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.
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.