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Got It Down Cold: Cryo-Electron Microscopy Named Method of the Year

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Cryo-EM

Caption: Composite image of beta-galactosidase showing how cryo-EM’s resolution has improved dramatically in recent years. Older images to the left, more recent to the right.
Credit: Veronica Falconieri, Subramaniam Lab, National Cancer Institute

In the quest to find faster, better ways of mapping the structure of proteins and other key biological molecules, a growing number of researchers are turning to an innovative method that pushes the idea of a freeze frame to a whole new level:  cryo-electron microscopy (cryo-EM). The technique, which involves flash-freezing molecules in liquid nitrogen and bombarding them with electrons to capture their images with a special camera, has advanced dramatically since its inception thanks to the efforts of many creative minds. In fact, cryo-EM has improved so much that its mapping performance now rivals that of X-ray crystallography [1], the long-time workhorse of drug developers and structural biologists.

To get an idea of just how far cryo-EM has come over the last decade, take a look at the composite image above, which shows a bacterial enzyme (beta-galactosidase) bound to a drug-like molecule (phenylethyl beta-D-thiogalactopyranoside). To the left, you see a blob-like area generated by cryo-EM methods that would have been considered state-of-the-art just a few years ago. To the right, there’s an exquisitely detailed structure, which was produced at more than 10-times greater resolution using the latest advances in cryo-EM. In fact, today’s cryo-EM is so powerful that researchers can almost make out individual atoms! Very impressive, and just one of the many reasons why the journal Nature Methods recently named cryo-EM its “Method of the Year” for 2015 [2].


Digging Up New Antibiotics

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iChip being removed from dirt

Caption: Microfluidic chip being used by scientists to search dirt for new sources of antibiotics.
Credit: Slava Epstein/Northeastern U.

Last fall, President Obama issued an Executive Order aimed at combating a growing public health threat: antibiotic-resistant infections that claim the lives of 23,000 Americans every year [1]. So, I’m pleased to report that biomedical research has made some exciting progress on this front with the discovery of what promises to be a powerful new class of antibiotic drugs—the first such discovery in more than 25 years.

There are two significant things about this feat. The first is that the new antibiotic, called teixobactin, not only has the ability to kill a wide range of infection-causing bacteria, but to kill them in a way that may greatly reduce the problem of resistance. The second is that researchers identified teixobactin using an ingenious approach that enhances our ability to search one of nature’s richest sources of potential antibiotics: soil [2, 3].


Alzheimer’s-in-a-Dish: New Tool for Drug Discovery

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Alzheimer's Disease in a dish

Caption: A plaque (orange) disrupts the normal network of human neurons (green) grown in a three-dimensional gel in the lab, mimicking the brain anatomy of Alzheimer’s patients.
Credit: Doo Yeon Kim and Rudolph E. Tanzi, Massachusetts General Hospital/ Harvard Medical School

Researchers want desperately to develop treatments to help the more than 5 million Americans with Alzheimer’s disease and the millions more at risk. But that’s proven to be extremely challenging for a variety of reasons, including the fact that it’s been extraordinarily difficult to mimic the brain’s complexity in standard laboratory models. So, that’s why I was particularly excited by the recent news that an NIH-supported team, led by Rudolph Tanzi at Boston’s Massachusetts General Hospital, has developed a new model called “Alzheimer’s in a dish.”

So, how did Tanzi’s group succeed where others have run up against a brick wall? The answer appears to lie in their decision to add a third dimension to their disease model.  Previous attempts at growing human brain cells in the lab and inducing them to form the plaques and tangles characteristic of Alzheimer’s disease were performed in a two-dimensional Petri dish system. And, in this flat, 2-D environment, plaques and tangles simply didn’t appear.


Cool Videos: Diving for Drugs

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Therapies From the Sea video sceenshot

Who says biomedical scientists always have to work indoors? The next installment in our mini-film fest proves otherwise, offering a close-up look at some medicinal chemists who are busy carrying out their research in warm waters off the Florida Keys.

This aquatic adventure may not be as action-packed as “Pirates of the Caribbean” or “Finding Nemo.” But these researchers from the University of Florida College of Pharmacy in Gainesville are out to discover something far more valuable to patients than sunken treasure: marine life with chemical compounds that may provide the basis for new treatments and cures.


Fishing for Answers in Human Disease

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Images of both a wild type zebrafish and a vhnf1 mutant zebrafish. The mutant fish shows abnormal bulging in its upper body.

Caption: Researcher Zhaoxia Sun, at Yale, uses the zebrafish to study Polycystic Kidney Disease, which affects more than 600,000 Americans. Mutations in the zebrafish vhnf1 gene, and its human counterpart, cause cysts in both zebrafish and human kidneys (as shown by the large “bubble” seen in the mutant fish). [3]
Credit: Zhoaxia Sun, Biological & Biomedical Sciences, Yale University

Wouldn’t it be instructive if we could see the effect of a genetic mutation in real time, as the gene was misbehaving? Well, that’s one of the perks of using the zebrafish—a tiny, striped, transparent fish.

Just last month, an international team of scientists—funded in part by NIH—published the entire genetic code of the zebrafish [1]. This is a vital resource for understanding human health and disease. How does the genetic blueprint of a fish help us or accelerate drug discovery? Well, it turns out that more than 75% of the genes that have been implicated in human diseases have counterparts in the zebrafish. So, if we discover a mutation in a human, we can make the corresponding mutation in the zebrafish gene—and often get a pretty good idea of how the gene works, how the mutation causes havoc, and how it causes disease in humans. We can even use the zebrafish to test potential drug candidates, to see whether they can alter or fix the symptoms before moving on to mice or humans.


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