By Alex Daley
My job helps me learn all kinds of amazing things, and it lends itself well to exploring some very big questions. Like last week. I was casually chatting about biotechnology companies with a friend, when she asked a question deviously complex despite its simplicity: "Why don't we really have cures for anything?" She then proceeded to list off diseases from cancer to AIDS to malaria to strokes in order to hammer home her point.
My answer, in short, was that we are far, far, far more complex than most people understand. Not just us humans, either – every form of biological life, right down the microbes, is very complex. But getting someone who has not spent years of his or her life immersed in science to really grok that concept is difficult.
Sure, unlike in the Middle Ages, we all grow up being exposed to concepts like skin cells, bacteria, and viruses, and their building blocks, including proteins, fats, and DNA. But do we really understand just how inordinately complex we are? Even the number of cells in the human body at any one time is a mind-bogglingly high number. Estimates range from 40 to 100 trillion, each one its own factory with locked doors (selectively permeable cell walls), manufacturing equipment (ribosomes), computer cores (the nucleus), and billions of lines of programming (genes). Each is a factory that can make new factories, or blueprints for other factories. But even that only scratches the surface of our immense complexity – one example being that, for the dazzlingly huge number of cells each human body contains, we each carry many more bacteria within and on ourselves... and we've barely identified those species, let alone understand how they work with us for good and sometimes for ill.
So, I hereby present some amazing facts and short stories from just the past few weeks, to illustrate just how complicated we are and why we're not going to wake up any day soon and find all the world's diseases cured. Before I dig in, let me say this: We didn't know any of this just a few decades ago. Most of it remained undiscovered a few years ago, and some of it, even a few months ago. The simple fact is that our understanding of biology is increasing exponentially right now. We're turning up the steep side of the curve, just like we did for computers three decades ago. This is the golden age of biological research, and like the Industrial and Information Ages before it, we've got one hell of a ride in store.
The difference is that the mechanical systems that we had to master to move into the Industrial Age were remarkably simple: from conveyor belts to nanoscale silicon etching and out to the limits of Newtonian physics, the mechanical world is relatively easy to understand, predict, and work with. It all just comes down to levers and pulleys.
The same, to an extent, is also true of the computer age. The rules of the mathematical worlds we've created inside computers are many-fold more complex, yes. However, they were painted on a blank canvas of our own creation, using rules we made up as we went along – virtually every bit had been anticipated. Increasing complexity multiplied the possible problems, of course. Unexpected inputs came first as bugs, then as viruses, and we fight to wrap our arms around all the many things that can go wrong, by accident or through attack. Yet we can invariably solve any problem, because it is still a game we designed for ourselves.
With biology, we face a much bigger uphill battle: learning a system that has evolved over billions of years, and which we've really only gotten a peek at during the last half century or so. We've had millennia to tinker with the physical, and at least two dozen centuries to work on math beyond counting our fingers and toes, but just a few decades of electron microscopy and stereo spectrographs. If it takes two pages to explain the recently understood genetic and chemical roots of gray hair, then you can imagine how complicated something like the human brain must really be. Thus, despite the leaps forward that our research may take, cracking the code that makes us may take some considerable time. However, the progress being made today is still pretty amazing, despite the hill left to climb.
That said, without further ado, from the most “simple” to the amazing:
The Genetic Roots of Gray Hair
Eventually, nearly every adult has this experience: looking in the mirror and seeing the telltale signs of age staring back at him- or herself.
Mine didn't show until my mid-thirties. A few wrinkles here, a stray gray hair here and there. My brother, on the other hand, was lucky enough to follow in our father's footsteps and see his dark black hair salted with grays from his early twenties on. "Lucky," of course, is meant in jest. Despite how distinguished the average woman will tell a man that his gray hair makes him look, at the end of the day he still looks older. For most people, that is an unwelcome change.
And for any problem – even vanity – that is so universal, you can be sure that there are scientists hard at work looking for a way to overcome it. Yet despite decades of study, scientists are just now beginning to converge on the complex processes that lead to this "most alarming" of age-related medical conditions.
It all roots (so to speak) in a group of chemicals: melanins. These are created from the combination of two amino acids – some of the fundamental building blocks of life itself, which are made from a particular combination of hydrocarbons (i.e., combinations of hydrogen and oxygen from air and water, and carbon from our food) and at least one molecular group containing nitrogen. In particular, melanin is a mix of tyrosine and phenylalanine, two remarkably similar and simple amino acids.
Buried just beneath your skin is a thin layer of billions of specialized cells called melanocytes, which developed explicitly for the purpose of coloring skin and hair. If you slice up a sample of your skin and look at in a microscope, it'll look pretty much like this cross section:
That green arrow points to the melanoctyes. Those small cells each have a microscopic factory inside of them, which combines the two aforementioned amino acids and produces melanins, through a complex, chemical computeresque algorithm called the KEGG pathway. Here is a diagram of that interaction (unless you are a biophile, don't try to parse it – just note that it's really complicated for such a seemingly simple task):
Meanwhile, elsewhere there is another set of cells hard at work growing hair. These other cells, known as keratinocytes, make hair by excreting fibers called keratins, which are long strings of useless (for things other than growing hair) proteins, often referred to as "dead proteins."
The natural color of these fibers is white. In other words, white hair is simply hair that has yet to be colored.
Hair gets its color from the melanins (also responsible for skin color) produced by those melanocytes. Those cells combine the two core amino acids to produce one of two different pigment colors:
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Eumelanin – responsible for dark browns and blacks
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Pheomelanin – produces reddish/yellow tints
Our bodies each produce and maintain a pretty even balance of cells for each melanin – hence our relatively consistent hair color throughout our lives. These two pigments are carried over to the adjacent keratinocytes, where they are blended into the hair mixture as it's made. Voilà: colored hair.
Despite this scientific understanding of how hair is colored, we still don't know why it is. We don't know what functions – genetic, chemical, environmental, or otherwise – regulate exactly which mix of the keratins each person ends up with. Each melanocyte can only produce one particular melanin; and what determines the balance of each type one's body produces is still a mystery.
There do appear to be genetic roots. For example, a recessive mutation of a gene called MC1R plays a key role in creating natural redheads. But as anyone who has had a baby whose hair changed colors as it grew can attest, it's certainly not all decided at birth. Jet-black hair in the cradle to blond just months later... or a blond kid who grows into a dark brunette adult are both common scenarios.
So what causes our hair to gray, and eventually to go white in many cases? Failure of melanocytes to keep pumping out coloring. Keratocytes keep pushing out hair (albeit less effectively), but there's not as much melanin to go into the mixture... and eventually, none at all.
Why this should be is a more complicated question. It can be due to genetic abnormalities or exposure to certain chemicals. These can cause melanocytes to malfunction or fail completely.
The most common cause, though, is obvious: age. But exactly what age has to do with it is still partially unknown. One theory, posited in a 2009 study, blames a chain reaction. Hair follicles all contain small amounts of hydrogen peroxide, it was found. Normally, an enzyme (these are complex biological chemicals that govern chemical reactions, and another, key building block of life) called catalase consumes this bleaching agent. But over time, our bodies produce less and less catalase. The peroxide then builds up in follicles, impairing the function of the melanocytes in the region, turning hair gray or white, while not affecting its presence in skin coloring. Why, then, do we stop producing the catalase? That currently isn't known.
Another potential age trigger has to do with the production of melanocyte-specialized stem cells. For still unexplained reasons, our body produces less and less of these replacement cell lines as we grow older. The mechanisms that govern adult stem-cell specialization remain an intense, and largely uncracked, area of study for scientists.
Another old adage says that stress is a cause. Like so many other lasting social observations, this one has proven to have some scientific basis. Stress – especially prolonged stress – has been shown to release certain neurotransmitters and hormones that, while beneficial in working through threatening situations by speeding reaction time or strengthening muscles for short periods of time, cause genetic damage and accelerate the overall aging process. (We see this in stark relief with our presidents: Note how fast the relatively youthful Clinton, Bush, and Obama each went gray.) The effect includes not just bringing on gray hair earlier, but also promoting the growth of tumors, the likelihood of miscarriage, and many other conditions.
Our bodies are incredibly efficient, self-regulated factories. They fight a 24/7 battle with chemical and biological assailants, while replicating trillions of copies of thousands of different cell types, day in and day out... and too often, with as little as Coca-Cola and pepperoni pizza as building materials. That our hair doesn't just fall out, and much worse, is testament to the amazing engineering of the human body. So we can probably forgive a few gray hairs. That is, until someone develops a pill to promote more melanin production. Or a little less eumelanin and a little more pheomelanin. After all, if blonds really do have more fun, then it stands to reason that they'll have less stress and go gray just a little bit slower.
Now consider that that has been an overly simplified telling of the story, which neglects to explain the mechanisms for creating and transporting raw ingredients for the melanocytes, or just how the pigments make it from there into the keratinocytes, and much more. Just imagine what doctors are up against trying to understand something like how to treat an aggressive form of brain cancer, or to reverse the effects of smoking on the lungs.
It's not just human anatomy that is so complicated. Next up, our understanding of the complex inner workings of seemingly simple little plants takes a leap forward. Then, we look at what makes one of the most persistence viruses of our age so hard to fight.
I'll keep those quite a bit shorter, as the last part of this four-step walk through biology's maze of complexity is the most amazing: a breakthrough that promises to nearly wipe out one of heart disease's most prominent risk factors.
The Amazing Counting Chicken Plant
Forget chickens that can play checkers or chess. I've got a trick to show you: plants that can multiply and even do long division.
No, I am not talking about some genetic mutant bred for the enjoyment of math nerds the world over. I'm referring to a comment by a scientist in a recent paper describing the biological processes that caught the attention of news organizations around the world, because it suggested that plants are capable of metaphorically "doing maths."
While you won't see a Venus flytrap stepping up to the chalkboard anytime soon, behind the expression is quite an intriguing bit of science. You see, plants are like living solar cells. Every sixth-grade science student has learned about photosynthesis, the mechanism by which plants use sunlight to convert carbon dioxide (CO2) into sugars and starches used for food.
The science lesson usually left off there, however. Little was usually said about just what happens inside a plant when night falls and the sun isn't shining. It was just assumed that every plant kept lots of energy in reserve and used what it had stored to get through the night or a stormy day.
But, the research from the team in Norwich's John Innes Center has shown that it is far more complex than that. Plants actually go through a complex rationing system to regulate their usage of starch – they must consume enough to survive the night, but not so much that they waste or reserve excess energy that could be used instead to grow larger and grab more sunlight the next time around.
What the team did was to suddenly shift a plant's normal 12-hour day-night cycle into a much shorter 8-hour day and 16-hour night. The result: it would quickly adapt and enter the morning with nearly the same energy left over as when it had more time to make it and a shorter storage interval. The plant had adapted rapidly to changes in the environment by using less energy to grow and more to survive, like a person rationing food in a lifeboat.
Researchers found that if they mutated certain portions of the plant's "starch degradation pathway," the process broke down, and regulation failed. Disrupting night with quick bursts of light also threw off the process. The conclusion: chemicals in the leaves of the plants they studied were dynamically responding to lack of sunlight in an arithmetically designed way, feeding signals out to the energy-consuming parts of the plant to control the level of starch used over time.
This did not happen at a genetic level either, with the environment affecting the transcription of genes to produce the enzymes that consume starch – that would be far too slow. Instead, some novel mechanism is at work, regulated by the same kind of circadian internal clock that we equate with more advanced life forms. The exact chemical pathway will take time to track down. However, scientists have shown clearly that there is basic linear arithmetic happening within the plant to regulate food usage and to balance the odds of surviving a period of darkness with the need to grow. Plants are, unconsciously, doing math to adapt. So might many other living things, from molds to people.
Cracking the HIV Super Code
As a technology writer, I regularly strive to take in facts from all sorts of different media and translate them into a compelling story that is both informative and entertaining. I consider myself to be, at times, moderately successful at that. But then sometimes I come a cross a story that is told much better than I could possibly hope to do.
That was the case recently, when I stumbled upon a story by Gizmodo's Andrew Tarantola, detailing a recent breakthrough in understanding how the HIV virus is so effective in defeating our immune system. Using a supercomputer, researchers spent countless computing cycles running through potential permutations of how an ingeniously complex protein could be folded and stitched together into a shape uniquely designed to do just that. You can read his excellent piece on the subject: How a Supercomputer May Have Finally Unlocked a Way to Beat HIV.
Along with the seemingly simple but ultimately immensely complex examples above, this is a clear demonstration of just what levels of complexity scientists are up against in trying to discover, understand, and influence the operations of the most amazing machines ever built (or rather, grown) without doing more damage than good along the way – and just how much further we have to go to move beyond the low-hanging fruit of medicine and into an age of custom-tailored biological and genetic therapies. That is not to say we aren't making progress, however.
How to Stop a Runaway Gene
As an example, we've talked in this column before about the amazing potential of antisense drugs (to recap in the simplest terms possible: specially tailored chemicals designed to block the signals a targeted gene sends to the body's production centers). Antisense therapy represents the beginnings of what is called "rational drug design," where a system can be developed for building drugs from the ground up to effect certain reactions, as opposed the traditional spaghetti-at-the-wall approach of throwing thousands of chemicals at the body to see how it reacts. From accidental discovery to purposeful design.
Following decades of research and a number of important advances in recent years, including the approval of the first ever antisense drug last year, the new science is starting to show off some real muscle.
In results posted last week, antisense leader Isis Pharmaceuticals (a position recommended in our Casey Extraordinary Technology portfolio of high-growth tech leaders) revealed that one of its new drugs – codenamed ISIS-APOCIII for its role in reducing production of apolipoprotein C-III (called apoC-III for short), a protein linked to high blood triglycerides, which is a major risk factor in heart disease – showed some pretty amazing results in a Phase II trial.
The drug was being tested in patients with both high triglycerides and type 2 diabetes, an all too common combo, and study results showed:
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an average 88% reduction in apoC-III, as one would hope from a drug that blocks its production;
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a whopping 72% reduction in triglyceride levels(!); and
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a 40% increase in high-density lipoprotein cholesterol (i.e., the good cholesterol).
These results in and of themselves show the drug's incredible potential as a treatment for high triglycerides. But that's not all of the benefit. Patients taking the drug also showed enhanced insulin sensitivity – a very good thing for type 2 diabetics, as lack of insulin sensitivity is the root of the condition – with improvements in multiple measures of glucose control.
Diabetes has long been understood as encouraging high triglycerides, resulting in an increased risk of heart disease among its sufferers. It's an inevitable side effect. With this study we're seeing the reverse, as lowering triglycerides seems to also lessen the severity of diabetes, instead of just vice versa.
As you can imagine, the company's stock popped on the news, shooting up 25% in just one day, and bringing the gains since January to well over 150%.
ISIS-APOCIII is also being evaluated in a separate Phase II trial in patients with moderate to severe high triglycerides. It is expected to read out later this summer and will really tell how much market potential there might be for the drug. Positive results as well as good readouts later on could eventually push the drug's potential up into the range of previous blockbuster treatments for heart disease risk factors. Maybe, just maybe, if all goes well, it scales the heights of drugs like Lipitor, whose peak sales were $11 billion annually.
Not bad for a company that started this year with a market cap of less than $1 billion. And to think it has 28 drugs in trials right now.
There is a long and interesting road ahead for ISIS – and for many of the other small biotech companies followed in Casey Extraordinary Technology. As we probe and discover more about the mechanics of the human body and biology in general, the possibilities for new treatments are virtually limitless. It's an exciting time to be alive. Why not make it just as exciting a time for your investment portfolio? Take Casey Extraordinary Technology for a risk-free test drive today, and let amazing companies like ISIS breathe some new life into your bank account too.
Until next week,
Alex Daley
Chief Technology Investment Strategist
Casey Research
