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Tech Visionaries

by Ted Alcorn, MHS ’10

A Map of the Human Toxome

We like to think that manufactured products have grown safer over the last century, that careful toxicological testing and stringent regulation now protect us from medicines that can poison and cosmetics that can blind us. The reality is not so rosy. Humans are potentially exposed to 80,000 chemicals for which no toxicological assessment has ever taken place. And the current methods of evaluation—high-dose animal tests extrapolated to human beings—are at best crude and at worst unscientific.

“The current toolbox simply doesn’t allow us to do the testing we want,” says Thomas Hartung, MD, PhD, who saw the limitations of these approaches in his previous work as director of the European Center for the Validation of Alternative Methods. Now the Doerenkamp-Zbinden Endowed Chair in Evidence-Based Toxicology and director of the Center for Alternatives to Animal Testing (CAAT), he says he was drawn to the Bloomberg School in 2009 by “the opportunity to become involved in something that could revolutionize the field.”

The opportunity he envisioned was to identify and catalog comprehensively what are known as “pathways of toxicity” (PoT): the molecular pathways that, when perturbed, produce adverse health effects. Whereas current toxicological tests typically expose animals to a substance in order to provide a crude characterization of its toxicity, Hartung wants to comprehensively document the substance’s interactions with human cells and compile the results in an open-source database.

“There are a couple of hundred ways to kill a cell," says Thomas Hartung. "If we had a map of this, we could start to look into which cell has which of these pathways, and we might start to understand why a substance is toxic for mice and not for rats, or why it affects liver cells and not heart cells.”

With a $6 million NIH Director’s Grant, he has set out to do just that. “The first step,” he says, “is to develop a language to describe toxicity—describing these pathways in relation to the genes that are involved and metabolic pathways that are involved.” With this shared vocabulary, a global consortium can begin contributing to the database and building what he calls a “human toxome.”

The need to improve present-day toxicological testing is apparent. From food additives to medications to the ubiquitous materials of our built environments, we are both surrounded by and dependent on novel substances of unknown toxicological safety. “Products worth $10 trillion are rated with [the old] suite of toxicological tests, and people know they aren’t necessarily making the best business decisions,” says Hartung, a professor of Environmental Health Sciences (EHS). “But technologies that are young, from the last few decades, offer a new approach to solving this problem.”


Seeking Hidden Hunger

The emblematic images of famine—emaciated children, skin taut across delicate bones—have habituated Americans to think of malnutrition primarily as brutal starvation. While famine relief is vitally important, too little recognized is the larger problem of “hidden hunger.”

Though their external symptoms aren’t necessarily obvious nor is their prevalence in a population easy to gauge, micronutrient deficiencies affect one-third of the world’s people and are a leading cause of child disability and mortality. Keith P. West, Jr., DrPH ’87, MPH ’79, hopes research on protein biomarkers will bring the problem into the light.

Insufficient intake of a few dozen micronutrients essential to healthy development is implicated in a wide range of preventable illnesses. However, characterizing these deficiencies at the population level has been hampered by the cost and difficulty of measurement. Blood samples drawn in the field must be shipped to distant laboratories for analysis with expensive machinery, and it may take years to assemble the results. Performing the recurrent tests necessary to maintain consistent micronutrient surveillance is thus untenable; in Nepal, for example, the last time such data were collected was 1998, says West, the George G. Graham Professor of Infant and Child Nutrition.

“It dawned on us that we needed a change in paradigm," he recalls.

West and his colleagues in the Bloomberg School and the Johns Hopkins School of Medicine aspire to identify a cheap and quick way to measure a spectrum of micronutrient deficiencies. They have focused on blood plasma, which contains a cross-section of the body’s proteins, and which the new field of proteomics has made more accessible. Since the proteins present in plasma at any moment may reflect what is going on in the tissues, the investigators hypothesized that changes in the concentration of certain proteins might indicate micronutrient deficiencies. For example, measures of the protein transthyretin may parallel the plasma content of retinol (vitamin A).

“The circulation becomes a window for viewing the way that nutrients and proteins interact in the body,” West explains.

What began as “a hobby that kept us up late at night” has grown into a full-scale pilot project funded by the Gates Foundation. West and his colleagues have already identified proteins that co-vary reliably with nutrient levels and, within the next 10 years, they are determined to develop an onsite, real-time test for multiple micronutrient deficiencies. This would allow investigators to quickly and accurately profile an entire population and take effective action.

“It would change the entire information landscape for making more rapid decisions about the nutritional conditions of populations affected today,” says West.


A Red Flag for Nanotechnology

While some visionaries extend the boundaries of human investigation and problem solving, others bring the world that’s already visible into a remarkable, new perspective. Ellen Silbergeld, PhD ’72, does both. An authority on the toxicology of lead and mercury, she is now leading a push to give the blooming field of nanotechnology more critical examination, before it’s too late.

Nanomaterials—often defined as smaller than a tenth of a micrometer in at least one dimension—are being rapidly integrated into everyday life. The large surface area of nanoparticles relative to their volume confers special properties. Nanotechnologies make fabrics stain-resistant, inhibit bacterial growth in food packaging and increase the clarity of cosmetics. They also hold the promise to revolutionize medicine, by penetrating cells and delivering drugs with a precision that was previously impossible.

“I am as capable of being intrigued by nanomaterials as anybody and I think that the promise is potentially very great,” she says. But having witnessed the trajectory of other hyped technologies such as leaded gasoline—which was trumpeted as a 'gift of God' at the time of its introduction and then, once its toxicity became apparent, took decades to remove from the market—Silbergeld, an EHS professor, argues for a more cautious approach, writing articles on the subject and chairing workshops to engage the attention of government as well as fellow scientists. “We’ve just had too much of a history of doing things where the promise was very great.”

Nanotechnologies raise a red flag because the deliberately engineered properties that make them so valuable could make them hazardous. A molecule designed to deliver a drug through a membrane, perhaps administered into the bloodstream, could pick up mercury from the circulation and deliver it instead to intracellular targets like DNA. (Silbergeld describes this as a “sorcerer’s apprentice” problem. The nanotechnology is like the story’s enchanted broom, which continues to draw water from a well even after the room is flooded.)

More careful scrutiny can only be good for nanotechnology in the long term, says Silbergeld, since the belated emergence of hazards would almost certainly undermine the public’s confidence in the technology.

But with an almost total lack of information on the effect of chronic exposure to nanomaterials, a change in course is overdue. “The most important step a responsible society can take is to come to an agreement about the knowledge that’s needed to make decisions about nanotechnology, be it in the private sector in terms of product development, in the public sector in terms of regulation and guidance, or in the public in terms of acceptability,” she says.