In a lecture he delivered in 1906, the German physician Paul Ehrlich coined the term Zauberkugel, or "magic bullet," as shorthand for a highly targeted medical treatment.
Magic bullets, also called silver bullets, because of the folkloric belief that only silver bullets can kill supernatural creatures, remain the goal of drug development efforts today.
A team of scientists at Washington University in St. Louis is currently working on a magic bullet for cancer, a disease whose treatments are notoriously indiscriminate and nonspecific. But their bullets are gold rather than silver. Literally.
The gold bullets are gold nanocages that, when injected, selectively accumulate in tumors. When the tumors are later bathed in laser light, the surrounding tissue is barely warmed, but the nanocages convert light to heat, killing the malignant cells.
In an article just published in the journal Small, the team describes the successful photothermal treatment of tumors in mice.
The team includes Younan Xia, Ph.D., the James M. McKelvey Professor of Biomedical Engineering in the School of Engineering and Applied Science, Michael J. Welch, Ph.D., professor of radiology and developmental biology in the School of Medicine, Jingyi Chen, Ph.D., research assistant professor of biomedical engineering and Charles Glaus, Ph.D., a postdoctoral research associate in the Department of Radiology.
"We saw significant changes in tumor metabolism and histology," says Welch, "which is remarkable given that the work was exploratory, the laser 'dose' had not been maximized, and the tumors were 'passively' rather than 'actively' targeted."
Why the nanocages get hot
The nanocages themselves are harmless. "Gold salts and gold colloids have been used to treat arthritis for more than 100 years," says Welch. "People know what gold does in the body and it's inert, so we hope this is going to be a nontoxic approach."
"The key to photothermal therapy," says Xia, "is the cages' ability to efficiently absorb light and convert it to heat. "
Suspensions of the gold nanocages, which are roughly the same size as a virus particle, are not always yellow, as one would expect, but instead can be any color in the rainbow.
They are colored by something called a surface plasmon resonance. Some of the electrons in the gold are not anchored to individual atoms but instead form a free-floating electron gas, Xia explains. Light falling on these electrons can drive them to oscillate as one. This collective oscillation, the surface plasmon, picks a particular wavelength, or color, out of the incident light, and this determines the color we see.
Medieval artisans made ruby-red stained glass by mixing gold chloride into molten glass, a process that left tiny gold particles suspended in the glass, says Xia.
The resonance - and the color - can be tuned over a wide range of wavelengths by altering the thickness of the cages' walls. For biomedical applications, Xia's lab tunes the cages to 800 nanometers, a wavelength that falls in a window of tissue transparency that lies between 750 and 900 nanometers, in the near-infrared part of the spectrum.
Light in this sweet spot can penetrate as deep as several inches in the body (either from the skin or the interior of the gastrointestinal tract or other organ systems).
The conversion of light to heat arises from the same physical effect as the color. The resonance has two parts. At the resonant frequency, light is typically both scattered off the cages and absorbed by them.
By controlling the cages' size, Xia's lab tailors them to achieve maximum absorption.
Passive targeting
"If we put bare nanoparticles into your body," says Xia, "proteins would deposit on the particles, and they would be captured by the immune system and dragged out of the bloodstream into the liver or spleen."
To prevent this, the lab coated the nanocages with a layer of PEG, a nontoxic chemical most people have encountered in the form of the laxatives GoLyTELY or MiraLAX. PEG resists the adsorption of proteins, in effect disguising the nanoparticles so that the immune system cannot recognize them.
Instead of being swept from the bloodstream, the disguised particles circulate long enough to accumulate in tumors.
A growing tumor must develop its own blood supply to prevent its core from being starved of oxygen and nutrients. But tumor vessels are as aberrant as tumor cells. They have irregular diameters and abnormal branching patterns, but most importantly, they have thin, leaky walls.
The cells that line a tumor's blood vessel, normally packed so tightly they form a waterproof barrier, are disorganized and irregularly shaped, and there are gaps between them.
The nanocages infiltrate through those gaps efficiently enough that they turn the surface of the normally pinkish tumor black.
A trial run
In Welch's lab, mice bearing tumors on both flanks were randomly divided into two groups. The mice in one group were injected with the PEG-coated nanocages and those in the other with buffer solution. Several days later the right tumor of each animal was exposed to a diode laser for 10 minutes.
The team employed several different noninvasive imaging techniques to follow the effects of the therapy. (Welch is head of the oncologic imaging research program at the Siteman Cancer Center of Washington University School of Medicine and Barnes-Jewish Hospital and has worked on imaging agents and techniques for many years.)
During irradiation, thermal images of the mice were made with an infrared camera. As is true of cells in other animals that automatically regulate their body temperature, mouse cells function optimally only if the mouse's body temperature remains between 36.5 and 37.5 degrees Celsius (98 to 101 degrees Fahrenheit).
At temperatures above 42 degrees Celsius (107 degrees Fahrenheit) the cells begin to die as the proteins whose proper functioning maintains them begin to unfold.
In the nanocage-injected mice, the skin surface temperature increased rapidly from 32 degrees Celsius to 54 degrees C (129 degrees F).
In the buffer-injected mice, however, the surface temperature remained below 37 degrees Celsius (98.6 degrees Fahrenheit).
To see what effect this heating had on the tumors, the mice were injected with a radioactive tracer incorporated in a molecule similar to glucose, the main energy source in the body. Positron emission and computerized tomography (PET and CT) scans were used to record the concentration of the glucose lookalike in body tissues; the higher the glucose uptake, the greater the metabolic activity.
The tumors of nanocage-injected mice were significantly fainter on the PET scans than those of buffer-injected mice, indicating that many tumor cells were no longer functioning.
The tumors in the nanocage-treated mice were later found to have marked histological signs of cellular damage.
Active targeting
The scientists have just received a five-year, $2,129,873 grant from the National Cancer Institute to continue their work with photothermal therapy.
Despite their results, Xia is dissatisfied with passive targeting. Although the tumors took up enough gold nanocages to give them a black cast, only 6 percent of the injected particles accumulated at the tumor site.
Xia would like that number to be closer to 40 percent so that fewer particles would have to be injected. He plans to attach tailor-made ligands to the nanocages that recognize and lock onto receptors on the surface of the tumor cells.
In addition to designing nanocages that actively target the tumor cells, the team is considering loading the hollow particles with a cancer-fighting drug, so that the tumor would be attacked on two fronts.
But the important achievement, from the point of view of cancer patients, is that any nanocage treatment would be narrowly targeted and thus avoid the side effects patients dread.
The TV and radio character the Lone Ranger used only silver bullets, allegedly to remind himself that life was precious and not to be lightly thrown away. If he still rode today, he might consider swapping silver for gold.
Source:
Diana Lutz
Washington University in St. Louis
понедельник, 6 июня 2011 г.
Having An Older Brother Raises A Male's Chances Of Being Gay
A male is more likely to be gay if he has an older brother, the likelihood grows the more older brothers he has. The percentage of gay males is estimated to be around 3%, this probability can go up to 5% for males with several older brothers, say researchers from Brock University, St. Catharines, Canada.
The researchers are certain there is a biological basis for sexual orientation - in other words, there is a prenatal effect. It is not a case of older brothers having a psychological effect on the male baby after it is born. Males with older stepbrothers, or adopted brothers, are not more likely to be gay, only males with blood brothers. The scientists say the effect has to be through the mother, the only link between them.
You can read about this study in the Proceedings of the National Academy of Sciences.
Previous studies have shown a link between male homosexuality and the number of older brothers. This study is the first one to factor out social and environmental effects.
Study leader, Anthony Bogaert, and team examined four groups of men - 944 males. They looked at how many male and female siblings they had, whether they were blood related and lived in the same house when they grew up. The also looked at whether the men had been adopted.
They found that males with one older blood brother were more likely to be gay than males with no older brother(s). The more older brothers a male had the higher his chances of being gay. They said the likelihood had the same increase when blood brothers were raised in different households.
The team stressed that even with several older brothers, the chances of a male being heterosexual is 95%. 97% of all males are heterosexual.
Only males who had an older brother from the same mother had a higher chance of being gay, said the researchers.
The researchers said the environment the male was brought up in makes no difference at all. The only link is that the older brother(s) shared the same womb.
Proceedings of the National Academy of Sciences
pnas
The Social Sciences and Humanities Research Council of Canada funded the research
sshrc.ca/web/home_e.asp
Written by:
The researchers are certain there is a biological basis for sexual orientation - in other words, there is a prenatal effect. It is not a case of older brothers having a psychological effect on the male baby after it is born. Males with older stepbrothers, or adopted brothers, are not more likely to be gay, only males with blood brothers. The scientists say the effect has to be through the mother, the only link between them.
You can read about this study in the Proceedings of the National Academy of Sciences.
Previous studies have shown a link between male homosexuality and the number of older brothers. This study is the first one to factor out social and environmental effects.
Study leader, Anthony Bogaert, and team examined four groups of men - 944 males. They looked at how many male and female siblings they had, whether they were blood related and lived in the same house when they grew up. The also looked at whether the men had been adopted.
They found that males with one older blood brother were more likely to be gay than males with no older brother(s). The more older brothers a male had the higher his chances of being gay. They said the likelihood had the same increase when blood brothers were raised in different households.
The team stressed that even with several older brothers, the chances of a male being heterosexual is 95%. 97% of all males are heterosexual.
Only males who had an older brother from the same mother had a higher chance of being gay, said the researchers.
The researchers said the environment the male was brought up in makes no difference at all. The only link is that the older brother(s) shared the same womb.
Proceedings of the National Academy of Sciences
pnas
The Social Sciences and Humanities Research Council of Canada funded the research
sshrc.ca/web/home_e.asp
Written by:
New Biological Models Of Homeopathy Published In Special Issues
The journal Homeopathy has published a two part special issue focusing on biological models of homeopathy. The special issue highlights experiments on homeopathic treatments in biological models, ranging from whole animals and plants to cell cultures and enzymes, showing a remarkable range of findings.
Homeopathy is a form of complementary medicine which is controversial because of its use of extremely dilute medicines. Although there is considerable clinical research, homeopathy remains the subject of a heated debate. The special issue makes an important contribution to this debate, by reviewing laboratory experiments with high dilutions. It includes reviews and new findings in biosystems, ranging from whole animal behavioral, intoxication and inflammation models through diseased and healthy plant models, to test tube experiments using isolated cells, cell cultures or enzymes.
Featured articles include one on the basophil degranulation test, a test tube model of allergy, developed by Jean Sainte Laudy. These results have now been confirmed in multi-centre and independent experiments. Other articles include systematic reviews of healthy and diseased plant models and experimental work on the effect of homeopathic arsenic on wheat seedlings. There are reviews of mouse and rat models of homeopathic responses and a review, including original results of animal models of homeopathic treatment of anxiety-like behaviours.
Other articles focus on the basic concept of homeopathy 'like cures like': in a series of cell-culture experiments Fred Wiegant's team at the University of Utrecht demonstrated the importance of similarity. Christian Endler and his multinational team conclude that seven different biological models of high dilution response with positive results have been reproduced in multi-centre and/or independent experiments.
Editor-in-Chief Dr Peter Fisher commented: 'Throughout its 200 year history claims that homeopathy has 'real' (as opposed to placebo) effects have been hotly contested. Our special issue brings together a wide range of scientific work in biological systems, where there can be no placebo effect, showing that there are now several biological experiments which yield consistently positive results with homeopathic dilutions'.
Source: Fiona Macnab
Elsevier
Homeopathy is a form of complementary medicine which is controversial because of its use of extremely dilute medicines. Although there is considerable clinical research, homeopathy remains the subject of a heated debate. The special issue makes an important contribution to this debate, by reviewing laboratory experiments with high dilutions. It includes reviews and new findings in biosystems, ranging from whole animal behavioral, intoxication and inflammation models through diseased and healthy plant models, to test tube experiments using isolated cells, cell cultures or enzymes.
Featured articles include one on the basophil degranulation test, a test tube model of allergy, developed by Jean Sainte Laudy. These results have now been confirmed in multi-centre and independent experiments. Other articles include systematic reviews of healthy and diseased plant models and experimental work on the effect of homeopathic arsenic on wheat seedlings. There are reviews of mouse and rat models of homeopathic responses and a review, including original results of animal models of homeopathic treatment of anxiety-like behaviours.
Other articles focus on the basic concept of homeopathy 'like cures like': in a series of cell-culture experiments Fred Wiegant's team at the University of Utrecht demonstrated the importance of similarity. Christian Endler and his multinational team conclude that seven different biological models of high dilution response with positive results have been reproduced in multi-centre and/or independent experiments.
Editor-in-Chief Dr Peter Fisher commented: 'Throughout its 200 year history claims that homeopathy has 'real' (as opposed to placebo) effects have been hotly contested. Our special issue brings together a wide range of scientific work in biological systems, where there can be no placebo effect, showing that there are now several biological experiments which yield consistently positive results with homeopathic dilutions'.
Source: Fiona Macnab
Elsevier
Advanced BioHealing Enrolls First Patient In Celaderm(TM) Pilot Venous Leg Ulcer Clinical Trial
Advanced BioHealing, Inc. (ABH)
announced today that it has enrolled the first patient in its initial
Celaderm(TM) pilot study. The study, whose primary purpose is to evaluate
the safety of Celaderm in humans, will also assess the potential for
Celaderm to accelerate healing of venous leg ulcers compared with optimal
standard therapy. The study is designed to enroll 55 patients who will be
evaluated throughout a 12-week healing period and then be observed for an
additional three months to assess the safety of the product. Separately,
ABH announced that it has requested permission from the U.S. Food and Drug
Administration (FDA) to add two more clinical sites to facilitate
enrollment, bringing the number of clinical sites to eight.
"We are very pleased to officially begin evaluating the safety of
Celaderm, our next-generation bioengineered tissue product, in humans,"
said David Eisenbud, M.D., Executive Vice President and Chief Medical
Officers of Advanced BioHealing. "This marks the first clinical trial with
our own internally-developed product, allowing us to expand on our existing
product portfolio that currently includes two FDA approved wound healing
products. Celaderm utilizes a proprietary cryopreservation technology which
we believe will provide doctors and patients with advancement over earlier
bioengineered products."
"When first-generation bioengineered tissue products were introduced,
physicians who treat wounds were provided a tremendous option that changed
our approach to wound care," said William Marston, MD, Associate Professor
of Surgery, Division of Vascular Surgery at the University of North
Carolina at Chapel Hill. "As an investigator in the Celaderm study, I am
thrilled to test this next-generation product that could significantly
expand the market for advanced wound therapy by being both highly effective
and immediately available at the point-of-care."
Success in this clinical study would allow Celaderm, which is regulated
as a medical device, to move directly into a pivotal trial of clinical
efficacy and this would culminate in a subsequent PreMarket Approval (PMA)
submission. If approved for sale, Celaderm would complement ABH's current
portfolio of approved products: Dermagraft(R) (Dermagraft,) which
is approved for diabetic foot ulcers and TransCyte(R) for the treatment of
full and partial- thickness burns.
About Advanced BioHealing, Inc.
Advanced BioHealing is a leader in regenerative medicine. The company
is focused on the development and marketing of cell-based and
tissue-engineered products. Privately held, ABH has two approved products:
Dermagraft and TransCyte. The company's development pipeline also includes
a next-generation bioengineered wound therapy for which two Investigational
Device Exemption (IDE) exemptions have been approved by the FDA. The
company's manufacturing and corporate offices are located in La Jolla, CA
with research and development offices in New York, NY.
For more information visit AdvancedBioHealing.
Advanced BioHealing, Inc.
AdvancedBioHealing
announced today that it has enrolled the first patient in its initial
Celaderm(TM) pilot study. The study, whose primary purpose is to evaluate
the safety of Celaderm in humans, will also assess the potential for
Celaderm to accelerate healing of venous leg ulcers compared with optimal
standard therapy. The study is designed to enroll 55 patients who will be
evaluated throughout a 12-week healing period and then be observed for an
additional three months to assess the safety of the product. Separately,
ABH announced that it has requested permission from the U.S. Food and Drug
Administration (FDA) to add two more clinical sites to facilitate
enrollment, bringing the number of clinical sites to eight.
"We are very pleased to officially begin evaluating the safety of
Celaderm, our next-generation bioengineered tissue product, in humans,"
said David Eisenbud, M.D., Executive Vice President and Chief Medical
Officers of Advanced BioHealing. "This marks the first clinical trial with
our own internally-developed product, allowing us to expand on our existing
product portfolio that currently includes two FDA approved wound healing
products. Celaderm utilizes a proprietary cryopreservation technology which
we believe will provide doctors and patients with advancement over earlier
bioengineered products."
"When first-generation bioengineered tissue products were introduced,
physicians who treat wounds were provided a tremendous option that changed
our approach to wound care," said William Marston, MD, Associate Professor
of Surgery, Division of Vascular Surgery at the University of North
Carolina at Chapel Hill. "As an investigator in the Celaderm study, I am
thrilled to test this next-generation product that could significantly
expand the market for advanced wound therapy by being both highly effective
and immediately available at the point-of-care."
Success in this clinical study would allow Celaderm, which is regulated
as a medical device, to move directly into a pivotal trial of clinical
efficacy and this would culminate in a subsequent PreMarket Approval (PMA)
submission. If approved for sale, Celaderm would complement ABH's current
portfolio of approved products: Dermagraft(R) (Dermagraft,) which
is approved for diabetic foot ulcers and TransCyte(R) for the treatment of
full and partial- thickness burns.
About Advanced BioHealing, Inc.
Advanced BioHealing is a leader in regenerative medicine. The company
is focused on the development and marketing of cell-based and
tissue-engineered products. Privately held, ABH has two approved products:
Dermagraft and TransCyte. The company's development pipeline also includes
a next-generation bioengineered wound therapy for which two Investigational
Device Exemption (IDE) exemptions have been approved by the FDA. The
company's manufacturing and corporate offices are located in La Jolla, CA
with research and development offices in New York, NY.
For more information visit AdvancedBioHealing.
Advanced BioHealing, Inc.
AdvancedBioHealing
A Novel Approach For Treating Cognitive Impairments Identified By Animal Model For Schizophrenia
Researchers have been seeking a safe and effective way to treat cognitive impairments associated with schizophrenia by enhancing N-methyl-D-aspartate (NMDA) glutamate receptors. Functional deficits in NMDA receptors may contribute to the underlying neurobiology of this disorder. The first generation of studies trying to stimulate NMDA receptors administered large amounts of substances, like glycine or D-serine, which indirectly enhance NMDA receptor function. While there were some positive reports of efficacy, findings across studies were more inconsistent than was hoped.
New approaches following this line of research are just beginning to be tested in patients. For example, several pharmaceutical companies are studying drugs that block the glycine transporter (GlyT1) and thereby raise synaptic glycine levels. A new study in Biological Psychiatry, published by Elsevier, by Dr. Kenji Hashimoto and colleagues may represent a "next step," which is to prevent the inactivation of D-serine by the enzyme D-amino acid oxidase (DAAO). The authors found that this approach enhances the efficacy of D-serine in an animal model for deficits in NMDA glutamate receptor function.
To put it more simply, although D-serine is used as a treatment for schizophrenia, it is metabolized by DAAO, reducing its availability in the brain. So, using an animal model of schizophrenia, these scientists co-administered D-serine and a compound that blocks the effects of DAAO. This increased the levels of D-serine in the mice and therefore its effectiveness in treating the abnormal behaviors in this animal model that may be relevant to schizophrenia.
"We still do not have effective treatments that specifically target the cognitive and functional impairments associated with schizophrenia. These findings are very interesting because there is a continued sense that we have not yet captured the therapeutic promise associated with the glycine site of the NMDA receptor. GlyT1 blockers and DAAO inhibitors may be important new clinical research tools," comments John Krystal, M.D., Editor of Biological Psychiatry.
Further research is still needed to see whether these findings can be extended to humans, but it is hoped that this combination therapy proves to be a novel and effective treatment of schizophrenia.
Notes:
The article is "Co-Administration of a D-Amino Acid Oxidase Inhibitor Potentiates the Efficacy of D-Serine in Attenuating Prepulse Inhibition Deficits After Administration of Dizocilpine" by Kenji Hashimoto, Yuko Fujita, Mao Horio, Shinsui Kunitachi, Masaomi Iyo, Dana Ferraris, and Takashi Tsukamoto. Authors Hashimoto, Fujita, Horio, and Kunitachi are affiliated with the Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. Iyo is from the Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan. Ferraris and Tsukamoto are with the Eisai Research Institute, Baltimore, Maryland. The article appears in Biological Psychiatry, Volume 65, Issue 12 (June 15, 2009), published by Elsevier. The authors' disclosures of financial and conflicts of interests are available in the article. John H. Krystal, M.D. is affiliated with both Yale University School of Medicine and the VA Connecticut Healthcare System and his disclosures of financial and conflicts of interests are available at journals.elsevierhealth/webfiles/images/journals/bps/Biological_Psychiatry_Editorial_Disclosures_08_01_08.pdf.
Source:
Jayne Dawkins
Elsevier
New approaches following this line of research are just beginning to be tested in patients. For example, several pharmaceutical companies are studying drugs that block the glycine transporter (GlyT1) and thereby raise synaptic glycine levels. A new study in Biological Psychiatry, published by Elsevier, by Dr. Kenji Hashimoto and colleagues may represent a "next step," which is to prevent the inactivation of D-serine by the enzyme D-amino acid oxidase (DAAO). The authors found that this approach enhances the efficacy of D-serine in an animal model for deficits in NMDA glutamate receptor function.
To put it more simply, although D-serine is used as a treatment for schizophrenia, it is metabolized by DAAO, reducing its availability in the brain. So, using an animal model of schizophrenia, these scientists co-administered D-serine and a compound that blocks the effects of DAAO. This increased the levels of D-serine in the mice and therefore its effectiveness in treating the abnormal behaviors in this animal model that may be relevant to schizophrenia.
"We still do not have effective treatments that specifically target the cognitive and functional impairments associated with schizophrenia. These findings are very interesting because there is a continued sense that we have not yet captured the therapeutic promise associated with the glycine site of the NMDA receptor. GlyT1 blockers and DAAO inhibitors may be important new clinical research tools," comments John Krystal, M.D., Editor of Biological Psychiatry.
Further research is still needed to see whether these findings can be extended to humans, but it is hoped that this combination therapy proves to be a novel and effective treatment of schizophrenia.
Notes:
The article is "Co-Administration of a D-Amino Acid Oxidase Inhibitor Potentiates the Efficacy of D-Serine in Attenuating Prepulse Inhibition Deficits After Administration of Dizocilpine" by Kenji Hashimoto, Yuko Fujita, Mao Horio, Shinsui Kunitachi, Masaomi Iyo, Dana Ferraris, and Takashi Tsukamoto. Authors Hashimoto, Fujita, Horio, and Kunitachi are affiliated with the Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. Iyo is from the Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan. Ferraris and Tsukamoto are with the Eisai Research Institute, Baltimore, Maryland. The article appears in Biological Psychiatry, Volume 65, Issue 12 (June 15, 2009), published by Elsevier. The authors' disclosures of financial and conflicts of interests are available in the article. John H. Krystal, M.D. is affiliated with both Yale University School of Medicine and the VA Connecticut Healthcare System and his disclosures of financial and conflicts of interests are available at journals.elsevierhealth/webfiles/images/journals/bps/Biological_Psychiatry_Editorial_Disclosures_08_01_08.pdf.
Source:
Jayne Dawkins
Elsevier
Artificial Enzyme Removes Natural Poison
For the first time ever, a completely man-made chemical enzyme has been successfully used to neutralise a toxin found naturally in fruits and vegetables.
Proof of concept for artificial enzymes
Chemzymes are designed molecules emulating the targeting and efficiency of naturally occurring enzymes and the recently graduated Dr. Bjerre is pleased about her results.
"Showing that these molecules are capable of decomposing toxins required vast amounts of work and time. But it's been worth every minute because it proves the general point that it's possible to design artificial enzymes for this class of task", explains Bjerre.
Simple molecules performing complex tasks
Most people know enzymes as an ingredient in detergents. In our bodies enzymes are in charge of decomposing everything we eat, so that our bodies can absorb the nutrients. But they also decompose ingested toxins, ensuring that our bodies survive the encounter.
In several important aspects artificial enzymes function in the same way as naturally occurring ones. But where natural enzymes are big and complex, the artificial ones have been pared down to the basics.
The flat-nosed plier of the molecular world
One consequence of this simplicity is that designing chemzymes for targeted tasks ought to be easier. With fewer parts, there's less to go wrong when changing the structure of chemzymes. And for enzymes as well as for their artificial counterparts even small changes in structure will have massive consequences for functionality.
In this, enzymes are very much like hand-tools, where scissors and flat nosed pliers, though almost identical, have very different duties.
Hardwearing replacement enzymes
Even though naturally occurring enzymes are several orders of magnitude smaller than flat-nosed pliers, they are still unrivalled tools. Some of the fastest chemical reactions blast off when enzymes are added to the broth.
Several known enzymes in the body catalyze more than one million reactions per second when they decompose compounds. There's just one drawback to enzymes. They are extremely fragile.
If an enzyme in our body was to be warmed above sixtyfive degrees centigrade or subjected to organic solvents, they would immediately denature. They would unravel and stop functioning.
Taking the heat
So far no one has succeeded in designing chemzymes that are anywhere near as fast as their naturally occurring cousins. But they are far more resilient.
Manmade enzymes take on heat and solvents without batting a molecular eyelid. One of the consequences of this is that chemzymes can be mass-produced using industrial chemical processes. This is a huge advantage when you need a lot of product in a hurry.
Factory-made enzymes
Producing natural enzymes in industrial settings is considerably more time-consuming because they have to be grown. Rather like one grows apples or grain.
So the robust and designable compounds may turn out to be just what's needed for a wide variety of jobs. Not least in the pharmaceutical industries, where the need is massive for chemical compounds which can solve problems that no amount of designing could ever tweak the natural ones to work on, which are unaffected by industrial processes, and to top it of, cheap to produce.
Source:
Jes Andersen
University of Copenhagen
Proof of concept for artificial enzymes
Chemzymes are designed molecules emulating the targeting and efficiency of naturally occurring enzymes and the recently graduated Dr. Bjerre is pleased about her results.
"Showing that these molecules are capable of decomposing toxins required vast amounts of work and time. But it's been worth every minute because it proves the general point that it's possible to design artificial enzymes for this class of task", explains Bjerre.
Simple molecules performing complex tasks
Most people know enzymes as an ingredient in detergents. In our bodies enzymes are in charge of decomposing everything we eat, so that our bodies can absorb the nutrients. But they also decompose ingested toxins, ensuring that our bodies survive the encounter.
In several important aspects artificial enzymes function in the same way as naturally occurring ones. But where natural enzymes are big and complex, the artificial ones have been pared down to the basics.
The flat-nosed plier of the molecular world
One consequence of this simplicity is that designing chemzymes for targeted tasks ought to be easier. With fewer parts, there's less to go wrong when changing the structure of chemzymes. And for enzymes as well as for their artificial counterparts even small changes in structure will have massive consequences for functionality.
In this, enzymes are very much like hand-tools, where scissors and flat nosed pliers, though almost identical, have very different duties.
Hardwearing replacement enzymes
Even though naturally occurring enzymes are several orders of magnitude smaller than flat-nosed pliers, they are still unrivalled tools. Some of the fastest chemical reactions blast off when enzymes are added to the broth.
Several known enzymes in the body catalyze more than one million reactions per second when they decompose compounds. There's just one drawback to enzymes. They are extremely fragile.
If an enzyme in our body was to be warmed above sixtyfive degrees centigrade or subjected to organic solvents, they would immediately denature. They would unravel and stop functioning.
Taking the heat
So far no one has succeeded in designing chemzymes that are anywhere near as fast as their naturally occurring cousins. But they are far more resilient.
Manmade enzymes take on heat and solvents without batting a molecular eyelid. One of the consequences of this is that chemzymes can be mass-produced using industrial chemical processes. This is a huge advantage when you need a lot of product in a hurry.
Factory-made enzymes
Producing natural enzymes in industrial settings is considerably more time-consuming because they have to be grown. Rather like one grows apples or grain.
So the robust and designable compounds may turn out to be just what's needed for a wide variety of jobs. Not least in the pharmaceutical industries, where the need is massive for chemical compounds which can solve problems that no amount of designing could ever tweak the natural ones to work on, which are unaffected by industrial processes, and to top it of, cheap to produce.
Source:
Jes Andersen
University of Copenhagen
Key Fat And Cholesterol Cell Regulator Identified, Promising Target
Researchers at Harvard Medical School and Massachusetts General Hospital have identified how a molecular switch regulates fat and cholesterol production, a step that may help advance treatments for metabolic syndrome, the constellation of diseases that includes high cholesterol, obesity, type II diabetes, and high blood pressure. The study is now published in the online version of the scientific journal Nature and will appear in the August 10th print edition.
"We have identified a key protein that acts together with a family of molecular switches to turn on cholesterol and fat (or lipid) production," says principal investigator Anders Naar, PhD, assistant professor of cell biology at Harvard Medical School and the Massachusetts General Hospital Cancer Center. "The identification of this protein interaction and the nature of the molecular interface may one day allow us to pursue a more comprehensive approach to the treatment of metabolic syndrome."
High levels of cholesterol and lipids are linked to a number of interrelated medical conditions and diseases, including obesity, type II diabetes, fatty liver, and high blood pressure. This set of conditions and diseases, known as metabolic syndrome, are afflicting a rapidly increasing portion of society and serve as a major risk factor for heart disease, the leading cause of death in the developed world.
Treatments for diseases associated with metabolic syndrome have focused primarily on individual elements, such as high LDL-cholesterol (targeted by the cholesterol-lowering statin drugs). However, more effective ways to treat all of the components of metabolic syndrome are needed. One attractive approach might be to target the genetic switches that promote cholesterol and lipid synthesis, but it would require a detailed understanding of the regulatory mechanisms before drug targets can be identified.
After eating a meal, a family of proteins act as switches to turn on cholesterol and fat (or lipid) production. This family of proteins is known as SREBPs, or sterol regulatory element binding proteins. Between meals, the production of cholesterol and lipids should be turned off, however, excess intake of foods, coupled with lack of exercise, appear to disturb the normal checks and balances that control SREBPs, resulting in overproduction of cholesterol and lipids.
In the Nature paper, the HMS and MGH Cancer Center team has shown that a protein called ARC105, which binds to SREBPs, is essential in controlling the activity of the SREBP family of proteins. "ARC105 represents a lynchpin for SREBPs control of cholesterol and lipid biosynthesis genes, which may provide a potential molecular Achilles heel that could be targeted by drugs" says Dr. Nддr.
The researchers initially found that after removing ARC105 from human cells by a process called RNAi, SREBPs were no longer able to activate cholesterol and lipid biosynthesis genes. To validate these findings in a physiological setting, the researchers turned to the microscopic worm C. elegans, a favorite model organism among those studying evolutionarily conserved biological processes because of its rapid generation time and relative simplicity of genetics, and which had previously been used to study mechanisms of fat regulation.
Through a collaborative effort with the worm genetics group of Anne Hart, PhD, HMS associate professor of pathology at the MGH Cancer Center, the team demonstrated that the C. elegans homologues of SREBP and ARC105, known as SBP-1 and MDT-15, respectively, are necessary for production and storage of fat. The worms had regular fat production when SBP-1 and MDT-15 functioned normally, but when researchers used RNAi to knock out function of either SBP-1 or MDT-15, the worms lost their ability to properly store fat, lay eggs, and move normally.
"The striking effects of the RNAi knock downs in C. elegans suggest that the ARC105/SREBP pathway may play a key role in lipid production in humans," said Laurie Tompkins, PhD, of the National Institute of General Medical Sciences, which partially supported the research. "This work highlights the value of model organisms in helping us understand cellular processes that impact human health."
The research team also showed that removal of ARC105 in human cells by RNAi also negatively affects the same key SREBP target gene as identified in C. elegans. This suggests that the molecular switch is evolutionarily conserved (and therefore likely physiologically important).
Exhaustive biochemical detective work performed by the Nддr group together with the group of Gerhard Wagner, PhD, HMS professor in the Department of Biological Chemistry and Molecular Pharmacology, identified exactly how SREBP and ARC105 interact. They found a flexible tail on the SREBP molecule that fits into a specific groove on a region of ARC105 called KIX.
The researchers analyzed the amino acid sequence of the ARC105 protein, testing many different sections using NMR spectroscopy to eventually find the KIX area--just one tenth the area of the larger ARC105 protein--that specifically binds to SREBP. This specific interaction between SREBP and ARC105 might be a target for small molecule drugs, according to Dr. Wagner.
"While RNAi completely knocks out a protein including its other functions, perhaps not related to fat metabolism, a small molecule is a more subtle tool that could eliminate one protein-to-protein interaction," says Dr. Wagner. Finding a molecule that attaches to and inhibits the flexible tail of SREBP is unlikely, but a search for inhibitors to fit the grooved KIX site looks much more promising.
The team is already initiating high-throughput screening at Harvard Medical School's Institute of Chemistry and Cell Biology to identify small molecule inhibitors of the KIX site.
"Of course there are numerous hurdles that would need to be overcome before finding specific and effective treatments based on these findings," says Dr. Naar. If small molecules that specifically interfere with the interaction of SREBPs and ARC105 could be identified, careful studies in human cells and in mice would be needed to verify the specificity and efficacy in repressing cholesterol and fat production. "Unforeseen side effects of such small molecules in mouse studies or in human clinical trials could also emerge, prohibiting further follow-up", cautions Dr. Naar.
The National Institutes of Health, the Damon Runyon Cancer Research Foundation, and the Milton Foundation of Harvard University supported the study.
HARVARD MEDICAL SCHOOL
hms.harvard/
Harvard Medical School has more than 7,000 full-time faculty working in 10 academic departments housed on the School's Boston quadrangle or in one of 48 academic departments at 18 Harvard teaching hospitals and research institutes. Those Harvard hospitals and research institutions include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, The CBR Institute for Biomedical Research, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and the VA Boston Healthcare System.
MASSACHUSETTS GENERAL HOSPITAL
mgh.harvard/
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of nearly $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, transplantation biology and photomedicine. MGH and Brigham and Women's Hospital are founding members of Partners HealthCare HealthCare System, a Boston-based integrated health care delivery system.
Contact: John Lacey
Harvard Medical School
"We have identified a key protein that acts together with a family of molecular switches to turn on cholesterol and fat (or lipid) production," says principal investigator Anders Naar, PhD, assistant professor of cell biology at Harvard Medical School and the Massachusetts General Hospital Cancer Center. "The identification of this protein interaction and the nature of the molecular interface may one day allow us to pursue a more comprehensive approach to the treatment of metabolic syndrome."
High levels of cholesterol and lipids are linked to a number of interrelated medical conditions and diseases, including obesity, type II diabetes, fatty liver, and high blood pressure. This set of conditions and diseases, known as metabolic syndrome, are afflicting a rapidly increasing portion of society and serve as a major risk factor for heart disease, the leading cause of death in the developed world.
Treatments for diseases associated with metabolic syndrome have focused primarily on individual elements, such as high LDL-cholesterol (targeted by the cholesterol-lowering statin drugs). However, more effective ways to treat all of the components of metabolic syndrome are needed. One attractive approach might be to target the genetic switches that promote cholesterol and lipid synthesis, but it would require a detailed understanding of the regulatory mechanisms before drug targets can be identified.
After eating a meal, a family of proteins act as switches to turn on cholesterol and fat (or lipid) production. This family of proteins is known as SREBPs, or sterol regulatory element binding proteins. Between meals, the production of cholesterol and lipids should be turned off, however, excess intake of foods, coupled with lack of exercise, appear to disturb the normal checks and balances that control SREBPs, resulting in overproduction of cholesterol and lipids.
In the Nature paper, the HMS and MGH Cancer Center team has shown that a protein called ARC105, which binds to SREBPs, is essential in controlling the activity of the SREBP family of proteins. "ARC105 represents a lynchpin for SREBPs control of cholesterol and lipid biosynthesis genes, which may provide a potential molecular Achilles heel that could be targeted by drugs" says Dr. Nддr.
The researchers initially found that after removing ARC105 from human cells by a process called RNAi, SREBPs were no longer able to activate cholesterol and lipid biosynthesis genes. To validate these findings in a physiological setting, the researchers turned to the microscopic worm C. elegans, a favorite model organism among those studying evolutionarily conserved biological processes because of its rapid generation time and relative simplicity of genetics, and which had previously been used to study mechanisms of fat regulation.
Through a collaborative effort with the worm genetics group of Anne Hart, PhD, HMS associate professor of pathology at the MGH Cancer Center, the team demonstrated that the C. elegans homologues of SREBP and ARC105, known as SBP-1 and MDT-15, respectively, are necessary for production and storage of fat. The worms had regular fat production when SBP-1 and MDT-15 functioned normally, but when researchers used RNAi to knock out function of either SBP-1 or MDT-15, the worms lost their ability to properly store fat, lay eggs, and move normally.
"The striking effects of the RNAi knock downs in C. elegans suggest that the ARC105/SREBP pathway may play a key role in lipid production in humans," said Laurie Tompkins, PhD, of the National Institute of General Medical Sciences, which partially supported the research. "This work highlights the value of model organisms in helping us understand cellular processes that impact human health."
The research team also showed that removal of ARC105 in human cells by RNAi also negatively affects the same key SREBP target gene as identified in C. elegans. This suggests that the molecular switch is evolutionarily conserved (and therefore likely physiologically important).
Exhaustive biochemical detective work performed by the Nддr group together with the group of Gerhard Wagner, PhD, HMS professor in the Department of Biological Chemistry and Molecular Pharmacology, identified exactly how SREBP and ARC105 interact. They found a flexible tail on the SREBP molecule that fits into a specific groove on a region of ARC105 called KIX.
The researchers analyzed the amino acid sequence of the ARC105 protein, testing many different sections using NMR spectroscopy to eventually find the KIX area--just one tenth the area of the larger ARC105 protein--that specifically binds to SREBP. This specific interaction between SREBP and ARC105 might be a target for small molecule drugs, according to Dr. Wagner.
"While RNAi completely knocks out a protein including its other functions, perhaps not related to fat metabolism, a small molecule is a more subtle tool that could eliminate one protein-to-protein interaction," says Dr. Wagner. Finding a molecule that attaches to and inhibits the flexible tail of SREBP is unlikely, but a search for inhibitors to fit the grooved KIX site looks much more promising.
The team is already initiating high-throughput screening at Harvard Medical School's Institute of Chemistry and Cell Biology to identify small molecule inhibitors of the KIX site.
"Of course there are numerous hurdles that would need to be overcome before finding specific and effective treatments based on these findings," says Dr. Naar. If small molecules that specifically interfere with the interaction of SREBPs and ARC105 could be identified, careful studies in human cells and in mice would be needed to verify the specificity and efficacy in repressing cholesterol and fat production. "Unforeseen side effects of such small molecules in mouse studies or in human clinical trials could also emerge, prohibiting further follow-up", cautions Dr. Naar.
The National Institutes of Health, the Damon Runyon Cancer Research Foundation, and the Milton Foundation of Harvard University supported the study.
HARVARD MEDICAL SCHOOL
hms.harvard/
Harvard Medical School has more than 7,000 full-time faculty working in 10 academic departments housed on the School's Boston quadrangle or in one of 48 academic departments at 18 Harvard teaching hospitals and research institutes. Those Harvard hospitals and research institutions include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, The CBR Institute for Biomedical Research, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and the VA Boston Healthcare System.
MASSACHUSETTS GENERAL HOSPITAL
mgh.harvard/
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of nearly $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, transplantation biology and photomedicine. MGH and Brigham and Women's Hospital are founding members of Partners HealthCare HealthCare System, a Boston-based integrated health care delivery system.
Contact: John Lacey
Harvard Medical School
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