“A rose by any other name would smell as sweet”

When I tell people that it’s becoming more and more clear, based on recent research, that fructose is bad for health, they almost always have one of two reactions. Some people, who have heard of the recent data, just nod. Others pause, raise their eyebrows and say, “wait, does that mean fruit is bad for you?” (The answer is that the amount of fructose in an apple is small compared to the amount that is in, say, chocolate cake, and there are a lot of other things in a fruit such as fiber, so no, unless you eat a lot of fruit.) They hear fructose and think fruit.

There is a reason why the food companies, when they started using corn syrup instead of sugar, called it high fructose corn syrup. Natural fructose comes from fruit. Now that fructose is acquiring a poor reputation, the same companies want to call it something else. (FDA recently rejected a petition to rename high fructose corn syrup “corn sugar.”

For the same reason why a company called Human Genome Sciences saw their stock rocket in 1999 when the human genome project was at its pitched fervor, when scientists hear of a molecule, they tend to assume name describes function. For example, if a molecule is called tumor necrosis factor, most people, including scientists, tend to think that it makes tumors die. Never mind that there is a fair amount of data suggesting that it may often actually encourage tumors to grow.

Names give scientific phenomenon a tag. It also defines the phenomenon. For the most part, this is necessary and good, because it would be impossible to do science without naming things.

However, there are pernicious effects in names that can lead us astray, and lead us to completely wrong paths. They are: misunderstanding of the phenomenon because of misnaming; drift in the boundaries of the name; confusion between names and phenomenon.

The first is easy to explain, and is often recognized. In fact, it’s a standing joke among some scientists. Many molecules in a body do more than one thing. However, when a scientist identifies a molecule for the very first time, it is often named for the first biological effect the scientist notes. Human growth hormone, for example, makes people grow.

When other biological effects for the molecule are later identified, though, the name often doesn’t change. Scientists don’t like to change names around too much, because it makes things very confusing. (It’s also harder to look up old scientific papers that way. I would venture to say that many physicians never search for “consumption” when they’re doing a literature search for tuberculosis.)

Of course, growth hormone does a lot of other things, including regulation of sugar and promoting cancer growth. But it’s often hard to remember all that, and people make the mistake of thinking that blocking growth hormone will only stop growth. Or that giving growth hormone or insulin won’t have an effect on cancer. If growth hormone were named “Type III Tumor Growth Factor” and insulin were named “Type V Tumor Growth Factor” (insulin also makes tumors grow) then the regulatory paths for those molecules probably would have been a bit more difficult. Or, if colon cancer, breast cancer, and other obesity-related tumors were called “insulin-dependent tumors” then the drug development programs for those tumors might have taken a different path. Names, I am afraid to say, do affect drug development efforts, and often in a deleterious way, because they can lead scientists astray. And most likely, they also affect other scientific pursuits and research.

It’s human nature–it’s hard to think of a molecule as doing something else than its name. Vascular endothelial growth factor is thought to promote blood vessel growth. People often forget that it was originally called vascular permeability factor. If insulin were called “fat cell growth factor” (increasing fat storage is another thing that insulin does) then there would probably be a lot less argument about whether food that stimulated insulin secretion promoted obesity.

Similarly, if the new name for Alzheimer’s disease, “Type III diabetes,” sticks, then I suspect that the number of companies that take a metabolic approach to the disease will increase, versus those taking a beta-amyloid based approach.

The take-away is that scientists have to consciously struggle against being biased by the name of the molecule.

The second problem is a lot more pernicious. I call it the “rose by any other name” phenomenon. When Shakespeare wrote, “a rose by any other name would smell as sweet,” he was right. But his rose was not our rose. His rose was the classical, original rose, a small flower with only five petals that bore little resemblance to the rose you and I see today. The name has stayed the same but not the flower. Similarly, the eggplant of yore was white and oval, like an egg, not the black, club-like vegetable you see today. If someone had said something was chocolate colored in 1860, he would have meant a reddish color, not brownish, because chocolate back then was reddish.

When the name stays the same but the definition of the disease changes, then we can run into major problems. For example, there are many subgroups of breast cancer. Depending on what kind of protein it has on the cell surface, how it looks under the microscope, and a whole host of other factors, breast cancer is divided into many categories. This is done because different cancers in different categories act differently and more importantly, because they respond to therapies differently.

For example, breast cancer is treated differently depending on whether it’s HER2 positive or negative. Women with HER2 positive breast cancer receive Herceptin, for example, and women with HER2 negative breast cancer do not. The definition of the HER2 positive breast cancer was changed in 2011 (updated 2013). [www.asco.org/guidelines/her2]

This was done in order to make HER2 testing more consistent and in order to improve patient care. This solved one problem but created a different problem because the previous studies and data were based on the old definition. Now when an oncologist treats a HER2+ patient, she may or may not be the same kind of HER2+ patient that were studied. The old data may or may not apply. Similarly, AJCC classification of node positive has hanged over time. I must acknowledge an eminent oncologist, Dr. Elizabeth Tan-Chiu, for pointing this out to me.

A more pernicious problem is that some physicians may not know or may forget that the definitions have changed over time. For example, let’s say you walk into your doctor’s office for a checkup and your blood glucose reading is 100. Well, the definition of diabetes (yes diabetes) was changed several years ago. Whereas a blood glucose reading of 100 would have meant you didn’t have diabetes, now you do. The doctor wants to put you on metformin. He wants to start you on statins because now you have enough risk factors. The problem of course, is that the studies on diabetes that were done were not done on people like you. They were done on people with “diabetes,” not “diabetes with blood sugar of 100.” The data on how and when to treat diabetes is a bit murky to start with (which I will blog about eventually), and when you add the shifting definitions, it gets even murkier.

The third problem is unique to drug development. When we give diseases a name, we make it seem like a disease is a biological phenomenon. When a doctor says a patient has pneumonia or cystic fibrosis, it seems like these are diseases that exist, that has existed, and will always exist.

No. Diseases are intellectual constructs. They’re like boundaries of countries. Sometimes they’re based on the contours of natural geography, much like borders that wind along rivers or stop at mountains. Other times, they’re arbitrary, like vertical lines dividing some of the American Midwestern states. What’s the dividing line between pneumonia vs. bronchitis? What’s the difference between a heart attack and angina? Where we divide the diseases into categories and how many divisions we draw, as physicians, are not God-given. They’re man made.

In fact, there are sometimes controversies about categories. For example, on May 18, 2013, the new Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) was published by American Psychiatric Association. This is the book that tells physicians the criteria for psychiatric diseases (yes, there is a book that tells you how to do this). The DSM-5 created a tornado of controversy, highly unusual for something like this. Over ten thousand people signed an open letter protesting the criteria. [dsm5-reform.com] Many people were were very upset that the diagnoses were based not on “biology” but only on symptoms. There were insinuations that drug companies influenced the new criteria. [www.newscientist.com/article/dn21580-many-authors-of-psychiatry-bible-have-industry-ties]

Sometimes people get upset because it seems that pharmaceutical companies are inventing new ideas. For example, more than one layperson has complained to me about Restless Leg Syndrome. They think it’s a disease pharma companies invented.

Well, let me be the first to admit. Yes, pharma companies do invent new diseases. That’s because pharma companies invent new therapies, and there is often no reason to give a disease its own name, even f it exists, until there is a therapy for it. It’s not that the disease hasn’t existed, but rather than no one bothered to name it because there was no reason to name it.

Here is an example of a disease that a pharma company invented: high blood pressure. Until the 1970s, there was a great deal of debate over whether hypertension was a disease that needed to be treated, especially in the elderly. Some physicians thought that as we aged, and as our blood vessels became stiffer, hypertension was a natural effort by the body to maintain blood flow to all the important parts of the body. It wasn’t until a strenuous effort by Merck and other companies to change people’s minds that it became accepted that hypertension had to be treated.

I should note that it is not clear still how, when, and with what we should treat hypertension. As more data comes out, it is becoming clear that some drugs work better than others (and some are actually harmful). Recently, the guidelines were changed to make treatment of elderly patients less aggressive. The complexity of the consensus guidelines suggests that there are still many unanswered questions.

While some diseases are named for the biological phenomenon, and others based on the constellation of symptoms, those are not the primary driver for disease names. Physicians are pragmatic, and most of the time, the diseases are named or created if the treatments for the diseases would differ. In general, diseases or subcategories of diseases exist because they are treated differently. For example, heart attacks (MIs) and angina are treated differently. Heart attacks get clot busters or emergent angioplasties; anginas don’t.

This is part of the reason why diseases appear and disappear, and why they get renamed sometimes. Here are some diseases that don’t exist any more, or don’t exist with the same name: dropsy, melancholy, hysteria. Here are some diseases that didn’t exist until modern times: depression, autism, Crohn’s disease.

In some cases, there are actual new diseases, such as AIDS. But in many cases, like dropsy or depression, we have reclassified the disease and changed the boundaries of the diseases.

And we should remember, the very idea of a disease is context dependent. For example, every child born in the U.S. gets tested for a condition called PKU. If you look at a diet Coke can, you will see a warning that it “contains phenylalanine.” PKU is a genetic disease, and the people who have it have a mutation in the gene for the enzyme that allows them to digest phenylalanine.

But take a step back. If instead being a tiny percent of the population, if the mutation were prevalent – for example, like the mutation that allows us to digest milk – then it wouldn’t be considered a disease. It would be considered normal, and phenylalanine would simply be considered to be a toxin. Similarly, if instead of 1% of the population, 99% of the population had the CCR5 mutation that made you immune to HIV, then HIV would not be an infectious disease but a genetic disease instead.

So what does this mean for drug development?

One: Names don’t always describe the function of a molecule. Don’t be led astray by molecule names.

Two: A disease name stay the same but the disease itself may change over time, especially if a committee decides what the disease is.

Three: Diseases are set up by clinicians as categories. The categories change over time, and importantly, reflect the available therapies. Diseases are often separated by their responses to specific therapies. So don’t be afraid to split or lump disease together when thinking about new drugs.