Why Science Matters

DRAFT – NOT COMPLETE AT THIS POINT

What Am I Writing About?

About medicine, all we know of any practical consequence more than what was said in Babylon comes from science as practiced in the West since Harvey and Galileo.

And, of all topics in medicine, my rather global and presently unsupported assertion applies remarkably to our common project here, the prevention of kidney stones. To say this more exactly, rational, modern, effective kidney stone prevention arises naturally from knowing what crystals make kidney stones and what forces drive such crystals to form.

Prevention arises from cause, cause from science.

Why Am I Writing This?

Few would doubt that science drives medical progress, so why have I taken on so vast an attitude and written this high flown article?

Because although kidney stone prevention exemplifies precision medicine at its most exacting heights, patients and even some physicians neglect, even disdain, perhaps, the remarkable and simple tools that decades of research have provided for their prevention. They often turn, instead to empiric remedies of doubtful value, or to mere hydration – inefficient at best, and unhelpful against the unwanted consequences of those factors that cause stones or of stones themselves.

Why? Is it we fail to present the case for science? Is it that stones rarely kill us and seem more a painful bother than a dangerous disease? I do not know, but since less than half of all patients with high blood pressure – an established assassin – get treated effectively, I suspect it is the former more than the latter.

I am set against such folly. Until new science can convince me otherwise and contradict the work of a generation, I stand for personalized kidney prevention specific to what is wrong with an individual patient. perhaps because kidney stones do not kill us as some diseases do,

It is my burning glass.

I have written a more practical and useful article about it as the first chapter of my kidney stone book. This is an opinion piece. No one will want to read it. Perhaps no one should read it. I wrote it and put it here as the scholium for the chapter. I may never read it again.

Even so, it has virtues, and I have preserved it. For at the end, as an afterthought, lies my intent as a physician, the wellsprings of my life in pursuit of a prevention of stones for so many patients I can scarcely imagine them all. That pursuit is aimed and fashioned as this airy writing says. So some my read it to the end out of curiosity, perhaps.

The magnificent Tower of Babel Pieter Brueghel the Elder  (1526/1530–1569) hangs in the Kunsthistorisches Museum, Vienna, Austria.

Science Tells Stories

I prepared for this at the beginning in four articles about science that follow the work of Karl Popper, and Thomas Kuhn. Although I claim no special skills in philosophy, I have learned to apply it in my work as scientist, narrator, and critic. Rather than paraphrase my articles, here is a brief gloss by way of connection to them.

Two Realities

Everything begins with what we can plainly observe – in the physical world and in the body of relevant writing about that world. Here, the world is kidney stone disease, its patients, the science done and published, and for each of us who work in it what I might call present paradigms concerning unsolved problems. About these two worlds we observe, measure, catalog and study.

How Kidney Stones Form

The other reality evades our senses. We cannot plainly see it but know it exists. Take for example how stones grow in human kidneys. Perhaps someday scientists will implant tiny cameras in human kidneys and record time lapse videos. But that is present fantasy. Right now we cannot observe the process. So, how can we progress matters?

If you cannot watch it happen,you have to imagine how it happens.

No amount of detail about what stones look like, or where they are in kidneys, or how stones are themselves constructed will tell you how they formed in that kidney. True, as you learn more and more details, you will discard any imagined process that does not produce those details you already know about.

For example, we have learned in detail how calcium oxalate stones form over calcium phosphate ‘plaque’ that itself forms in kidney tissue. So any imagined process for formation of such stones has to include formation of plaque and all the details of how a calcium oxalate stone grows over it. But no amount of detail can get you all the way – unless you have the camera I just spoke about. You have to imagine how things came into being in that kidney. You have to imagine because you cannot observe the process.

We Make Prophecies

That is not enough. An imagined process may include all the details we know about yet be utter fantasy. We already know what happened – we observed it – so the imagination is just that, a story. But, a valid story – I like the word ‘valid’ here – will make predictions about things we have not as yet observed. As an example, I have reasons to believe plaque forms because of how idiopathic hypercalciuria works. I cannot observe idiopathic hypercalciuria producing plaque – no camera. But I can write down a set of realistic steps by which it could. All the steps fit with what we know already.

That is the problem – the story, the set of steps, was made to fit with what we know. It has no value apart from narrative appeal, a kind of organization of our knowledge.

But what if that story led us to predict observations we have not as yet made or even thought to make yet were necessary predictions if the story was true? For example that plaque must form on only one of the two loops of Henle or else the story could not be true.

We reserve the word ‘hypothesis’ for an imagined story about how something – like plaque – came to be if from that story we can deduce, with strict logic, predictions about the real world that must be true and are as yet unknown.

We mean by a useful hypothesis one whose specific predictions can be tested using available methods.

So, hypothesis means a story of cause from which we can deduce specific new – not the basis for the story – predictions about the real world. Useful hypothesis means the predictions can be tested using available methods.

We Test in Opposition

Should what was deduced prove true the story is not untrue. But often we deceive ourselves. Successes lead to folly. All we have against our own deceptions is to test in other ways, always hoping to disprove. And time will prove us always wrong even if we cannot ourselves.

That is what science does.

That is how we have about this one disease what we have now concerning how what all we can observe might come to be the way it is. We who have worked the fields here, have dreamed, deduced our singular prophesies, gone out to try their worth and found them not untrue, sometimes.

We Build the Treasure House and Theory of a Field

The collection of useful hypotheses – stories that have been tested and found not untrue – we might call the theory of the kidney stone field. The observations are the treasure house. Theory will never stay the same; new tests always upend old stories and new ones come along that can do better and be disproved in their turn. But correct observations remain what they are. Superseded, perhaps, by better instruments or better methods, the old observations remain correct within their sphere and forever useful for what they are. That is why observations made on humans have immortality about them – so hard to make, so valuable.

Why Bother With Hypotheses – With Theory?

Theory Tells Us What to Measure

In a field without theory all facts have equal value. At the beginning, that is fine. When the 20th century began we did not know the abundances of the kidney stone crystals. We did not measure blood calcium and therefore could not recognize primary hyperparathyroidism. We did not measure urine chemistries and could not recognize, as an example, hypercalciuria. Supersaturation as a clinical tool lay beyond imagining.

As measurement progresses, however, and hypotheses emerge from imagination, they direct scientists to certain measurements as opposed to others. As an example we already used, how could we think to test if plaque indeed forms in only one of the two loops of Henle unless imagination led us to undertake such an arcane and difficult task?

For another example, many decades ago we imagined that idiopathic hypercalciuria arose in part or whole because kidneys do not conserve calcium normally. This led to scholarship that revealed a treasure of data showing loss of bone mineral in hypercalciuric people, as one would predict from kidney calcium losses. That, in turn, led to experiments about bone mineral in more patients. We imagined that hypercalciuria might be inherited because we knew stones ran in families. We found it was which led to breeding rodents for high urine calcium. That, in turn, gave new information about vitamin D. Over time, the whole field of hypercalciuria in stone formers grew organically through measurements directed by hypotheses.

Progress depends on measurement and theory together.

But do not believe that by progress I mean toward a greater and greater truth. It is progress toward a larger and larger body of information collected in the service of theory. Likewise it is toward theories whose individual hypotheses we accept as useful because survivors of many different tests. A field consists in its data and theories, and grows as I have said by their mutual interactions as a kind of bootstrap process. Plaque production and idiopathic hypercalciuria are just two examples.

Applied Science

But theory driven science is only one of three.

Theories and their hypotheses concern how nature does things. Another branch of science concerns how we can do things. It seeks to apply what we know about the world to fashion ways of doing what we want.

Imagination Concerns Ways to do Things

Called practical or applied science it may well call on discoveries of theoretical science but seeks answers to how we can use those discoveries to do things we want to do. For example, if we believe hypercalciuria causes kidney stones and bone disease, applied science seeks ways to use scientific knowledge about hypercalciuria to prevent them.

As example, salt intake controls kidney calcium conservation to such an extent that low sodium diet can almost completely reverse hypercalciuria. That sodium has such power arose from theory based science. Practical science would, as an example, seek to test if such a diet prevented stones, or loss of bone mineral.

As such, applied science needs no intrinsic theory of its own, but specializes in invention and testing ways to use known scientific knowledge to perform tasks – such as stone prevention. In medicine we use name the testing of a proposed way a ‘trial’ and speak of clinical trials and trialists.

Results Concern Practical Value

A positive result  – low sodium intake reduces new stone production, for example – means such a diet may have practical value. It is provisional only to the extent we need repetition with different kinds of patients. A negative result does not falsify the original scientific theory but only the claim that the theory leads to practical benefits – in this case – stone prevention. Effects of sodium on urine calcium can be a true finding but not useful to stone prevention.

Objectives

This term of art names what we came for, what we want to have as a result of a particular scientific work. Obviously, objectives must be nouns – physical things, elements of new knowledge.

Theory Driven Science

Think again about the hypothesis that idiopathic hypercalciuria produces plaque by virtue of its physiology. Usefulness depends upon specific predictions one can deduce and these arise from the details of how hypercalciuria works. One such detail, in this case, predicts as a logical consequence that plaque begin in the ascending and not the descending thin loop of Henle. So an objective from that hypothesis is to determine in which side of the loop plaque forms.

The objective arises from the test of the hypothesis – it is what a scientist works to get in everyday science.

The value of the objective must be, therefore, twofold. Valuable within science – as a test of an hypothesis, and valuable outside science because of the hypothesis itself – if we knew how it formed perhaps we might fashion efficient preventions.

Value as a test has a lot of complexity. Could the test defeat – falsify – the hypothesis? If plaque forms on both sides, or on the ascending side can we somehow evade falsification – save the hypothesis? To that extent the objective lacks value. How well can be make the measurements? If well enough that the result can defeat the hypothesis, the objective has value.

Value outside science arises from societal concerns. How important are kidney stones and their prevention? How much will we improve prevention if we know for certain – or have a tested theory about – how plaque forms because of hypercalciuria?

Applied Science

The two fold rule applies in the same way. In our example how well can we test if reduced diet sodium to lower urine calcium prevents stones? If well enough that the result will defeat the hypothesis the objective is valuable. Outside of science, value is the same for theory driven science – the importance of stone prevention to society.

Science and Medicine

The most practical yield of science to medical practice is tests and remedies. A more subtle yield is understanding of how diseases arise in the first place.

Medicine Depends on Science

If the tests and remedies arise from science, they benefit patients only via physicians. A patient with stones collects urine for testing, for example, because science has established links between such chemistry and stone formation. Science has established links between a change in such chemistries and reduction of stone formation. Given this seems like straightforward application of science to patient care, one might think the physician’s role trivial, a role that could be played by a machine.

Physicians Enact What Science Offers

But consider the reality. Urine composition varies with diet, fluids, activity and all these vary at the will of the person who makes that urine. Who can tell the physician if that sample represents when stones formed or not? Who can explain to patients that they must provide the right kinds of samples.

More. You must, a physician might say, do this or that with fluids or diet – and for perhaps a lifetime. Who will convince someone to do this? How?

Then, there is understanding. Will someone willingly alter life habits without some understanding of why? Can a physician counsel to this or that without an understanding of why?

Evidence arises in science, from science. The rest, its actuation into reality arises from something else – faith, personality, education, storytelling? We say evidence based medicine and our heads bow in affirmation – far superior to some arcane art of medicine. But we need both. Always. People need people to enact change.

The Main Biologies of Kidney Stone Disease

 

One Force, One Outcome, One Actor

The force is saturation, the outcome crystal formation. The actor, the kidney.

All things arise from the work and shapes of the kidney. Of stones, actor principalis.

The kidney supersaturates the urine. Its cells are the surfaces on which crystals anchor, and those anchored crystals form the base on which common calcium stones form. By middle age or older, kidneys have usually accumulated some mineral deposits. But kidneys of stone formers generally have accumulated more deposits for any given age.

Water Balance

Kidneys supersaturate tubule fluid and urine as they conserve water. This work of water conservation produces the free energy of supersaturation. That energy may lie dormant in the tubule fluids until they exit the urinary system. Or it may dissipate in forming crystals that can become kidney stones.

Kidneys are indifferent to whether they supersaturate or cause stones. They serve the needs of water balance for the body. But that water balance depends entirely on our behavior. If we present more water than the body needs to cool itself, kidneys will not retain it. They will let it go by and in the process, incidentally to them, dilute the urine and dissipate much of its supersaturation.

We evolved on dry land and survived, often, by conserving water. So kidneys are good at it, and our brains, that control how kidneys handle water and how we feel about thirst, lean to the dry side. We can feel happy when our water intake is very modest and our kidneys conserving as much as possible.

Salt Balance

Perhaps because rather scarce where we evolved in Africa, we absorb virtually all the sodium we eat and our kidneys can conserve almost all of it, losing daily a tiny pittance. For example, if we eat 20 mEq of sodium daily (460 mg), we can lose less than that in the 24 hour urine and therefore remain in sodium balance.

Kidney Anatomy

Supersaturation produces crystals anchored within the kidneys themselves. Local supersaturations and special tissue conditions determine where anchored crystals form. The stones we seek to prevent form on those anchoring sites.

Given normal kidneys and urinary tracts, the main two anchoring sites are plaque and tubule plugs. But any distortions of the collecting system – congenital ureteropelvic obstruction, bifid ureters as examples – offer a place for crystals to lodge. Innumerable tiny stones may form in the blind end cysts of medullary sponge kidney.

Kidney Transporters

Tubule cell transporters regulate the amounts of stone forming ions and molecules in tubule fluid and urine. Therefore, for any amount of water conservation they determine the resulting supersaturations.

Those transporters serve the needs of the body that regulates them. Perhaps over the dim uncertain eons we evolved to some compromises between systemic needs and the hazards stones pose to the flourishing of our species. Perhaps not. Certainly, gene variations commonly cause humans to vary in transporter function for calcium, and perhaps citrate and protons. Rarely, gene defects produce such kidney disorders that make stones inevitable.

Urine Polymers

Kidneys add many protein molecules and other large polymers to the urine. Some are filtered out of blood, many are too large for filtration and we presume kidney cells provide them. Many of these large molecules bind to crystal surfaces and affect their growth and whether they stick together. They can be surfaces on which ions in urine bind to form the initial crystal nuclei. Being so numerous as they are, over 1,000 in urine alone and not as yet enumerated in kidney tissues, no one knows which matter, if any, in kidney stone formation.

The many proteins in urine and many other large urine molecules lie between supersaturation and crystal formation. I think they glue crystals together so as to make out of their multitudes of tininess the full bulk of clinical stones.

No doubt gene variation, and epigenetic modulations so affect these polymers that perhaps no two people express quite the same mix. They are a dark continent, an almost unexplored world.

Systemic Diseases

Because they serve the body, diseases of the body that affect bone and mineral handling, or water balance, or acid base balance, or oxalate metabolism all can drive kidneys to make stones. Whereas we prevent common stones by altering diet and use of a few medications that affect urine composition, stones from systemic diseases require we treat the underlying diseases. Of their manifestations, stone are but one and not always the one most important. So emphasis shifts from stone formation to that disease.

Kidney Diseases

Inherited or acquired kidney diseases can promote stones. Some cause excessive amounts of stone forming material in urine. Some cause too alkaline or acid a urine. Of these diseases some progress to kidney failure. Stones are only a part of a more serious problem.

Behavior and Inheritance

Than kidney stones, no disease better illustrates how behavior and inheritance cross to cause human disease. For although our species fashioned everything about the kidneys as we evolved into what we are now, how we use the kidneys depends upon what we do. Culture, habit, accident, and chance much determine whether stones will form.

Fate and Choice

My themes run like the threads of a loom.

The kidneys, the whole body, even, string their warp on its tensioners. How kidneys work, how constructed, what polymers they put into their tubules and urine, and the entire vastness of bone and mineral metabolism, gastrointestinal functioning, liver metabolism, brain control of water balance  – all these await the thread of the weft.

And that, which runs through all the rest to make reality, is what we do. We choose the yarns and throw the shuttlecock.

The warp is what we start with, fair or poor as chance may have it.

The warp is the body of fate, the weft our will.

And the cloth what we make of what we are.

Accident and Chance

Uncertain indeed are the threads of the loom.

For they must separate, open a way for the shuttle to pass with threads above and threads below.

But threads can break or tangle, and the shuttle go wrong so the pattern disclose some waywardness to an expert eye.

All this is metaphor, of course, taken lightly, by way of imagistic explanation of things too deep for words. But we have the long threads, do we not, strung on their elaborate tensioners and only so long and so durable. We have indeed their separation into the two, between which runs the shuttlecock; is that not true? And the cloth, do we not throw our patterns on the long threads of the warp?

Of course we do not – we are not looms. Even so, cannot one striking image set imagination free, engage the mind, perhaps, in ways unthought of?

As I Am a Physician

As I am a physician I am first a student of choice and chance. About the biologies, I can measure. But what about life as lived – my guidon, my pointer of the way?

There is in this high rigor, for the kidneys enact what the body needs, and we set what the body needs by what we ask it to do. Even worse, or more complex, stones are geological relics of whats past. So I must consider what was asked of the kidneys, especially before  the first stone, or before some acceleration of stone production.