Finding Offers Promise of New Treatments for Iron Deficiency
and Parasitic Worm Infections
Almost 50 years ago, scientists began thinking that our bodies must
have a special protein 'container' to safely transport heme -- the form
of iron found in living things -- during the breakdown and recycling of
old red blood cells and other types of heme metabolism. Now a team of
scientists from the University of Maryland, Harvard Medical School, the
National Institutes of Health and the University of Utah School of
Medicine have identified this long-sought heme-iron transporter and
shown that it is the same HRG1 protein that a common microscopic worm,
C. elegans, uses to transport heme. In humans, the iron in heme is the
component that allows hemoglobin in red blood cells to carry the oxygen
needed for life.
The team's findings are based on studies in human, mouse, zebrafish and
yeast systems and are published in the Feb. 5, issue of the journal
"Our current work reveals that the long-sought heme transporter that
permits humans to recycle over 5 million red blood cells per second in
our spleen and liver, is the same HRG1 transporter protein that my
students and I discovered in worms in 2008, and which we showed at that
time is used by C. elegans to safely carry heme-iron that it obtains
from dirt into its intestine," says team leader and corresponding
author Iqbal Hamza., a University of Maryland associate professor in
the Department of Animal & Avian Sciences. "Moreover, we show in this
current study that mutations in the gene for HRG1 can be a causative
agent for genetic disorders of iron metabolism in humans," he says.
[Microscopic image of a macrophage digesting worn-out red blood cells.
The blue is the nucleus of the macrophage. The red within the
macrophage is HRG 1 protein molecules (highlighted by HRG1 antibodies
containing red dye). The circle of red shows HRG1 proteins surrounding
a red cell and ready to take its iron-containing heme. ]
First author Carine White, a UMD post-doctoral researcher and three
other students from his lab joined Hamza in the research, along with
researchers from Harvard, NIH and Utah.
This study's findings are the third major piece that Hamza and his
Maryland lab have added to the puzzle of understanding how humans and
other organisms safely move heme around in the body. In addition to
their two studies showing the role of the HRG1, that Hamza showed in a
2011 Cell paper that in C. elegans there is a different, but related,
protein called HRG3 that transports heme from the mother worm's
intestine to her developing embryos. According to Hamza, the
HRG3-mediated pathway that worms use for transporting heme to
developing oocytes also appears to be an excellent target for stopping
the reproduction of hookworms and other parasites that feed on host red
blood cell hemoglobin. Together these three findings could lead to new
methods for treating two age-old scourges - parasitic worm infections,
which affect more than a quarter of the world's population, and
problems of iron metabolism and iron deficiency. The latter is the
world's number one nutritional disorder.
With the help of UMD's Office of Technology Commercialization and the
university's Maryland Technology Enterprise Institute, Hamza has
started a company, Rakta Therapeutics, Inc. that "based on
groundbreaking discoveries in heme biology seeks to develop novel
therapeutic approaches to target parasites that afflict humans,
livestock and plants, and design innovative treatment modalities to
treat human iron deficiency."
Heme, Humans and Bloodless worms In living organisms -- ranging from
humans to baker's yeast -- iron enclosed in a heme cage is a critical
molecule for health because it binds to oxygen and other gases needed
for survival. However, because heme is toxic, scientists long ago
started searching for the existence of proteins that could safely
transport heme between cells and throughout the body.
However, identifying such proteins has been a very difficult task
because organisms generate heme in a complicated eight-step process
that is hard to control for in studies of heme transport pathways.
Hamza first started trying to uncover the secrets of heme transport in
2003. After briefly and unsuccessfully studying the question of heme
carrying proteins in traditional bacteria and mice models, Hamza
switched to a non-intuitive study subject, one that doesn't make heme,
but needs it to survive, that doesn't even have blood, but shares a
number of genes with humans - the C. elegans roundworm. C. elegans gets
heme by eating bacteria in the soil where it lives. "C. elegans
consumes heme and transports it into the intestine.
C. elegans has had several other benefits for studying heme transport.
Hamza's team had control of the amount of heme the worms were eating.
With only one valve controlling the heme transport, the scientists knew
exactly where heme was entering the worm's intestine, where, as in
humans, it is absorbed. Moreover, C. elegans is transparent, so that
under the microscope researchers could see the movement of the heme
ingested by a live animal. "HRG1 Is Essential for Heme Transport from
the Phagolysosome of Macrophages during Erythrophagocytosis," Cell
Metabolism, Feb. 5, 2013.
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