researchers to study questions of interest in archeology. Looking at the scheme's website, some 732 projects are in process or completed, with an outsize number of the projects being at the undergraduate, master's, or PhD level of research. There have been numerous papers published in the peer-reviewed literature as well, mainly statistical analyses of the collective hauls of this or that cultural object that illuminates some important part or interesting aspect of British history.

This brings us to the subject of citizen science. If an army of mudlarkers and metal detectorists can, working for free, provide the raw data for over 700 research projects in a single field, what can non-academics do to forward research across the broad sweep of science? The answer is quite a lot.

That we even ask a question like this says something about the times we live in. In the 19th century, one would not have even raised the question. Amateurs ruled science, or at least played a major and important role. Was Charles Darwin, who held no academic position for his entire career after coming home from the voyage of the Beagle, a professional scientist? Yes, though not an academic: he had no lab or office hours in Cambridge or Oxford. We so equate academic science with professional science today that we have a hard time grasping the 19th century career of a Darwin.

But that was then. Today science requires infrastructure, financial support, and extensive training. What is the role for the inspired amateur?

If one goes to our friend Wikipedia and queries for “Citizen Science" a whole world of scientific projects in which nonscientists provide major contributions is revealed: amateur astronomy, ornithology, studies of coral reefs, biodiversity, pollution monitoring, and many, many others.

Medical science has been somewhat of an outlier in this regard. The Wiki section on “Health and Welfare" has this sad comment: “In the last decades, researchers and funders have gained awareness of the benefits from involving citizens in the research work, but the involvement of citizens in a meaningful way is not a common practice." Is this a function of some of the specific rules of the road for medicine, the highly structured, overly legalized nature of medical research, with reams of paper devoted to informed consent statements? Or are we just slower off the mark than our colleagues in other sciences?

It is a wasted opportunity. Within the breast cancer field, my area of specialization, I'm certainly aware of—and have participated in—studies carried out through volunteer patient organizations, and some of these (such as the 390,000 member-strong Love Research Army) were explicitly created to connect breast cancer patients to researchers with specific research projects. In addition, the innovative translational scientist Nikhil Wagle created the MBCproject, a national registry in which breast cancer patients with metastatic disease donate clinical data, biopsy material, blood, and saliva for research purposes, escaping the institutional walls that so limit cancer discover. Indiana University's Komen Tissue Bank, at the other end of the breast cancer spectrum, collects demographic data, normal breast tissue biopsies, and blood from a diverse group of volunteers at sites around the country for use by investigators globally.

Outside of breast cancer, the field of protein chemistry has benefitted from the existence of [email protected], in which citizen scientists can link their PlayStation 3s (and other graphical user interface devices) to a distributed computing network that then teases apart the mysteries of potentially druggable molecules. The project has contributed data to over 225 scientific papers in a wide array of fields, including cancer.

For instance, [email protected] performed the first computer modelling of the molecular dynamics of p53 refolding. It is wicked fast, the first computer system (it is claimed) with exaflop capability. An exaflop, for those not sufficiently computer-geeky, is one quintillion (1018) floating-point operations per second. If one were to do this by hand at a calculation per second, it would take 1,688,765,000 years, which is longer than most funding agencies allow.

These projects, valuable as they are, have largely employed cancer patients and others as donors of raw materials rather than as investigators in their own right. Might we not be able to open up the vast databases that have accumulated over the years to non-academics, allowing them to be, not just the mudlarkers and metal detectorists of medical science, but true hypothesis-testing citizen scientists? The will to do this among our patients, who are desperate for answers, would be huge, and my clinics are stuffed with people who are smart and statistically literate. The barriers (legitimate privacy concerns, siloed information, byzantine regulations, fear of being scooped, the snobbishness of the scientific priesthood) are of our own creation and stand athwart our efforts to beat this disease.

Until we change this, we will continue to scour the banks for the odd glittering coin, the pretty shard of pottery, the clay pipe buried in the mud. 

Monday, November 30, 2020

By George W. Sledge, Jr., MD​

As I write this, it is Thanksgiving morning in Palo Alto. It is a lovely fall day, a little cool with clear blue skies. It is a deeply strange Thanksgiving, and for me a sad one. My three sons are spread across the continent, in Louisiana, Texas and New York, the first year ever we've not shared a dinner table for Thanksgiving. We will meet on a Zoom videoconference this evening, but it will not be the same.

Thanksgiving is my favorite holiday: uniquely American, not overly commercialized, devoted to families gathering and sharing the Earth's bounty. Or, to put it another way, a holiday devoted to eating too much and watching football on TV. What's not to love?

In addition, there's the comforting history of the first Thanksgiving, celebrated in September or October (not November) of 1621. The Pilgrim fathers had landed in Plymouth, Massachusetts, the previous year and had spent the winter starving, with half of those brought on the Mayflower lost to famine and despair. The following year the survivors had raised crops (especially corn, learned from Native Americans), and after the crops came in decided to hold a harvest banquet.

The banquet was attended by 53 Pilgrims and about 90 members of the Wampanoag tribe, led by their chieftain Massasoit. We know the names of the cooks, which is pleasing: Eleanor Billington, Elizabeth Hopkins, Mary Brewster, and Susanna White. And we have a pretty good idea of what the attendees ate: wild turkey, waterfowl, cod, and corn. The Wampanoag, being good guests, brought five deer they had killed, so venison was on the menu. The historical sources make no mention of cranberries, though the first Pilgrim cookbook, admittedly published a generation later, has a recipe for cranberry sauce, and cranberries are found in local bogs, so I'd like to think that was served as well. An interesting fact: their alternate name for cranberries was bearberry. Bears find cranberries quite tasty. Never get between a bear and cranberries.

The feasting went on for 3 days. The Pilgrims early survival was contingent on the Native Americans, who might easily have wiped them out but instead taught them how to grow corn, beans, and squash. Within 2 generations, the English settlers' ethnic cleansing of Massachusetts largely eliminated their Wampanoag guests, with the exception of a small number who still live on Martha's Vineyard and a few other sites. An important lesson: never assume that, just because someone invites you over for Thanksgiving dinner, they are friends for life. But for those 3 days they were friends.

Why didn't the Wampanoag simply eliminate the Pilgrims before they became an existential threat? It is likely because the Pilgrims landed in an area that had just undergone the massive decimation of the local Native American population. John Smith, who had sailed along the coast of New England in 1614, has found it “well inhabited with a goodly, strong and well proportioned people." But within a few years, a devastating disease outbreak (probably smallpox, though other diseases have been suggested) killed something like nine out of every 10 of the Wampanoag. Did the survivors speak, like our President, of having been infected with the "English virus?" I doubt they considered it a political hoax aimed at undermining the re-election of Chief Massasoit.

Culture, as much as biology, plays a role in infectious outbreaks. One cultural practice that historians point to as possibly important was the existence of sweat lodges, heated rooms where the infected would come to sweat out the disease, surrounded by family and friends. These could become super-spreader events in populations with no prior exposure to foreign microbes. Will 2020 Thanksgiving dinners, where Covid-weary Americans, heedless of CDC warnings, fly across the country to congregate with those they love, turn into modern sweat lodges? I hope not, but fear so.

One can rewrite American history quite easily. No pandemic, and the Pilgrims become unwanted immigrants, easily overwhelmed by a populous, well-organized Wampanoag tribe, backed by a larger Algonquian federation. But I want to believe that the Wampanoag, having like their Pilgrim hosts survived terrible tragedy, felt the need to share and care for their fellow humans. Historical contingencies fascinate, and we are living through one: 2020 without the coronavirus would have gone very differently.

Let me move on to today's Thanksgiving dinner. A survey of thanksgiving dinner dishes I came across suggests that 84 percent of those polled listed turkey as the main source of protein. The side dishes are a more diverse mix: mashed potatoes come in at 34 percent, stuffing at 27 percent, with smaller numbers voting for mac and cheese, green bean casserole, cranberry sauce, and sweet potatoes. Pumpkin pie is the favorite desert by far.

But is all this good for you? That's a legitimate, and somewhat complicated question. I'll try to address it here. And, since I'm a medical oncologist, let me ask if there any cancer implications. As if you didn't already have enough to worry about as 2020 draws to a close.

Let's start with turkey, assuming you are not, like one of my sons, a vegetarian. Turkey is a health food, a great source of protein, as well as Vitamins B2, B3, B6 and B12, selenium and zinc. It has a low glycemic index and is relatively low fat. It is full of tryptophan, which through conversion to serotonin is good for your sleep. Unlike processed meats or barbequed beef, it isn't particularly carcinogenic. Overall, two thumbs up.

The Sledge family has always been big on cranberries for Thanksgiving. Cranberries have been touted as a means of reducing the risk of urinary tract infections through alkalinization of urine, though apparently the number of cranberries this would require is excessive. I've also read, in the August Journal of Agricultural and Food Chemistry, that cranberry extracts have chemopreventive effects against colitis-associated carcinogenesis in mice, which sounds nice, though I'd still want a randomized controlled trial before we start prescribing it to familial polyposis patients. Cranberries also prevent H. pylori colonization in the stomach, so fewer ulcers and stomach cancer. Cranberry juice lowers systolic blood pressure a few points, which is all to the good. Mostly I just like how they taste.

Sweet potatoes are also quite healthy, to my delight. They are high in Vitamins B6, C and D, and contain goodly amounts of iron, magnesium, and potassium. They are loaded with beta carotene, with its presumed chemopreventive effects. Presumed, because Vitamin A failed to prevent carcinogenesis in several randomized controlled trials. But I still give sweet potatoes an “A" for effort.

Pumpkin pie for dessert also gets high marks in my book. Pumpkins are a great source of fiber, better than whole wheat bread. They contain the antioxidants lutein and zeaxanthin, which a Google search assures me may prevent cataracts. I have early cataracts, so I will be sure to eat an extra slice of pie. Like sweet potatoes, they are high in vitamin A (though I probably have enough of that already), as well as riboflavin and folate. But pumpkin pies are pretty fatty, so maybe just one slice after all.

Mashed potatoes, as far as I can tell, are somewhat of a wash. The recently reported NIH-AARP study, which recruited over 566,000 participants and followed them for over 15 years, reported no excess in cancer or cardiac mortality for high potato consumption. The American Diabetes Association considers potatoes an appropriate food for diabetics, as their starches are broken down more slowly than the simple sugars found in so many foods.

I could go on and on, depending on which side dishes you like. Overall, though, Thanksgiving dinner seems pretty healthy, assuming you don't drown in calories. Maybe even good for you from a chemoprevention standpoint. Especially the cranberries. But in this year of COVID-19, the health effects of Thanksgiving dinner are something more than cranberries and pumpkin pie.

Let me end with Abraham Lincoln, that great man who, in addition to saving the Union and ending slavery, issued the 1863 presidential proclamation that established Thanksgiving as an American holiday. Lincoln's proclamation noted the horrors of war through which the United States was passing, but also reminded his fellow citizens of all they had to be thankful for: “the country, rejoicing in the consciousness of augmented strength and vigor, is permitted to expect continuance of years with large increase of freedom."

His proclamation concluded with these lovely words, which I'll quote in full: “I do therefore invite my fellow citizens in every part of the United States, and also those who are at sea and those who are sojourning in foreign lands, to set apart and observe the last Thursday of November next, as a day of Thanksgiving and Praise to our beneficent Father who dwelleth in the Heavens. And I recommend to them that while offering up the ascriptions justly due to Him for such singular deliverances and blessings, they do also, with humble penitence for our national perverseness and disobedience, commend to His tender care all those who have become widows, orphans, mourners or sufferers in the lamentable civil strife in which we are unavoidably engaged, and fervently implore the interposition of the Almighty Hand to heal the wounds of the nation and to restore it as soon as may be consistent with the Divine purposes to the full enjoyment of peace, harmony, tranquility and Union."

To which I can only add my own “Amen." Let those of us who give care, care for those who have become widows, orphans, mourners or sufferers. And let me wish all of you peace, harmony, tranquility and Union, and our world continuance of years with a large increase of freedom. We, like Lincoln's America, certainly need all of these. Some thoughts are for the ages.

Friday, October 9, 2020

By George W. Sledge, Jr., MD

The COVID-19 pandemic, and the "sheltering in place" it brought with it, has made me appreciate my backyard. It's not a large space, just a smallish rectangle bordered on two sides by stucco walls, on the third by a freestanding garage that we used as a storage area, and on the fourth by our house. I've enjoyed sitting on the back porch doing my work these past few months, but often I'm just taking in my majestic domain.

Backyards in my Palo Alto neighborhood are small. I can walk across mine in 15 or 20 seconds. It is a humble locale and will never find its way to Better Homes and Gardens, but it is the place of small miracles. Let me share some of them with you.

Surveying the Landscape

Taking a census of the denizens of my backyard doesn't take too long. I am horrible at identifying plants. I've lost most of what I learned in the Boy Scouts, or in that single semester of college botany. Nor am I an amateur landscape architect. The previous owners clearly set store by their ability to populate the backyard with interesting flora, but much is wasted on me.

I do see two small palms, which I am unable to identify with online resources. There are a few pines, quite lovely in their own way, and what looks to be a young willow. But the plant I appreciate the most is a sage bush with lovely pink and white flowers. I've looked through books trying to decide what species this is. One online resource said that there are 89 different species of sage in California. I looked at their pictures trying to decide which is mine, but nothing I saw looked quite right.

I love the sage because it is beloved by honeybees and hummingbirds. I'll be outside early in the morning and suddenly a hummingbird will dart in, place its beak in a sage flower, then another, then dart away again.

I'm fascinated by these small creatures. They weigh less than an ounce, insubstantial little beauties. They are, I have read, the only bird that can fly both forwards and backwards. Sometimes one will hover a few feet away from me for a few seconds, eyeing me as I look at it, then zip off. Hummingbird facts seem like fake news: their wings beat up to 80 times a second, and their hearts 1,200 times a minute when in flight. To maintain such a high metabolism (the highest of any non-insect animal) they eat prodigiously, and love plant nectar, though they also cleanse my backyard of mosquitoes and gnats. They may eat half their body weight in nectar every day. They are small miracles.

Hummingbirds are limited to North and South America. The ones in my backyard appear to be Anna's hummingbirds, the most common species in California. The males are quite beautiful, a mix of iridescent green on the body and reddish pink around the head and throat. The females are less flashy, mostly gray-colored, though for some reason it is the females that always look me over the most when I'm watering the plants.

Anna's hummingbirds, in case you are interested, are named after Anne D'Essling, a courtier in the court of Empress Eugenie, the wife of Napoleon III of France. Anne is described as having been "pretty and refined in appearance, with an exceedingly lofty manner, though small in stature," which could be a pretty good description of her eponymous hummingbird. Why were my hummingbirds named after her? She was friends with René Primevère Lesson, the ornithologist who first described the species. It's good to be friends with scientists: they name things after you.

None of this matters, of course, other than in a Trivial Pursuit sort of way, but that's sheltering in place during a pandemic for you.

I love the hummingbirds, for their beauty and acrobatic grace. But I respect the California scrub jays (Aphelocoma californica) that patrol my backyard. These birds have a mixed reputation. They are—how shall I put this—thugs and thieves. They attack hummingbirds and eat baby birds of other species. For that matter, they are quite willing to attack people if riled up enough. Gangs of scrub jays will even murder their own, pecking them to death in grisly territorial displays. One recent local newspaper article called them "bullying," "harassing," and "the most hated birds in the Bay area." They steal food from other animals. Their bird calls are not mellifluous. The calls—no one would ever call them songs—have been described as, variously, a scratchy weep, a harsh scold, a guttural growl, and (when alarmed) a rapid, mechanical "hiccup" sound. You cannot confuse a scrub jay for a lark.

So not loveable, indeed downright obnoxious, but a species I respect. They are quite brilliant members of the genius Corvid family (along with crows, ravens, and magpies), arguably the most intelligent of birds. There is an extensive scientific literature devoted to the California scrub jay. Though not large—they weigh in at just over 3 ounces—their brain-to-body mass ratio is the equal of chimps and whales, and only surpassed by humans.

I mentioned that they steal, and the food they steal they cache for later eating. They may hide food in as many as 200 places. Here's what's fascinating: they not only remember where they have cached food, they remember what they have cached. If they cache a worm or a grub—limited shelf life—they will come back and eat it before it spoils. But give them a peanut (they love peanuts) and they will store it for the long haul. As my wife pointed out to me, that makes them smarter than a lot of people we know with stinky refrigerators. And because scrub jays are total paranoids, they will frequently move their caches. They will watch other birds store food and steal from their caches. They have prodigious memories for human faces, even years later. They appear to be one of the few species that plans for the future.

They also appear to mourn their dead. Maybe mourning is not the right word, but jays appear to understand death, at some level. If a California scrub jay comes upon a dead member of its species, it will call other jays, who will perch over the dead jay, screeching for up to half an hour. Then, for the next day or two, they will avoid the area. I haven't seen jays sitting shiva myself, but it is extensively well-documented. Anyways, they are smart, and intelligence deserves respect, even if they are not beautiful like hummingbirds. Or so my inner nerd says.

Tending the Garden

Moving on. We harvest some small amounts of food from my backyard. We have a lovely and productive lemon tree that never seems to give up, balanced by a small, miserable tangerine tree that has never really gotten going.

As I'm writing this, it is summer, so we're raising tomatoes. I carefully water them every other day. We only planted five this year, mostly cherry tomato varietals. They love the hot, sunny California summer but are greedy for water, so I visit them regularly with a garden hose. Last week it poured rain for 2 hours or so, the first rain in months, and it allowed me some respite from watering them. The cherry tomatoes taste like candy—I pick them off the vine and pop them straight into my mouth.

I said we planted five tomato plants, but now there are only three. I came out in the morning to water the plants, and one had been pulled up by its roots, leaving only a few shredded leaves behind. And then, a few days later, another disappeared, chewed off at the base. I don't think it was a jay, and I know it wasn't me. The only other identifiable culprits large enough that I can identify are the neighbor's cats and the squirrels.

The squirrels are black, and like the scrub jays they are polarizing figures. Black squirrels, some think, fall into the "so ugly they are cute" category, but for others they are just rats with furry tails. I'm partial to them, even if one actually is the culprit in the great tomato heist. There is a wonderfully persistent urban legend attached to them, suggesting that they are the result of an experiment gone wrong in some Stanford genetics laboratory, released by mistake into the wild. Totally untrue, of course: the black squirrel is just a melanistic subgroup of the more common gray squirrels, the result of a 24-base pair deletion from their melanocortin 1 receptor gene, if you want to get all sciency about it. And CRISPR-Cas9 technology is too new to be blamed for their genetic engineering.

I'm at best a mediocre gardener. I can water tomatoes and do some minor weeding, but that is the extent of my accomplishments. When the weeds overgrow the backyard, we bring in some handymen who spend several hours pulling them out and mulching them, and filling bags for later disposal. Which reminds me of my clinic.

Oncologists are fond of analogies. We use them to turn complex concepts into something with a more human scale, something bite-sized and at least a little comprehensible. Antibody-drug conjugates become smart bombs, cell surface receptors are catchers' mitts for baseball-ligands, and immune checkpoints and their inhibitors call to mind having your foot off and on car brakes. The list could go on and on. We all have our favorites.

A common one involves the yard. Imagine, I tell my patients, a lovely green yard. Now imagine crabgrass proliferating and taking over that yard. Sometimes you pull the crabgrass out if there's a small localized patch. Let's call that surgery. Sometimes the lawn needs a good coating of herbicide: that's systemic chemotherapy for microscopic metastases.

But the analogies aren't that good in my backyard. When I lived in the verdant Midwest with its plentiful rain and lush green lawns, I could easily visualize that crabgrass analogy. All I had to do was step out my front door. Here in the Bay Area, where it's dry 9 months of the year and drought is the default mode to such an extent that we have an actual fire season, I have no grass in my backyard, hence no crabgrass.

But I do have weeds. After our brief wet season, the backyard looking unruly and unloved, we had the gardeners come and de-weed. Through no fault of their own—we under-instructed or under-supervised—they pulled out too much. Some lovely California poppies disappeared as did some fragrant mints. Our iris plants were in full bloom, and obviously ornamental, so they survived. But the overall effect was to create sterile, brown-looking soil unencumbered with vegetation. Almost like, well, life after high-dose chemo in the bone marrow, or some such.

That weedy yard metaphor had metastasized to my own backyard, now revised to include the toxicity of therapy. Analogies are tricky things.

I'm hoping that next spring the green will return, and the pretty orange poppies and the fragrant mints. I'll even take the weeds. What is a weed after all but a plant that is out of place? Cancer cells are not just milk ducts growing in the lung or colonic epithelium in the liver. They're abnormal, not just out of place. The weeds in my backyard arguably are not even that: just normal California flora that doesn't quite look right.

Let me finish with a patch of lichen near my back porch. This is a gray-green amorphous thing hugging a rock for dear life. I have read that lichen cover 7 percent of the land surface, but my backyard is certainly dragging that average down. I doubt it amounts to a square foot of coverage. But this is another small miracle. Try and live off of the nutrients provided by a rock and see how long you last. I've seen it there for years, never really changing. And that gives me comfort.

Lichen are a mixture of fungi with either cyanobacteria or algae or both, living in synergistic harmony. They are old creatures, having existed for 250 million years. It was thought, until recently, that they preceded plants onto dry land, but that apparently is not the case. They latch on to all sorts of surfaces, happily breaking them down: soil, tree bark, dead animals. And in my backyard, on a rock.

How do you eat a rock? The lichen's fungal filaments penetrate small cracks in the rock, excreting oxalic acids (of kidney stone fame) that dissolve minerals and chelate metals locked in stone. Over time—a very long time—they break down the rock. These small wonders work patiently on a seemingly impossible, Sisyphean task and will do so long after I'm gone. The world goes on, and we barely know it or record it. There's something wonderful in that.

Thursday, August 20, 2020

By George W. Sledge, Jr., MD

I am a very boring traveler. While I have gone to many fascinating places in my career, the vast majority have been for meetings: society meetings, continuing medical education conferences, and advisory boards. I occasionally tacked on a day or two to see a museum or tour a place I had never been before, but no sane person would call those trips a vacation or mistake them for fun. The advent of the coronavirus has shown me, and I expect others as well, that all those frequent flyer miles, and all those dreary business hotels and all the cab fares and all the jet lag were unnecessary. I could have done 80 percent of these by Zoom, had Zoom actually existed throughout my career.

Well, it didn't. Bygones. I think of meetings where I flew to another continent, drove into a city, presented a talk for 10 minutes plus 5 of Question & Answer, headed back to the airport, missed a connection, stayed overnight in an airport hotel, and then flew home, taking a couple of days to recover. It's made me think how all that time could have been better spent, and I don't mean on work. Add up a lifetime of those, subtract the actual time spent on Zoom meetings, and you are talking about serious vacation time.

In the old days—the old days being pre-COVID—you could hop on a plane and travel wherever you wanted. One major outcome of the pandemic is to return us to an essentially 19th century existence, where our horizons are suddenly constricted and travel is limited. When I speak to my academic colleagues, I get no sense that they want to return to their pre-COVID travel madness, but I do intuit claustrophobia mingled with wanderlust. When you feel trapped, you yearn for escape.

And where to go? I've never seen the Taj Mahal, nor The Great Wall of China, nor Istanbul's Hagia Sophia. I am still awaiting that trip to the Acropolis, and to the Sydney Opera House. Not that I'm a huge opera fan, but still…

Then again, this is an oncology piece, not Conde Nast Traveler. Instead, let's talk oncotourism. Not the oncotourism of old, where aging professors flew elsewhere to give eminently boring talks, but actual tourism related to oncology. If COVID was over, and I wanted to make a pilgrimage to those places that should be special places in the hearts of cancer doctors, where would all those frequent flyer miles I've generated take me? Let's exclude the great cancer centers, since office buildings and hospitals have a sameness the world over. No Dana-Farber, no MSK, no MDACC, no Institut Curie, no Istituto Nazionale dei Tumori. Plus, I've already been to most of them.

First Stop: Italy

Let's start someplace sunny. Why not the city of Bari, Italy, on the Adriatic Sea? On Dec. 2, 1943, the Liberty ship John Harvey was attacked by German bombers and blew up, spraying poisonous mustard gas over American sailors. The ship was there as a precaution, a promise of mutually assured destruction in the midst of the worst war in human history. If the Germans used poison gas, well then so would we. In the event, the only people we used poison gas on in World War II were our own sailors, and the citizens of Bari.

It was one of those great natural experiments. The exposed sailors were carefully monitored and found to have significant lymphopenia. Flash-forward a few years, and nitrogen mustard becomes the first chemotherapy agent, an agent of death turned into a promise of life for lymphoma patients.

Or so I was taught in my oncology fellowship. It's a good story, and true so far as it goes: the boat did blow up, the seamen did get lymphopenia. But Louis Goodman and Alfred Gilman (of pharmacology textbook fame) were already working on it at Yale during World War II, and the first lymphoma patient received (and responded to) nitrogen mustard in December of 1942, a year before the Bari incident. That clinical trial had been preceded by mouse model work.

The work was performed at the government's request and under strict wartime secrecy (poison gas, right?), so secret that the first patient's chart said he received "0.1 mg. per kg. compound X given intravenously." This secrecy prevented publication of the first clinical study until a 1946 JAMA article, where Alfred Gilman is referred to as "Major Gilman." Goodman and Gilman were using nitrogen mustard because it had been known since World War I that mustard gas caused lymphopenia. The John Harvey didn't need to blow up for us to discover cancer chemotherapy. It could have been discovered a generation earlier.

Should we still go to Bari? I vote yes. Goodman and Gilman were working in New Haven at the time, and the Adriatic is warm, sunny and gorgeous, at least in my imagination. Besides, Saint Nicholas is buried in Bari's beautiful medieval Basilica di San Nicola. The actual Santa Claus. Try and top that, New Haven.

In the South Pacific

Where to next? How about Easter Island? Its other, original name is Rapa Nui. It has all those wonderful heads carved in stone and represents the farthest reach of the Polynesian diaspora. Also on my bucket list. It is an oncotourism site because it was the source of 73 soil samples collected from the Vai Atare region of Rapa Nui by a Canadian expedition. Investigators from the Wyeth-Ayerst Corporation then isolated a strain of Streptomyces hygroscopicus from one of the samples and isolated a natural product that was a wonderful antifungal. Unfortunately, it was immunosuppressive as well, which apparently is not a good thing if you have a systemic fungal infection. But no matter, it could be repurposed for transplant and cancer patients.

The investigators called it rapamycin, in honor of Rapa Nui. When molecular biologists began looking seriously at it, they found that rapamycin had a molecular target of some importance. Having no imagination whatsoever, they called it (pointlessly) the mammalian target of rapamycin, or mTOR, as oncologists everywhere now know it. mTOR is part of a pathway that includes PI3 kinase and AKT, important for a host of growth factor receptors. Rapamycin became sirolimus, still used by transplant patients, and its close relative everolimus is a drug used regularly by my breast cancer patients.

So, OK, when we go to Rapa Nui it won't be to get soil samples. I want to see those cool old statues, the stone moai. While we are walking around, let's ponder the paired phenomena of bioprospecting and biopiracy. Bioprospecting, Wikipedia tells me, is "the process of discovery and commercialization of new products based on biological resources." Something like a third of all FDA-approved new drug entities between 1980 and 2010 were natural products. Mother nature is really, really good at evolving compounds that interfere with crucial cellular processes, often as plant poisons to fight off predators. Bioprospecting has been an unalloyed good for patients the world over.

This leads to a related term, biopiracy, which (again per Wikipedia) is the "exploitative appropriation of indigenous forms of knowledge by commercial actors." When a drug company isolates a compound from soil samples or other natural products from a country rich in biodiversity, particularly a compound that comes with a folk history of medicinal use, and then gets rich off of its work, should any of the gains return to the place of origin? If the citizens of a low-or-middle income country cannot afford the drugs derived from their soil, does the company have any responsibility to provide it to them? The legal answer is no, but the ethical answer, some have argued, is yes. Those Rapa Nui statues are staring at you for a reason.

North By Northwest

Let's move on to the Pacific Northwest, to a forest in Washington State, for our next stop on the tour. I hear it's beautiful when it's not raining, which is…well, almost never. But in these forests, you find the conifer Taxus brevifolia, the Pacific yew tree. The Pacific yew grows to a height of 30-50 feet, and it grows extremely slowly.

Back in the 1960s, the National Cancer Institute's Natural Products Branch, in cooperation with the U.S. Department of Agriculture, began sending botanists hither and yon. One of them, Arthur Barclay, scraped some bark off a Western yew in 1962 and brought it home, where studies at the Natural Products Branch revealed that something they called taxol was pretty good at killing cancer cells. After a fairly long gestation period, caused by delays in determination of the compound's molecular structure and the low yield of extraction from yew bark, taxol burst on the scene in the early 1990s, originally for ovarian cancer, then breast cancer, then a slew of others. Even, eventually, cardiac stents.

I have real fondness for this stop on our tour. I participated in many taxane-related meetings in the early 1990s. Some of them were strange. I mentioned that Taxus brevifolia is a painfully slow grower. The USDA would send forestry specialists to meetings, who would warn participants that there weren't nearly enough yew trees in the Pacific Northwest to meet projected demand for taxol. What's more, the spotted owl loved—and probably still loves—sitting on yew trees. Harvest all the yew trees and the Audubon Society would start sending hit men after medical oncologists, who would be responsible for the extinction of a charming and wise bird whose only mistake was to embrace yew.

Fortunately, the medicinal chemists, in fairly short order, found a semisynthetic method for producing taxol. Spotted owls could breathe easy once again. When you are walking through the rain forests of Washington, give them a handwave. Wear a raincoat.

Treasure Island

Finally, let's fly to the foothills of Madagascar, the home of the rosy periwinkle plant, or Catharanthus roseus. Actually, you don't really need to fly to Masdagascar to see a periwinkle plant. Periwinkles are hardy, ubiquitous plants, and a few seconds googling shows that they are cheap as well: a hundred rosy periwinkle seeds go for $5.99 on Amazon. Amazon informs us that they have a long growing season, are drought-resistant, and will grow in poor, sunny soil. So, unlike the Pacific yew, no real ecologic problems here. And the rosy periwinkle grows on every continent save Antarctica. And it is pretty.

But I'd still like to go to Madagascar, if only in honor of the vinca alkaloids—vincristine and vinblastine. The rosy periwinkle was first described there, though it has travelled across the globe. Once again, a Canadian was involved in bringing home samples for study. Do Canadian botanists spend all their lives traveling to warmer climes, collecting samples as they avoid polar vortices?

Eli Lilly became interested in the rosy periwinkle because of folk medicine claims made for it as an antidiabetic. While that did not pan out, the periwinkle did serve as the source for the vinca alkaloids. Lilly set up periwinkle plantations in Texas to supply raw materials for compound isolation and production. Since the vincas are now off patent, I suppose you could set up a production facility on your back lot.

But I'd still like to go to Madagascar. The island is a biodiversity paradise, which ecologists refer to as the "eighth continent." More than 80 percent of its plant species are found nowhere else in the world. Even if the rosy periwinkle is as much a native of my back yard as of Madagascar, there are likely substantial numbers of medicinally valuable compounds there awaiting bioprospecting. The island is also home to over 100 species and subspecies of lemur, our cute though endangered primate relative. I'd like to see them.

While natural product-based antineoplastics have diminished somewhat in recent years as biologics and synthetic kinase inhibitors have increased in number, they have by no means disappeared. Novel antibody-drug conjugates regularly pair a monoclonal with a plant poison, given nature's wonderful ability to generate cellular toxins. The loss of biodiversity in places such as Madagascar, part of a the worldwide "Sixth Extinction" we have created, reduces our ability to discover new therapeutic payloads. In saving biodiversity, we may save our patients as well as those cuddly little lemurs.

So, Naples to Easter Island to Washington State to Madagascar. I am sure I could come up with others, but that is enough mental globetrotting for this sheltering-in-place frustrated oncotourist. Stay healthy, my friends, and let's hope that we will be able to visit with each other soon.

Friday, July 10, 2020

By George W. Sledge, Jr., MD

Of late, I have been considering pain. Or lack of pain. Jo Cameron is a 71-year-old woman living in Scotland who has led a fairly pain-free life. She considered childbirth "quite enjoyable really," and one time did not notice that her hand was being fried by a stove until she smelled burning flesh. She then had hand surgery of the sort guaranteed to hurt and barely noticed. She is essentially immune to pain, and this, in a "cherish your exceptions" sort of way, interested her doctors.

An article in the British Journal of Anaesthesia tells the science story. Jo has two linked mutations in the FAAH (fatty acid amide hydrolase) gene and in the related FAAH-OUT pseudogene (who says molecular biologists lack a sense of humor?). The end result of these mutations is a decreased ability to metabolize anandamide, an endocannabinoid compound that binds to a THC-like receptor. Anandamine, in elevated plasma concentrations, not only reduces pain sensitivity but increases happiness. There are genetically happy humans who have elevated anandamine levels in their blood, and mice genetically engineered to have increased anandamine levels are able to extinguish fear-based memories.

I suspect it is rare for articles in the British Journal of Anesthesia to go viral. I confess I had never read an article in the journal until now, and "Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity" is likely the last. But this article was written up in the popular press and read around the world. There's something about "feel no pain" that appeals to the public.

Nor is this the only pain-relief gene we know about. Ashlyn Blocker of Patterson, Georgia, has a mutation in the SCN9A gene. She grew up with a congenital insensitivity to pain, something totally dangerous for any young child. A November 15, 2012, New York Times Magazine story relates how the 6-month-old Ashlyn "rubbed big red splotches on her nose and almost chewed off part of her tongue with her emerging teeth." Once she "broke her ankle and ran around on it for two days before her parents realized something was wrong."

We think of pain as something bad, but Jo and Ashlyn's stories confirm something obvious: pain is an evolutionary necessity. It's not just some trivial "no pain, no gain" sports mantra. If an organism never feels pain, it never avoids those things that cause pain, and that does not, in simple Darwinian turns, support survival of the fittest, or—in my case—survival of the clumsy. Leaving your hand on a burning stove is not something likely to improve reproductive fitness, nor is biting off your tongue because it doesn't really hurt. One can easily understand why nature equips us with pain fibers, and why we should listen to them, other than not wanting to hurt.

Life is full of evolutionary double-edged swords, and oncologists are intimately familiar with the other edge of this particularly sharp weapon. A bone metastasis announces itself through constant unremitting pain in the back and pelvis, or a liver metastasis through the expansion of Glisson's capsule, or a parietal brain met through pounding headaches. From an evolutionary standpoint, pain doesn't accomplish too much when it trumpets an inevitably lethal event. It just hurts.

And this is where analgesia comes in. I need not bore you with an extensive review of the many ways in which cancer-related pain is eliminated, or at least controlled. Increasingly multidisciplinary approaches involving surgeons, anesthesiologists, radiation and medical oncologists, psychiatrists, and palliative care physicians, though still inadequate, have gone a long way to improving quality of life for patients with advanced cancer.

Despite the real advances made in pain management, I'm still impressed by how much of what we do for pain still involves the use of opioids. Whether short-acting or long-acting, natural or synthetic, they remain the mainstay of pain control in the majority of advanced cancers.

All of which brings us to the issue of addiction. In the United States, we are currently in the midst of an opioid addiction epidemic, an epidemic that is national in nature, devastating in impact for individuals and municipalities, tragic in its consequences, and—like everything in modern medicine—expensive. While the other epidemic, the viral pandemic, has largely pushed it out of the headlines, the opioid epidemic still tortures all too many of our fellow citizens.

All this, and something more: it is shameful. And we—the health care community writ large—are responsible for much of this shame.

Back in the day of ridiculous, over-the-top pharmaceutical parties at the ASCO Annual Meeting, the most egregious always involved the leading purveyor of pain medications, Purdue Pharma: its chocolate bar (a different addiction) was legendary. In my youthful naivete, I never thought much about these, other than their contribution to the cost of care. I believed, wrongly as it turned out, that addiction was not really a big problem for cancer patients. I used opiates almost entirely for metastatic disease, and I had been taught (and taught trainees and patients) that should a patient's cancer shrink on therapy, she would have diminished pain and therefore decreased need for pain medication. My patients were cancer patients, not drug addicts, after all. The addictive potential was low, unless you were one of those unfortunate, but fortunately rare, souls with a predilection for narcotics-seeking behavior.

We were also told that the newer generation of pain medications, like OxyContin and fentanyl patches, had lower addictive potential. Looking back, I don't have any memory of there being any supportive data for this claim, but the claim was part of the common conversation, and indeed was explicitly allowed by the FDA. Purdue trained its sales reps, who showed up in my clinic among others, to tell docs that oxy was less prone to abuse than morphine. We were taught that pain was the "fifth vital sign," and that the goal was drive the patient's pain away. Outside oncology, Purdue preached the virtues of oxy for chronic pain, where the data was incredibly mushy and a bit stinky as well. A veritable army of drug reps invited physicians on expensive boondoggles, usually vacations at five-star resorts in sunny climates. Key opinion leaders were enlisted in the crusade, for handsome fees.

And here the story gets ugly, fast. This new dogma, endorsed by government and spread by the profession and by company sales reps, was demonstrably wrong, and known to be so in a very short time. The first outbreaks of the current epidemic occurred in marginalized rural communities in states like West Virginia and Kentucky. Small pharmacies and doctor's offices, staffed by the greedy and corrupt, were suddenly prescribing huge amounts of OxyContin. That should have been a burning bush signal to all not willfully blind. When a Purdue sales rep discovered that one clinic he visited regularly was a drug mill for addicts, he notified his superiors at the company. His job, he was told, was to sell drugs, not to determine if a "doctor was a drug pusher," as a 2018 New York Times article subsequently reported.

We now know that Purdue Pharma was, for lack of a better word, evil. Purdue knew that OxyContin abuse was common by the mid-1990s and told no one: its drugs were crushed, snorted, sold by the corrupt to the emotionally frail. The company felt no responsibility to share this information with regulators or physicians, and when courageous physicians in the backwaters of Appalachia tried to get state health authorities to intervene, company doctors descended en masse to pooh-pooh the idea, treating the local doctors as country bumpkins, stupid hicks who did not understand the wonderful world of modern pain control. The story of Purdue's nauseating lack of conscience is told in Beth Macy's beautifully reported 2018 book Dopesick: Dealers, Doctors and The Drug Company That Addicted America.

And this was no low-level malfeasance in the company: the Sacklers, the family that owned the company, were well aware of this information, as were top company officials. Federal prosecutors recommended felony prosecutions for the company's executives but were overruled by the higher-ups in the Bush administration. Instead, they received a slap on the hand: a misdemeanor charge of "misbranding," accompanied by a (relatively large) fine. Rudolph Giuliani, still "America's Mayor," served as part of their defense team, in training for his later interactions with corrupt Ukrainian oligarchs and other related officials. He is said to have played an influential role in the decision to allow Purdue to keep manufacturing OxyContin, and in an agreement immunizing them against further lawsuits and keeping their officers out of jail.

I've often wondered why, if (as the Supreme Court affirms) companies have the rights of individuals under the Constitution, they can't also be convicted of mass murder and executed? The answer, in a roundabout way, appears to be that they can: Purdue Pharma has been the recipient of an avalanche of lawsuits, and filed for bankruptcy in September 2019, for its part in the epidemic. Through 2016 Purdue made $31 billion selling OxyContin; the proposed settlement would claw back $10-12 billion. While the Sacklers themselves have suffered the ignominy of art museums shedding their name from endowed wings, they have to date retained most of their ill-gotten gains, though the new settlement, if approved (and it may not be), would strip them of ~$3 billion.

One scion of the family complained, in a wonderfully droll June 19, 2019, article in Vanity Fair, of the unfairness of it all: "I really don't think there's much in the complaints, frankly, that's at issue that's not just, 'Oh, you shouldn't have marketed these things at all.' Right? And I guess that's a hindsight debate one can have." To paraphrase: We're sorry if anyone was harmed, but the opioid epidemic isn't out fault. We feel awful about all that. My entire family has been maligned, and for what? We were only doing what the then-current pain dogma suggested was appropriate. Well, no, but whatever allows you to sleep at night in your bed of riches.

Arthur Sackler, the founding member (along with his two brothers) of the Sackler empire, and paterfamilias of the Sackler clan, was one of those fascinating creatures you read about in a horror novel. He was a true polymath, conducting laboratory research of sufficient quality to be published in high-impact peer-reviewed journals. See, for instance, his "Effects of Thymectomy on the Resistance of Rats to Drowning and Histamine Stress", published in the November 4, 1961, issue of Nature. Certainly, few current articles in Nature include, for their material and methods section, phrases like "the remaining animals were subjected to drowning stress by immersion in water precooled and maintained at 6°C. Drowning time was determined by recording the time-interval up to the final submergence." A later (1963) Sackler article in Nature remains the definitive word on what happens to a rat's eosinophils when the rat is administered LSD. Answer: the eosinophils decrease. And the rats go crazy, man. To which I respond: it sure was easier to get a paper published in Nature in those days.

Sackler and his brothers took over Purdue, a failing pharmaceutical concern, and eventually turned it into the corporate powerhouse that created OxyContin. Along the way, he invented direct-to-consumer medical advertising, cordially despised by physicians but an inescapable aspect of evening news shows. An erudite man who prided himself on his culture and civility, Sackler and his descendants endowed museums and galleries around the world, including the Sackler wing at the Met, with its glorious Temple of Dendur. The Metropolitan Museum is now refusing to take any more Sackler money, as are sister institutions that happily held out their hands when the family were still considered legit philanthropists rather than sordid purveyors of addictive drugs.

The Oxy epidemic, followed by the related fentanyl and heroin epidemics, have had a devastating effect on communities around the United States. Deaths due to addiction have tripled in the last 30 years. The epidemic has also affected how physicians prescribe narcotics, and how those prescriptions are regulated by state and federal authorities. I've noticed a tendency by cancer doctors to outsource their pain medication prescribing to palliative care specialists, or to simply decrease the amount of pain medications they prescribe. This is a mixed bag, of course: reducing unnecessary or marginal uses of narcotics is a good thing, and palliative care specialists are a wonderful resource for my patients, but I worry that we might slip back to a time when cancer patients died in agony. That would be the Sackler's final, bitter bequest.

As if direct-to-consumer advertising wasn't bad enough. It's enough to want me to reach for some anandamide.