Archive for the ‘Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics’ Category

Activation of Efficient and Multiple Site-specific Nonstandard Amino Acid Incorporation

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Cytoskeleton, De novo synthesis, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Toxicity, Evolutionary cognition, Experimental validation, Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics, Immunodiagnostics, Infectious Disease & New Antibiotic Targets, Infectious Disease Immunodiagnostics, Innovation in Immunology Diagnostics, Molecular Genetics & Pharmaceutical, Pharmaceutical Analytics, Pharmacologic toxicities, Population Health Management, Genetics & Pharmaceutical, Proteomics, Systemic Inflammatory Response Related Disorders, Technology Advance Assessment of, Technology Transfer: Biotech and Pharmaceutical, Translational Effectiveness, Translational Research, Translational Science, tagged activation of biosynthesis, amino acid incorporation, Cell-free Protein Synthesis, chemical and biological engineering, incorporation of nonstandard AAs, Multiple Site-specific Nonstandard Amino Acid Incorporation, Release Factor 1, Synthetic biology on June 20, 2014| Leave a Comment »

Larry Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/6-19-3014/larryhbern/Activation of Efficient and Multiple Site-specific Nonstandard Amino Acid Incorporation

 

Cell-free Protein Synthesis from a Release Factor 1 Deficient Escherichia coli Activates Efficient and Multiple Site-specific Nonstandard Amino Acid Incorporation

Seok Hoon Hong †‡, Ioanna Ntai ‡§, Adrian D. Haimovich #, Neil L. Kelleher ‡§, Farren J. Isaacs #, and Michael C. Jewett *†‡

^†Department of Chemical and Biological Engineering,^‡Chemistry of Life Processes Institute, ^§Department of Chemistry, and Department of Molecular Biosciences,Northwestern University, Evanston, Illinois 60208,United States of America

Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut 06520, United States of America

^# Systems Biology Institute, Yale University, West Haven, Connecticut 06516, United States of America

Member, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, United States of America

Institute of Bionanotechnology in Medicine, Northwestern University, Chicago, Illinois 60611, United States of America

ACS Synth. Biol., 2014, 3 (6), pp 398–409

DOI: 10.1021/sb400140t

Publication Date (Web): December 13, 2013

Copyright © 2013 American Chemical Society

*Tel: +1 847 467 5007. Fax (+1) 847 491 3728. E-mail: m-jewett@northwestern.edu

Site-specific incorporation of nonstandard amino acids (NSAAs) into proteins

 

 

 

 

 

 

 

 

 

Site-specific incorporation of nonstandard amino acids (NSAAs) into proteins enables the creation of biopolymers, proteins, and enzymes with new chemical properties, new structures, and new functions. To achieve this, amber (TAG codon) suppression has been widely applied. However, the suppression efficiency is limited due to the competition with translation termination by release factor 1 (RF1), which leads to truncated products. Recently, we constructed a genomically recoded Escherichia coli strain lacking RF1 where 13 occurrences of the amber stop codon have been reassigned to the synonymous TAA codon (rEc.E13.ΔprfA). Here, we assessed and characterized cell-free protein synthesis (CFPS) in crude S30 cell lysates derived from this strain. We observed the synthesis of 190 ± 20 μg/mL of modified soluble superfolder green fluorescent protein (sfGFP) containing a single p-propargyloxy-l-phenylalanine (pPaF) or p-acetyl-l-phenylalanine. As compared to the parentrEc.E13 strain with RF1, this results in a modified sfGFP synthesis improvement of more than 250%. Beyond introducing a single NSAA, we further demonstrated benefits of CFPS from the RF1-deficient strains for incorporating pPaF at two- and five-sites per sfGFP protein. Finally, we compared our crude S30 extract system to the PURE translation system lacking RF1. We observed that our S30 extract based approach is more cost-effective and high yielding than the PURE translation system lacking RF1, 1000 times on a milligram protein produced/$ basis. Looking forward, using RF1-deficient strains for extract-based CFPS will aid in the synthesis of proteins and biopolymers with site-specifically incorporated NSAAs.

Keywords: 

cell-free protein synthesis; PURE translation; nonstandard amino acid;release factor 1; genomically recoded organisms

 

 

 

 

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Demythologizing sharks, cancer, and shark fins

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics, Molecular Genetics & Pharmaceutical, Nutritional Supplements: Atherogenesis, lipid metabolism, tagged Antibody, Cancer - General, immune system, Johns Hopkins University, Luer, Massachusetts Institute of Technology, Mote Marine Laboratory, Smithsonian Institution on June 22, 2013| 1 Comment »

Larry H Bernstein, MD, Writer, Curator
http://pharmaceutical intelligence.com/2013/06/22/ Demythologizing sharks, cancer, and shark fins/lhbern

 

Sharks have survived some 400 million years on Earth. Could their longevity be due in part to an extraordinary resistance to cancer and other diseases? If so, humans might someday benefit from the shark’s secrets—but leading researchers caution that today’s popular shark cartilage “cancer cures” aren’t part of the solution.

 

The belief that sharks do not get cancer is not supported in fact, but it is the basis for decimating a significant part of the shark population for shark fins, and for medicinal use.  The unfortunate result is that there is no benefit.

 

A basis for this thinking is that going back to the late 1800s, sharks have been fished commercially and there have been few reports of anything out of the ordinary when removing internal organs or preparing meat for the marketplace.  In addition, pre-medical students may have dissected dogfish sharks in comparative anatomy, but you don’t see reports of cancerous tumors.

 

Carl Luer of the MOTE Marine Laboratory’s Center for Shark Research in Sarasota, Florida, has been studying sharks’ cancer resistance for some 25 years.  Systematic surveys of sharks are difficult to conduct, as capturing the animals in large numbers is time-consuming, and cancer tests would likely require the deaths of large numbers of sharks. Of the thousands of fish tumors in the collections of the Smithsonian Institution, only about 15 are from elasmobranchs, and only two of these are thought to have been malignant.

 

Scientists have been studying cancerous tumors in sharks for 150 years.

 

The first chondrichthyes’ (cartilaginous fishes, including sharks) tumor was found on a skate and recorded by Dislonghamcps in 1853. The first shark tumor was recorded in 1908. Scientists have since discovered benign and cancerous tumors in 18 of the 1,168 species of sharks. Scarcity of studies on shark physiology has perhaps allowed this myth to be accepted as fact for so many years.

 

In April 2000, John Harshbarger and Gary Ostrander countered this shark myth with a presentation on 40 benign and cancerous tumors known to be found in sharks, and soon after a blue shark was found with cancerous tumors in both its liver and testes. Several years later a cancerous gingival tumor was removed from the mouth of a captive sand tiger shark, Carcharias Taurus. Advances in shark research continue to produce studies on types of cancer found in various species of shark.  Sharks, like fish, encounter and take in large quantities of environmental pollutants, which may actually make them more susceptible to tumorous growth. Despite recorded cases of shark cancer and evidence that shark cartilage has no curative powers against cancer sharks continue to be harvested for their cartilage.

 

Sharks and their relatives, the skates and rays, have enjoyed tremendous success during their nearly 400 million years of existence on earth, according to Dr. Luer. He points out that one reason for this certainly is their uncanny ability to resist disease. Sharks do get sick, but their incidence of disease is much lower than among the other fishes. While statistics are not available on most diseases in fishes, reptiles, amphibians, and invertebrates, tumor incidence in these animals is carefully monitored by the Smithsonian Institution in Washington, D.C.

 

The Smithsonian’s enormous database, called the Registry of Tumors in Lower Animals, catalogs tissues suspected of being tumorous, including cancers, from all possible sources throughout the world. Of the thousands of tissues in the Registry, most of them are from fish but only a few are from elasmobranchs. Only 8 to 10 legitimate tumors are among all the shark and ray tissues examined, and only two of these are thought to have been malignant.

 

An observation by Gary Ostrander, a Professor at Johns Hopkins University, is that there may be fundamental differences in shark immune systems so that they aren’t as prone to cancer.  The major thrust of the Motes research focuses on the immunity of sharks and their relatives the skates and rays. While skates aren’t as interesting to the public as their shark relatives, their similar biochemical immunology and their ability to breed in captivity make them perhaps more vital to Luer’s lab work.   The result is to study the differences and similarities to the higher animals, and what might possibly be the role of the immune system in their low incidence of disease.

 

This low incidence of tumors among the sharks and their relatives has prompted biochemists and immunologists at Mote Marine Laboratory (MML) to explore the mechanisms that may explain the unusual disease resistance of these animals. To do this, they established the nurse shark and clearnose skate as laboratory animals. They designed experiments to see whether tumors could be induced in the sharks and skates by exposing them to potent carcinogenic (cancer-causing) chemicals, and then monitored pathways of metabolism or detoxification of the carcinogens in the test animals. While there were similarities and differences in the responses when compared with mammals, no changes in the target tissues or their genetic material ever resulted in cancerous tumor formation in the sharks or skates.

 

The chemical exposure studies led to investigations of the shark immune system. As with mammals, including humans, the immune system of sharks probably plays a vital role in the overall health of these animals. But there are some important differences between the immune arsenals of mammals and sharks. The immune system of mammals typically consists of two parts which utilize a variety of immune cells as well as several classes of proteins called immunoglobulins (antibodies).

 

Compared to the mammalian system, which is quite specialized, the shark immune system appears primitive but remarkably effective. Sharks apparently possess immune cells with the same functions as those of mammals, but the shark cells appear to be produced and stimulated differently. Furthermore, in contrast to the variety of immunoglobulins produced in the mammalian immune system, sharks have only one class of immunoglobulin (termed IgM). This Immunoglobulin normally circulates in shark blood at very high levels and appears to be ready to attack invading substances at all times.

 

Another difference lies in the fact that sharks, skates, and rays lack a bony skeleton, and so do not have bone marrow. In mammals, immune cells are produced and mature in the bone marrow and other sites, and, after a brief lag time, these cells are mobilized to the bloodstream to fight invading substances. In sharks, the immune cells are produced in the spleen, thymus and unique tissues associated with the gonads (epigonal organ) and esophagus (Leydig organ). Some maturation of these immune cells occurs at the sites of cell production, as with mammals. But a significant number of immune cells in these animals actually mature as they circulate in the bloodstream. Like the ever-present IgM molecule, immune cells already in the shark’s blood may be available to respond without a lag period, resulting in a more efficient immune response.

 

Research was being carried out during the 1980’s at the Massachusetts Institute of Technology (MIT) and at Mote Marine Laboratory designed to understand how cartilage is naturally able to resist penetration by blood capillaries. If the basis for this inhibition could be identified, it was reasoned, it might lead to the development of a new drug therapy. Such a drug could control the spread of blood vessels feeding a cancerous tumor, or the inflammation associated with arthritis.

 

The results of the research showed only that a very small amount of an active material, with limited ability to control blood vessel growth, can be obtained from large amounts of raw cartilage. The cartilage must be subjected to several weeks of harsh chemical procedures to extract and concentrate the active ingredients. Once this is done, the resulting material is able to inhibit blood vessel growth in laboratory tests on animal models, when the concentrated extract is directly applied near the growing blood vessels.  One cannot assume that comparable material in sufficient amount and strength is released passively from cartilage when still in the animal to inhibit blood vessel growth anywhere in the body.

 

Tumors release chemicals stimulating the capillary growth so a nutrient-rich blood supply is created to feed the tumorous cells. This process is called angiogenesis. If scientists can control angiogenesis, they could limit tumor growth. Cartilage lacks capillaries running through it. Why should this be a surprise?  Cartilage cells are called chondrocytes, and they fuction to produce a acellular interstitial matrix consisting of hyaluronan (complex carbohydrate formed from hyaluronic acid and chondroitin sulfate) which is protective of interlaced collagen.   Early research into the anti-angiogenesis properties of cartilage revealed that tiny amounts of proteins could be extracted from cartilage, and, when applied in concentration to animal tumors, the formation of capillaries and the spread of tumors was inhibited.

 

Henry Brem and Judah Folkman from the Johns Hopkins School of Medicine first noted that cartilage prevented the growth of new blood vessels into tissues in the 1970s. The creation of a blood supply, called angiogenesis, is a characteristic of malignant tumors, as the rapidly dividing cells need lots of nutrients to continue growing.  It is valuable to consider that these neovascular generating cells are not of epithelial derivation, but are endothelial and mesenchymal. To support their very high metabolism, tumors secrete a hormone called ‘angiogenin’ which causes nearby blood vessels to grow new branches that surround the tumor, bringing in nutrients and carrying away waste products

 

Brem and Folkman began studying cartilage to search for anti-angiogenic compounds. They reasoned that since all cartilage lacks blood vessels, it must contain some signaling molecules or enzymes that prevent capillaries from forming. They found that inserting cartilage from baby rabbits alongside tumors in experimental animals completely prevented the tumors from growing. Further research showed calf cartilage, too, had anti-angiogenic properties.

 

 

 

A young researcher by the name of Robert Langer repeated the initial rabbit cartilage experiments, except this time using shark cartilage. Indeed, shark cartilage, like calf and rabbit cartilage, inhibited blood vessels from growing toward tumors. Research by Dr. Robert Langer of M.I.T. and other workers revealed a promising anti-tumor agent obtainable in quantity from shark cartilage. The compound antagonistic to the effects of angiogenin, called ‘angiogenin inhibitor’, inhibits the formation of new blood vessels, neovascularization, that is essential for supporting cancer growth.

 

The consequence of the”shark myth” is not surprising. An inhabitant of the open ocean, the Silky Shark is ‘hit’ hard by the shark fin and shark cartilage industries – away from the prying eyes of a mostly land bound public. As a consequence of this ‘invisibility’, mortality of Silkies is difficult to estimate or regulate.  North American populations of sharks have decreased by up to 80% in the past decade, as cartilage companies harvest up to 200,000 sharks every month in US waters to create their products. One American-owned shark cartilage plant in Costa Rica is estimated to destroy 2.8 million sharks per year. Sharks are slow growing species compared to other fish, and simply cannot reproduce fast enough to survive such sustained, intense fishing pressure. Unless fishing is dramatically decreased worldwide, a number of species of sharks will go extinct before we even notice.

 

Sources:
1.  National Geographic News: NATIONALGEOGRAPHIC.COM/NEWS

 

2. Do Sharks Hold Secret to Human Cancer Fight?
by Brian Handwerk for National Geographic News.  August 20, 2003

 

3. Busting Marine Myths: Sharks DO Get Cancer!
by Christie Wilcox   November 9th 2009

 

 

 

Related articles

 

• Sharks Extinction Imminent If Current Illegal Trade Persists (guardianlv.com)
• Cancer Cells More Than Just Proliferate, Overuse Blood Sugar To Evade Immune System [VIDEO] (medicaldaily.com)
• Combating Metastatic Cancer Through Immune System Modulation (medicalnewstoday.com)
• Study Finds Ways of Training Immune System to Fight Cancer (counselheal.com)

 

Sand tiger shark (Carcharias taurus) at the Newport Aquarium. (Photo credit: Wikipedia)

 

Angiogenesis (Photo credit: Wikipedia)

 

 

 

 

 

 

 

 

 

 

 

The immune response (Photo credit: Wikipedia)

 

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Naked Mole Rats Cancer-Free

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Biology and its relations to Metabolic Disease, Genome Biology, Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics, International Global Work in Pharmaceutical, tagged Cancer - General, DNA, genetics, Harvard School of Public Health, Naked mole rat, Spalax, University of Texas Health Science Center, University of Texas System on June 20, 2013| Leave a Comment »

Larry H. Bernstein, MD, Reviewer and Curator
Leaders in Pharmaceutical Intelligence
https://pharmaceuticalintelligence.com/2013/06/20/Naked Mole Rats Cancer-Free/lhbern

This discussion is a novel piece of investigations now and earlier  published in the Proceedings of the National Academy of Sciences, and another in Nature pertaining to aging, longevity, and cancer.  The blind mole rat has an unexpected lifespan compared to other rodents.  There are also findings of a related naked mole rat that comes into the picture.  They are related, but not exactly the same. In both cases, the moles are cold-blooded, live underground with a queen and workers and they don’t develop cancer. The naked mold rates don’t develop cancer because of the presence of an imbalance in the intercellular matrix caused by abundant naturally produced, sticky complex carbohydrate also found in human joints that repels the cells at their interstices.

This is fascinating because it is also an important aspect of joint mobility.  In the situation of chondomalacia before erosion of the articular cartilage, the movement and shearing stresses initially induced production of more chondrocytes and with that, a thickened cartilage that becomes taxed until it loses matrix fluid, followed by loss of matrix and loss of collagen by shearing stress.  This type of motion and shear stress plays no part in the life of the naked mole rat, which has a rough skin.  The property of the cellular matrix seems to be characterized by both the production of the intercellular goo…called hyalurenan (like hyaluronic acid) and sparse hyaluronidase to remove and remodel the cell architecture.  How this is related to extreme aging and no loss of cellular growth control, having sparce ubiqitination that is involve in cell death and repair is unclear.

The hyaluronidases (EC 3.2.1.35) are a family of enzymes that degrade hyaluronic acid.  In humans, there are six associated genes, including HYAL1, HYAL2, HYAL3, and PH-20/SPAM1. By catalyzing the hydrolysis of hyaluronan, a constituent of the extracellular matrix (ECM), hyaluronidase lowers the viscosity of hyaluronan.  http://upload.wikimedia.org/wikipedia/commons/2/2f/Hyaluronidase-1OJN.png

The blind mole rat is closely related, but it differs in that it has a mechanism by which the cells have limited proliferation and don’t proliferate to the point of getting out of control.  This is because after several generations of cellular proliferation they produce a protein,  IFN-β.  This protein induces massive apoptosis, limiting the size of the sell population. There are findings in these investigations that might be relevant to understanding cancer resistance, and perhaps it could provide clues to treatment approaches.  If that is too much to ask for, it gives us great insight into how cells organize.

Cancer resistance in the blind mole rat is mediated by concerted necrotic cell death mechanism

Gorbunovaa V, Hinea C, Tiana X, Ablaevaa J, Gudkovb AV, Nevoc E, and Seluanova A.
Contributed by Eviatar Nevo, October 3, 2012 (sent for review August 28, 2012)

Abstract

Blind mole rats Spalax (BMR) are small subterranean rodents common in the Middle East. BMR is distinguished by its adaptations to life underground, remarkable longevity (with a maximum documented lifespan of 21 y), and resistance to cancer. Spontaneous tumors have never been observed in spalacids. To understand the mechanisms responsible for this resistance, we examined the growth of BMR fibroblasts in vitro of the species Spalax judaei and Spalax golani. BMR cells proliferated actively for 7–20 population doublings, after which the cells began secreting IFN-β, and the cultures underwent massive necrotic cell death within 3 d. The necrotic cell death phenomenon was independent of culture conditions or telomere shortening. Interestingly, this cell behavior was distinct from that observed in another long-lived and cancer-resistant African mole rat, Heterocephalus glaber, the naked mole rat in which cells display hypersensitivity to contact inhibition. Sequestration of p53 and Rb proteins using SV40 large T antigen completely rescued necrotic cell death. Our results suggest that cancer resistance of BMR is conferred by massive necrotic response to overproliferation mediated by p53 and Rb pathways, and triggered by the release of IFN-β. Thus, we have identified a unique mechanism that contributes to cancer resistance of this subterranean mammal extremely adapted to life underground.

Source:

1To whom correspondence may be addressed. E-mail:  vera.gorbunova@rochester.edu, nevo@research.haifa.ac.il, or andrei.seluanov@rochester.edu.

2Present address: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115.

http://www.pnas.org/content/early/2012/10/31/1217211109

Image: Greg Goebel/Flickr

Long-Lived Rat May Hold Clues to Combating Aging

BY BRANDON KEIM02.17.09

The extraordinarily durable proteins in the world’s longest-lived rodent may contain a vital piece of the puzzle of aging.

• Like short-lived mice, the cells of naked mole rats are suffused with free-floating, cell-damaging oxygen free radicals. 
• Unlike the mice — and every other species that appears compromised by oxidative deterioration, including humans — they’ve found a way to live with it.

“When we compare the lab mouse with the naked mole rat, we find a striking difference in their systems,” said study co-author Asish Chaudhuri, a University of Texas Health Science Center biochemist. “Their proteins are still working. Even when damaged, the functions are maintained.”

The findings, published Monday in the Proceedings of the National Academy of Sciences, represent a new wrinkle in the oxidative-stress theory of aging. According to the theory, mitochondria — cellular machines that produce our bodies’ energy — pump out highly reactive oxygen molecules during respiration. Called free radicals, these molecules bind easily with other molecules, including DNA. Over time, DNA breaks down, compromising cellular function. Eventually whole tissues and organs no longer function.  Multiple studies have found evidence of mitochondrial malfunction in a range of diseases that become more common with age, from heart disease to neurodegeneration to cancer. Drugs designed to rejuvenate mitochondria have shown promise in treating diabetes, and are celebrated as possible therapies for other conditions.

DNA repair rate is an important determinant of cell pathology (Photo credit: Wikipedia)

Chaudhuri’s team’s findings don’t contradict the role of mitochondria, but expand the theory to include cellular proteins other than DNA. They also explain a condundrum: some long-lived species display plenty of oxidative damage. “We’ve studied a dozen species, half short-lived and the others long-lived. One long-lived species would have lots of oxidative damage, and another would have little. The one thing that seemed to be consistent was protein stability,” said University of Texas Health Sciences Center gerontologist Steven Austad, who was not involved in the current study. “Until recently I’ve focused on DNA damage and repair, but this strikes me as even more fundamental. For DNA repair to work, you need all the repair proteins to work properly.”  Mole rats caught the researchers’ attention because they can live for 30 years, or ten times longer than lab mice, even though the two are similarly sized.

They found that mole rats do have efficient mitochondria that release fewer free radicals than expected. But their mitochondria aren’t perfect. Free radicals still gather and cause damage. Two-year-old mole rats show just as much oxidative stress two-year-old mice — and then live for another quarter-century.  The key appears to be their proteins, which continue to function despite damage. Study co-author Rochelle Buffenstein, a University of Texas Health Sciences Center physiologist, likened the phenomena to rusting cars: in other species, the axles rust, but in naked mole rats, it’s just the doors.  With heat and urea — both of which typically cause complex protein spools to unfold — the researchers tried to break down the proteins, but to no avail.  “You can basically hit them with a sledgehammer, and the proteins don’t unfold,” said Buffenstein. “Something makes them inherently more stable. There might be small molecules that tack on to proteins and help them retain structure in the face of cellular stress.”

Mole rats also appear to delay protein repair until the last possible moment, thus saving energy and resources. When proteins finally do break down, mole rats do an especially efficient job of cleaning them up. Only a tiny bit of ubiquitin — the chemical tag used to label damaged proteins for disposal — is required.  Finally, specialized protein-disposal structures, called proteosomes (tied to ubiqitination), don’t appear to break down with age in mole rats.

English: Damaraland mole-rat (Fukomys damarensis) (Photo credit: Wikipedia)

The researchers will next try to determine what maintains the mole rat’s proteins and proteosome. If, as Buffenstein suspects, it turns out to be an as-yet-unidentified protein protectant, scientists could apply the findings to people. “If we can identify those proteins, we can use them to study aging and age-related diseases. These animals don’t have any symptoms of neurodegeneration, even in old age,” said Chaudhuri. “Then we can design peptides that act like the protein, and take it as a drug.”

Citation:

Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat.

By Viviana I. Perez, Rochelle Buffenstein, Venkata Masamsetti, Shanique Leonard, Adam B. Salmon, James Meleb, Blazej Andziak, Ting Yang, Yael Edrey, Bertrand Friguet, Walter Ward, Arlan Richardson and Asish Chaudhuri. Proceedings of the National Academy of Sciences, Vol. 106 No. 7, Feb. 16, 2009.

Why Blind Mole Rats Don’t Get Cancer

By Ian Steadman, Wired UK

Blind mole rats don’t get cancer. in 2011 it was found they have a gene that stops cancerous cells from forming. The same team thought that two other cancer-proof mole rat species might have similar genes, but instead it turns out that they do develop cancerous cells. It’s just that those cells are programmed to destroy themselves if they become dangerous.

The blind mole rat (Spalax typhlus) has tiny eyes completely covered by a layer of skin. (Photo credit: Wikipedia)

Mole rats, which live in underground burrows throughout Southern and Eastern Africa, and the Middle East, are fascinating creatures. The naked mole rat, in particular, is the only cold-blooded mammal known to man, doesn’t experience pain, and is also arguably the only mammal (along with the Damaraland mole rat) to demonstrate eusociality — that is, they live in large hierarchical communities with a queen and workers, like ants or bees.

The two species examined by the University of Rochester’s Vera Gorbunova and her team were the Judean Mountains blind mole rat (Spalax judaei) and the Golan Heights blind mole rat (Spalax golani), which live within small regions of Israel. The team took cells from the rodents and put them in a culture that would force them to multiply beyond what would happen within the animals’ bodies. For the first seven to 20 multiplications, things looked fine, but beyond 20 multiplications the cells started rapidly dying off.  Examining the cells as they died revealed that they had started to produce a protein, IFN-β, that caused them to undergo “massive necrotic cell death within three days”. In effect, once the cells had detected that they had multiplied beyond a certain point, they killed themselves. The cells of naked mole rats have a self-preservation mechanism tied to a hypersensitivity to overcrowding, which stops them from multiplying too much.  On the one hand (blind mole rat) you have self-destruction at a point at which there is crowding due to IFN-β.  On the other hand, you find an aversion to overcrowding (naked mole rat).

In the Proceedings of the National Academy of Sciences, Gorbunova hypothesizes that the blind mole rats’ unique habitat — almost entirely underground — might mean that they “could perhaps afford to evolve a long lifespan, which includes developing efficient anti-cancer defences”. Blind mole rats have extremely long lifespans by rodent standards, often living beyond 20 years at a time.

The reasons why this is, though, are still all hypothetical, as the precise mechanism that triggers the production of the IFN-β is still unknown. The hope is that this research could eventually lead to new therapies for cancer in humans.

Super Sugar Keeps Naked Mole Rats Cancer-Free

BY ELIZABETH PENNISI, SCIENCENOW 06.20.13

Although they are quite ugly and confined to a life underground, naked mole rats have at least one attribute that other animals, even humans, might aspire to: They don’t get cancer. Now, researchers have discovered that the secret to this rodent’s good health is a complex sugar that helps keeps cells from clumping together and forming tumors.  It exists in the spaces between cells called the extracellular matrix, “the work underlines the very important regulatory role of [the] extracellular matrix in cancer,” says Bryan Toole, a cancer biologist at the Medical University of South Carolina in Charleston who was not involved with the study. Molecular and cell biologist Vera Gorbunova of the University of Rochester in New York wanted to take a different tack and focus on animals that seem protected from tumors. So she tracked down the lifespans of 20 different rodents, looking for the ones that live a long time. Beavers and gray squirrels last a couple of decades, but naked mole rats outlive those larger animals by 10 years.  Furthermore, naked mole rats have a unique social structure, with one queen that produces all the young for an underground colony full of helpers. Thanks to these studies, scientists know for sure that this species doesn’t get cancer. Given that naked mole rats live long and are resistant to cancer, “we fell in love with them right away,” Gorbunova says.

At first, she and her colleagues did not know where to look for the source of animals’ cancer resistance. But when they grew naked mole rat cells in a lab dish, they noticed that cells wouldn’t get too close together. Furthermore, the dish contents got very gooey, and when they eliminated the goo, the cells would clump together. The researchers tracked the stickiness to a complex sugar called hyaluronan, which cells make and release into the extracellular matrix.  Hyaluronan exists in all animals, helping lubricate joints and serving as an essential component in skin and cartilage. However, naked mole rat hyaluronan is unusual in that each molecule is about 5 times the size of hyaluronan molecules from mice, rats, and humans. In addition, the researchers discovered that the enzyme that breaks down this sugar (hyaluronidase) is not very active in naked mole rats, allowing the compound to accumulate to higher concentrations than it does in other animals. The researchers think that this sugar evolved to make naked mole rat skin more elastic and able to cope with the tight squeeze of the narrow underground tunnels.

But does it prevent cancer? Gorbunova and her colleagues tried to stimulate naked mole rat cells to form tumors by exposing them to viral proteins that in mice lead to tumor growth. These proteins inactivate genes that suppress cancer, yet still naked mole rat cells did not show uncontrolled growth. However, when the researchers interfered with the production of hyaluronan or revved up the activity of the enzyme that breaks the sugar down, thereby reducing its concentrations, tumors did form in live animals, they report online today in Nature.

The work is “very thought-provoking [and] adds an interesting wrinkle to the role of the extracellular matrix in cancer,” says Roy Zent, a cell biologist at Vanderbilt University Medical Center in Nashville. Toole agrees. “It pushes our thoughts forward [about hyaluronan] in a very dramatic way,” he notes. “It establishes hyaluronan as an important player in cancer.”  “If we could alter our [hyaluronan] or stabilize it somehow, we may be able to suppress cancers,” suggests Carlo Maley, an evolutionary cancer biologist at the University of California, San Francisco, who was not involved with the work. The next step, he adds, is to “put the naked mole rat [hyaluronan] gene into mice and test if they are cancer resistant.”

Related articles

• Scientists have figured out why naked mole rats don’t get cancer (io9.com)
• Cancer Cure Found In Naked Mole Rats? Chemical, Hyaluronan, May Contain Anti-Cancer Properties (medicaldaily.com)
• The Latest Update on Naked Mole Rat Cancer Immunity (fightaging.org)
• “Goo” from naked mole rat appears to offer cancer protection (cbsnews.com)
• Naked Mole Rats Provide Cancer-Killing Insights: It’s All in the Goo [Video] (latinospost.com)
• Biologists identify chemical that makes naked mole rats cancer-proof (wired.co.uk)

English: Naked mole rats. Cropped version of File:Naked Mole Rats.jpg. (Photo credit: Wikipedia)

Naked Mole rat baby (Photo credit: Wikipedia)

English: Spalax leucodon, syn. Nannospalax leucodon Magyar: Földikutya (Photo credit: Wikipedia)

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  • From @Harvardmed Center for Bioethics: The Medical Ethics of the Corona Virus Crisis March 27, 2020
  • Live Notes from @HarvardMed Bioethics: Authors Jerome Groopman, MD & Pamela Hartzband, MD, discuss Your Medical Mind March 27, 2020
  • Glycobiology vs Proteomics: Glycobiologists Prespective in the effort to explain the origin, etiology and potential therapeutics for the Coronavirus Pandemic (COVID-19) March 26, 2020
  • US Responses to Coronavirus Outbreak Expose Many Flaws in Our Medical System March 25, 2020
  • How is the 3D Printing Community Responding to COVID-19? March 23, 2020
  • Promise of Synthetic Biology for Covid-19 Vaccine March 23, 2020
  • The Relevance of Glycans in the Viral Pathology of COVID-19 March 23, 2020
  • Lesson 7 of Cell Signaling 7 Motility: Tubulin and Tutorial Quizes for #TUBiol3373 March 23, 2020
  • Economic Implications of the Coronavirus March 21, 2020
  • Alaska Patient Tells Story March 21, 2020

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