A Pill For Los Angeles? Medicating the Megacities

Los Angeles — and other modern megacities — conjure increasingly unique genetic profiles that point the way to a new medical industry: Call it urbo-pharmaceuticals. Investors are needed.

Is there a pill that might inoculate us from smog?
Is there a gene we can target that would make us resistant to resurgent infectious diseases?
And is there a way to use genetic data to insulate new immigrants from some of the metabolic challenges of living in a new land of plenty?

Welcome to the slowly emerging world of environmental medicine and its inevitable outgrowth, environmental pharmaceuticals: compounds specifically suited for mitigating the physiological challenges of mega-city life in the 21st century.

The inchoate drive for such pills — disparate, proceeding in entrepreneurial fits and starts — is fueled by twin facts.

First: Inflammation, the chronic-over-firing of the body’s immune system, now sits at the core of almost all scientific discussion of chronic diseases, diseases that persist despite thirty years of lifestyle advice, medication and surgical intervention.

Second: Urban environments today are physiologically inflammatory beyond belief, their brew of fumes, crowding, germs and bad food wreaking all kinds of internal damage and prompting no end of lifelong medical problems. As Dr Marc Reidl, a specialist in respiratory disease at UCLA puts it, “Mega city life is an unprecedented insult to the immune system.”

The consequent diseases — asthma and COPD, heart disease, diabetes, alcohol and drug addiction — are costly and life-sapping. They are accentuated by the huge inflows of young populations, many from poor rural environments, from Mexico to the Middle East. These new migrants bring their own unique pathogens, and their own unique vulnerabilities. Poverty fuels excess consumption of cheap fruits and sugars, pushes people into smog-proximate neighborhoods and pest-filled homes, and drives them to unhealthful behaviors. And certain genes — most notably the well-studied “hungry gene” — exacerbate the reaction. Consider:

Asthma and COPD, considered among the world’s top medical concerns, seem to be activated by special sets of genes, some of which accentuate the impact of smog (along with tobacco smoke, the principle culprit in the industrialized world). Other genetic profiles seem to mitigate it. Researchers at the University of Southern California have identified both versions.

In the Latino population, mutations in liver genes, particularly one well-known one named CYP450, seem not only to fuel alcohol abuse, but also to accentuate some of its gravest consequences: fatty liver disease and cirrhosis.

Heart disease, as well as problem pregnancies, uncontrolled diabetes, and even sleep apnea, are increasingly driven not just by the traditional devils of unhealthy lifestyle and poverty, but by genes activated by uniquely urban pathogens and concentrated diesel and auto exhaust.

Genes governing stress responses may be at the root of why traditional antibiotics do not work within the germy reality of big cities. For years, speaking the words “genes,” “immigrants,” and “public health” was the proverbial ticket to a social and political nether-land. It was almost as bad as talking about obesity. It is still a messy brew.

Yet outside of “nannyism” (not necessarily such a bad thing), or trying to scare away any new migrants (which is), what can be done? One tack might be to take a cue from modern pharmacology’s attempt to develop a pill for Metabolic Syndrome, the debilitating mix of diabetes, high blood pressure and high cholesterol now prevalent in most developed nations. Can we design an urban poly-pill, one built specifically for the inflammatory storms of the mega-city? And can we point it at what might be called the big three: the impairment of respiration, metabolism and cardio vascular processes?

UCLA’s Riedl, a specialist in respiratory disease, has zeroed in on oxidative stress — the damage caused by unstable, burned-up nutrient particles in the blood stream. He knew that anti-oxidant supplement regimes have been an overwhelming bust, most of them weak and not very good at targeting the body’s native anti-oxidant systems. Then came a number of insights made possible by genetics. Perhaps the most important was a molecule dubbed GSTM1. It is deeply implicated in fighting oxidative stress from smog and other pollutants. Riedl traced the pathway upstream and found that it was driven by another gene product called Nrf-2.

Then he decided to pharmaceuticalize one molecule derived from broccoli sprouts, sulphoraphane, crafting a concoction using concentrates of the vegetable mixed with daikon root essence. The result was a compound he could try out in various concentrations in humans, then measure whether its effect on Nrf-2 were, in the lexicon of pharmaceutical development, “dose dependent.” It was. The next step will be to test how well it works in people exposed to constant high levels of smog.

Though the path to any therapy remains long and arduous, Riedl holds a picture in his mind of one possible future. “The Holy Grail for us is if we could identify the population sub group that is most likely to have the mutation that impairs Nrf-2, and who are environmentally vulnerable —say, people who live close to freeways — and essentially do targeted chemotherapy for environmental insults.”

Among urban woes, metabolic disorders are particularly troublesome. The NIH has singled out type 2 diabetes and fatty liver disease as the two biggest factors driving hospitalization, amputations and prescription drug use. Their effect on health care expenditure is huge and growing. Treatment — let alone prevention — has proved vexing.

Two promising compounds are under serious study. The first is the grape skin compound known as Resveratrol. Though mainly known for its claim to extend mammalian lifespan, its true value is quietly emerging in diabetes treatment, where early clinical trials showed promising results but, unfortunately, several safety issues.

And Metformin, a diabetes drug originally synthesized from the French lilac plant, may have huge protective benefits for urbanites. Researchers at UCLA Riverside have used microchip arrays to discover that it activates liver genes that dampen high insulin levels and vascular inflammation.

At USC, one of the world’s leading centers for studying diabetes and liver diseases, scholars have pinpointed a gene that, when activated, causes fatty liver disease, another potential urbo-drug target. As Michael Goran, the head of USC’s diabetes research, notes: “In Mexican Americans there is mutation in a gene called PNPLA1 which is related to an elevation in liver fat which could be related to increased diabetes risk and definitely [is] related to longer term increase in liver disease; this mutation is highly prevalent in Hispanics/Mexican Americans; moreover, in our own research we have just discovered that: a) the effect of this gene is manifested very early in life and b) the effect of this gene on increasing liver fat is promoted by high sugar intake.”

What about the heart? UCLA heart researcher Alan Fogelman, the dean of modern HDL research, has two compounds in small clinical trials that would help the body restore its ability to make good cholesterol, a process increasingly undermined by the smog, virii and bad food of mega-cities. Both are peptides — short, protein-like molecules — that target specific gene products activated by chronic inflammation, which can include everything from the flu to sleep apnea to unchecked diabetes. The compounds are being developed by Bruin Pharma, a commercial venture in which Fogelman is a principal and an officer.

What are his HDL peptide's chances? “It is so early to try to tell something like that,” he says. “We have no idea where that effort will take us, or whether it will hit the target we hope. We have to wait for the trials.”

Yet waiting, especially when it requires patience and foresightedness, is something we as a society seem incapable of, especially when dealing with complicated public health issues. But what if there were a faster, cheaper way? Urbo-pharmaceuticals might be one ticket. After all, we are patient and forgiving when it comes to pills and the time, cost and uncertainty that comes with their development.

Chalk that up to the ease-seeking nature of humans, something for which there is no pill, but which, in itself, might drive us to invest in a poly pill for modern life.

Greg Critser’s new book is Eternity Soup: Inside the Quest to End Aging (Random/Harmony 2010).

Photo by ilmungo / Luigi Anzivino, Los Angeles from the top of Temescal Canyon Trail, "...taken not at sunset, but at 11AM... that pretty peach-colored layer in the sky is the famous LA smog."