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drug development

A Ray of Molecular Beauty from Cryo-EM

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Rhodopsin

Credit: Subramaniam Lab, National Cancer Institute, NIH

Walk into a dark room, and it takes a minute to make out the objects, from the wallet on the table to the sleeping dog on the floor. But after a few seconds, our eyes are able to adjust and see in the near-dark, thanks to a protein called rhodopsin found at the surface of certain specialized cells in the retina, the thin, vision-initiating tissue that lines the back of the eye.

This illustration shows light-activating rhodopsin (orange). The light photons cause the activated form of rhodopsin to bind to its protein partner, transducin, made up of three subunits (green, yellow, and purple). The binding amplifies the visual signal, which then streams onward through the optic nerve for further processing in the brain—and the ability to avoid tripping over the dog.


Tagging Essential Malaria Genes to Advance Drug Development

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Red blood cell infected with malaria-causing parasites

Caption: Colorized scanning electron micrograph of a blood cell infected with malaria parasites (blue with dots) surrounded by uninfected cells (red).
Credit: National Institute of Allergy and Infectious Diseases, NIH

As a volunteer physician in a small hospital in Nigeria 30 years ago, I was bitten by lots of mosquitoes and soon came down with headache, chills, fever, and muscle aches. It was malaria. Fortunately, the drug available to me then was effective, but I was pretty sick for a few days. Since that time, malarial drug resistance has become steadily more widespread. In fact, the treatment that cured me would be of little use today. Combination drug therapies including artemisinin have been introduced to take the place of the older drugs [1], but experts are concerned the mosquito-borne parasites that cause malaria are showing signs of drug resistance again.

So, researchers have been searching the genome of Plasmodium falciparum, the most-lethal species of the malaria parasite, for potentially better targets for drug or vaccine development. You wouldn’t think such work would be too tough because the genome of P. falciparum was sequenced more than 15 years ago [2]. Yet it’s proven to be a major challenge because the genetic blueprint of this protozoan parasite has an unusual bias towards two nucleotides (adenine and thymine), which makes it difficult to use standard research tools to study the functions of its genes.

Now, using a creative new spin on an old technique, an NIH-funded research team has solved this difficult problem and, for the first time, completely characterized the genes in the P. falciparum genome [3]. Their work identified 2,680 genes essential to P. falciparum’s growth and survival in red blood cells, where it does the most damage in humans. This gene list will serve as an important guide in the years ahead as researchers seek to identify the equivalent of a malarial Achilles heel, and use that to develop new and better ways to fight this deadly tropical disease.


Basic Research: Building a Firm Foundation for Biomedicine

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Benchtop Centrifuge

Credit: National Institute of Allergy and Infectious Diseases, NIH

A major part of NIH’s mission is to support basic research that generates fundamental knowledge about the nature and behavior of living systems. Such knowledge serves as the foundation for the biomedical advances needed to protect and improve our health—and the health of generations to come.

Of course, it’s often hard to predict how this kind of basic research might benefit human populations, and the lag time between discovery and medical application (if that happens at all) can be quite long. Some might argue, therefore, that basic research is not a good use of funds, and all of NIH’s support should go to specific disease targets.

To counter that perception, I’m pleased to share some new findings that underscore the importance of publicly supported basic research. In an analysis of more than 28 million papers in the PubMed.gov database, researchers found NIH contributed to published research that was associated with every single one of the 210 new drugs approved by the Food and Drug Administration from 2010 through 2016 [1]. More than 90 percent of that contributory research was basic—that is, related to the discovery of fundamental biological mechanisms, rather than actual development of the drugs themselves.


Another Milestone in the Cystic Fibrosis Journey

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Avalyn Mahoney

Caption: Two-year-old Avalyn is among the cystic fibrosis patients who may be helped by targeted drugs.
Credit: Brittany Mahoney

As NIH Director, I often hear stories of how people with serious diseases—from arthritis to Zika infection—are benefitting from the transformational power of NIH’s investments in basic science. Today, I’d like to share one such advance that I find particularly exciting: news that a combination of three molecularly targeted drugs may finally make it possible to treat the vast majority of patients with cystic fibrosis (CF), our nation’s most common genetic disease.

First, a bit of history! The first genetic mutation that causes CF was discovered by a collaborative effort between my own research lab at the University of Michigan, Ann Arbor, and colleagues at the Hospital for Sick Children in Toronto—more than 25 years ago [1]. Years of hard work, supported by the National Institutes of Health and the Cystic Fibrosis Foundation, painstakingly worked out the normal function of the protein that is altered in CF, called the cystic fibrosis transmembrane regulator (CFTR). Very recently new technologies, such as cryo-EM, have given researchers the ability to map the exact structure of the protein involved in CF.

Among the tens of thousands of CF patients who stand to benefit from the next generation of targeted drugs is little Avalyn Mahoney of Cardiff by the Sea, CA. Just a few decades ago, a kid like Avalyn—who just turned 2 last month—probably wouldn’t have made it beyond her teens. But today the outlook is far brighter for her and so many others, thanks to recent advances that build upon NIH-supported basic research.


Missing Genes Point to Possible Drug Targets

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Human knockout projectEvery person’s genetic blueprint, or genome, is unique because of variations that occasionally occur in our DNA sequences. Most of those are passed on to us from our parents. But not all variations are inherited—each of us carries 60 to 100 “new mutations” that happened for the first time in us. Some of those variations can knock out the function of a gene in ways that lead to disease or other serious health problems, particularly in people unlucky enough to have two malfunctioning copies of the same gene. Recently, scientists have begun to identify rare individuals who have loss-of-function variations that actually seem to improve their health—extraordinary discoveries that may help us understand how genes work as well as yield promising new drug targets that may benefit everyone.

In a study published in the journal Nature, a team partially funded by NIH sequenced all 18,000 protein-coding genes in more than 10,500 adults living in Pakistan [1]. After finding that more than 17 percent of the participants had at least one gene completely “knocked out,” researchers could set about analyzing what consequences—good, bad, or neutral—those loss-of-function variations had on their health and well-being.


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