What is the Merit of Originality?

‘I am not young enough to know everything,’ as Oscar Wilde once said, and maybe the rest of us aren’t either. It is often an unquestioned assumption that New trumps Old, that innovation usually leads to improvement, and that by standing on the shoulders of giants, the view is necessarily better. Clearer.

But there is wisdom in both the long as well as the panoramic views. Neither changing  your shoes nor altering your hat, really improves the safety of a voyage -nor does it address the original goal of a safe arrival of everybody on board. Appearing modern, seeming prepared, only helps if it helps –a leak is still a leak, especially if there are only lifeboats for a few…

Let me explain. I happened upon an article in the journal Nature that chronicled the introduction of a new, and highly accurate method of diagnosing TB through genetic analysis.  https://www.nature.com/news/improved-diagnostics-fail-to-halt-the-rise-of-tuberculosis-1.23000?WT ‘The World Health Organization (WHO), promptly endorsed the test, called GeneXpert, and promoted its roll-out around the globe to replace a microscope-based test that missed half of all cases.’ It sounded like a perfect technological fix for a disease that has so far avoided effective control. ‘Some 10.4 million people were infected with TB last year, according to a WHO report published on 30 October [2016?]. More than half of the cases occurred in China, India, Indonesia, Pakistan and the Philippines. The infection, which causes coughing, weight loss and chest pain, often goes undiagnosed for months or years, spurring transmission.’

Unfortunately, ‘[…] the high hopes have since crashed as rates of tuberculosis rates have not fallen dramatically, and nations are now looking to address the problems that cause so many TB cases to be missed and the difficulties in treating those who are diagnosed. […] The tale is a familiar one in global health care: a solution that seems extraordinarily promising in the lab or clinical trials falters when deployed in the struggling health-care systems of developing and middle-income countries. “What GeneXpert has taught us in TB is that inserting one new tool into a system that isn’t working overall is not going to by itself be a game changer. We need more investment in health systems,” says Erica Lessem, deputy executive director at the Treatment Action Group, an activist organization in New York City.’

But I mean, just think about it for a minute. ‘The machines cost $17,000 each and require constant electricity and air-conditioning — infrastructure that is not widely available in the TB clinics of countries with a high incidence of the disease, requiring the machines to be placed in central facilities.’ Sure, various groups agreed to subsidize the tests in 2012, but: ‘each cost $16.86 (the price fell to $9.98), compared with a few dollars for a microscope TB test.’ So which test would you choose if you were a government strapped for cash to provide for healthcare for a broad spectrum of other equally pressing needs?

‘Even countries that fully embraced GeneXpert are not seeing the returns they had hoped for. After a countrywide roll-out begun in 2011, the test is available for all suspected TB cases in South Africa. But a randomized clinical trial conducted in 2015 during the roll-out found that people diagnosed using GeneXpert were just as likely to die from TB as those diagnosed at labs still using the microscope test.’ That seems counterintuitive to say the least.

So what might be happening? ‘Churchyard [a physician specializing in TB at the Aurum Institute in Johannesburg, South Africa] suspects that doctors have been giving people with TB-like symptoms drugs, even if their microscope test was negative or missing, and that this helps to explain why his team found no benefit from implementing the GeneXpert test. Others have speculated that, by being involved in a clinical trial, patients in both arms of the trial received better care than they would otherwise have done, obfuscating any differences between the groups.’

‘Even with accurate tests, cases are still being missed. Results from the GeneXpert tests take just as long to deliver as microscope tests, and many people never return to the clinic to get their results and drugs; those who begin antibiotics often do not complete the regimen.’ Clearly, technology alone, without an adequate infrastructure to support it –without a properly funded and administered health care system- is not sufficient.

And it’s simply not enough to have even a well-funded health system that benefits just those who can afford it, leaving the rest of the population to fend for itself, and only seeking help when they can no longer cope –often when it is too late. Health care is a right, not a privilege –no matter what those in power would have us believe.

I’m certainly not arguing that improving technology is not part of the solution, but sometimes I wonder if it is merely putting new clothes on a beggar. Handing out flowers in a slum.

Let’s face it, real Health Care is more than a sign on a door, more than a few people in white coats. It is a kind of national empathy. A recognition that even the poorest among us, have something valuable to contribute; that even those who have strayed from society’s chosen path, are who any of us might be, but in different clothes.

The myth of Baucis and Philemon tugs at my memory: They were an old married couple living in a small village in Anatolia (part of Asian Turkey nowadays) who, unlike everyone else in the town, welcomed two peasants at their door who were seeking refuge for the night. The couple, of course, were unaware that they were actually welcoming two gods, Zeus and Hermes, disguised as humans. A common enough trope, perhaps, but an instructive one, I think -one that transcends virtually all cultures, and borders: the idea of helping others without any expectation of reward. It is not an exchange -a transaction- so much as an action. Agape, in fact.

Health care is like that. Or should be… It’s not about the glittering display in the shop window –there to impress the passersby- it’s about the people in the shop.















Cycling in a Dish

Where do they get this stuff? Menses in a dish –or, to be more academically abstruse, ‘A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle’?

It has a pedantic ring to it, even though it doesn’t exactly roll off the tongue, but I have to ask a simple, quasi-lay interrogative: why? Critical Thinking 101 –at least as they used to teach it- would demand to know why it is important that we make this model. If the answer is vague, or even unnecessarily complicated,  then one begins to suspect academic foppery.

The model is unique –I’ll give them that –let me refer to a succinct description of the model from a BBC News article: http://www.bbc.com/news/health-39421396 ‘The 3D model is made up of a series of cubes that each represent the different parts of the female reproductive system.

‘Each cube contains collections of living cells from the respective bits of this system – fallopian tubes, uterus, cervix and vagina (all human cells), and the ovaries (taken from mice).

‘The cubes are connected together with small tubes, which allow special fluid to flow through the entire system, much like blood.

‘This also means the “mini organs” can communicate with each other using hormones, mimicking what happens in a woman’s body during a “typical” 28-day human menstrual cycle.

‘Tests suggested that the tissues in the system responded to the cyclical ebb and flow of hormones, in a similar way to those of the female body.’

At first, I have to admit, I was skeptical of the need for the model –and yes, I was inclined to see it as foppery. But when I actually read the paper (http://www.nature.com/articles/ncomms14584) I was impressed. Why not just obtain the same cells from, say, hysterectomy specimens, grow them, and subject them to whatever hormones or chemicals you pick to study? It quickly became evident that there are two types of scientists: clinical, and laboratory –as a practicing doctor, I’m afraid I fall squarely into the clinical end, and never the twain shall meet… The reason became all too clear as I continued to read.

First of all, as they explain in the introduction, ‘Preclinical studies often begin with individual cells, separated from cellular and physical contacts that are important for biological function. These dispersed cells must be propagated through weekly reduction divisions and maintained on flat plastic; however, these cells are missing the cell physicochemical microenvironment, three-dimensional (3D) tissue-specific architecture, and blood flow perfusion found in natural tissues.’ In other words, they take a long time to grow and aren’t subject to the same environment they would have in the body (i.e. in vivo).

Secondly, what is used to perfuse them may not have the same effect as the blood circulation they would receive in vivo: ‘typical media composition is based on basal nutrients, bovine serum and a few specialized factors that are placed in a static setting with random mixing. As a consequence, cell–cell and tissue-level cytokine and endocrine signals are not integrated into signalling pathways.’

So not only can delicate organs be assessed as if they were still in the body (like the rhythmic beating of the hair cells that line the Fallopian tubes –cilia), but the effects of different pharmaceuticals could be safely tested in the model before expensive clinical trials were undertaken. ‘Despite large investments in research funding, only ∼8% of drugs for which Investigational New Drug applications have been filed will be approved by the FDA.’

I have to say that I am intrigued, and not a little embarrassed that I was put off by the title of the article. Perhaps to expiate that guilt a little, I mentioned it to Ted, a –I hesitate to say ‘older’- colleague of mine that I met for lunch the other day.

We are both retired now so, apart from our similar past histories, talk heads more towards hobbies and bowels, than to scientific literature. I’m not even sure how it came up, except that his niece was trying –unsuccessfully, it seems- to conceive and his sister had phoned him for advice. She had mentioned several chemicals she’d discovered in an online search –both as potential therapies, as well as putative endocrine disruptors. She wanted to know what Ted thought.

“So what do you think?” he asked me as he carefully cut his hamburger in quarters so he could manage the entry problems. “You retired a couple of years after me…” he added, as if that meant that I was a couple of years smarter than him –or at least a bit more up to date.

“Ted, you know as well as I do that it’s dangerous to speculate on the effects of chemicals on human pregnancies. There are too many variables, too many potential effects that may not show up till birth, or even later…”

He nodded. “I remember DES for threatened first term miscarriages and the later damage to reproductive anatomy -not to mention the clear-cell cancers of the vagina that didn’t show up till years later…”

“Or thalidomide for morning sickness in pregnancies…” I added solemnly.

He nodded thoughtfully and after carefully picking out shreds of lettuce that were hiding under the bun, attempted to cram a freshly-cut piece of the hamburger into his waiting mouth, but it leaked somewhere south of his lips. “They can’t even design a portable hamburger,” he said, unsure whether to laugh or blush. He wiped his face, picked up the meat, and then searched for more hidden pieces of lettuce and placed them on his plate.

When he noticed me watching his lettuce hunt, he shrugged. “I’ve always hated lettuce,” he explained. “So does my niece for that matter. Probably hereditary,” he mumbled and then licked his fingers, contritely. “I mean, look,” he said with a crooked smile on his face, “I solved this problem using in vitro techniques.” And he held up his now-clean fingers and licked his lips in embarrassed satisfaction. “There’s gotta be a way to test these drugs without endangering a pregnancy. Mice and rats are not humans and you can’t safely extrapolate the results to us.”

“Amen,” I said, shaking my head sadly. We’d had similar discussions over the years, so I suspect he was merely venting his frustrations again.

We sat in silence for a moment while he tried to improve his in vitro technique, as he insisted on calling it.

“You know, Ted,” I said after it looked as if his practice runs at the lettuce were failing, “I did read about an in vitro way being developed for safely testing things in women. It was in the journal Nature and entitled something like ‘Microfluidic culture model of the human reproductive tract’. I’m not sure they could adapt it to pregnancies, but maybe it might be helpful in seeing what effects drugs or other chemicals could have on reproductive cells in the events leading up to a pregnancy…” I tried to remember more. “And it seems to me they were even able to replicate a 28 day menstrual cycle…”

His eyebrows shot up, and then one stayed elevated, as if scotch-taped to his forehead. “Micro fluidic what…? My god, is your retirement that bad?”

I think I blushed –he made it sound as if I’d been caught downloading porn. “Uhmm, it’s called ‘body on a chip’, or something –or at least this part is…”

He suddenly turned his attention to the chips still languishing on his plate and smiled. “Thanks for the excuse,” he said. Obviously his wife or maybe Chrissie, his sister, had warned him not to order them, let alone eat them.

“Yeah, I gather that the idea, eventually, is to be able to take cells from somebody who needs a particular treatment and test those cells in the model with various chemicals to see what happens.” It seemed quite exciting to me.

“Mmmh,’ he said, polishing off the last of his fries, while the puzzled lettuceal remnants stared at him from the plate. “I don’t think I can tell Chrissie about it, though.”

I looked up from my napkin and cocked my head. “Why not, Ted? Wouldn’t she find it interesting?”

He rested his head on his hands and peered at me as if he were looking over a pair of bifocals like a professor with a sleepy student. “She’d be on Craigslist trying to buy one as soon as she got off the phone… In fact she’d probably try for a matching set –a male one as well as a female one,” he added when I stared at him.

I must have still looked puzzled, because he smiled and picked up a piece of lettuce. “Chrissie’s a dietician and she thinks her daughter has a terrible diet… and she certainly remembers mine,” he explained, shaking his head. “She’d be trying to feed this to the model to prove her point.” He sighed. “I’d never hear the end of it…”

I suddenly realized I’d not thought about it that deeply. He’s right, maybe the ‘body on a chip’ thing needs a bit more work before they advertise it on Facebook…