The blog, Rael the Prophet, reports on an article in the UK Telegraph about a research on a genetically engineered tear-free onion being collaboratively conducted by researchers from Japan and the New Zealand Institute for Crop & Food Research. We’re all aware how teary an onion can be if mishandled when chopping. To men and women who spend considerable amounts of time cooking, this, definitely is news worth celebrating.

In addition to ridding onion of the gene that causes teary effects on our eyes, these researchers promise that this new variety will be sweeter and healthier.

What an exciting research? Indeed, it has generated quite a buzz. The journal Onion World, in its December edition, has featured this work, which is being piloted by Dr. Colin Eady. The popular environmental blog Environmental Grafita gleefully proclaims, GM onions means no more tears, with sarcasm:


Anti-GMO activists may soon be tearing up after a New Zealand company announced the development of a genetically modified tear free onion.


I can’t also wait to see their [anti-biotech activists] reactions. Instead of inserting a foreign gene into the onion, which has been the practice in crop genetic engineering, researchers in this project will be working to suppress the gene that makes onions teary.


The key is not to introduce a foreign gene but to silence one using a phenomenon called RNA interference. By stopping sulphur compounds from being converted to the tearing agent and redirecting them into compounds responsible for flavour and health, the process could even improve the onion.


So, which direction will the debate on safety of this new onion variety take? We’re always told there’s no guarantee of safety of genes inserted into crops such as corn, cotton, or soya. Will the anti-biotech groups now claim removing a gene from a crop, and onion onion for that matter, will compromise human health and the environment? Let’s wait for the debate to start.

Genetic Biotechnology

I rarely give stock advice. The last time I did was in the summer of 1964 when I read in the newspaper that a new company called ComSat was having an IPO in September. I considered this, perhaps naively, a sure thing. Yet being in my first job I had no money to invest. So, I decided to watch this stock with the fantasy of having invested $1,000 ($6,548 in today’s dollars). My plan was to buy at the IPO price of $10 a share and then sell just before the launch of the first commercial communications satellite, just in case the launch failed. The stock rose meteorically from $10 per share to $80 (the launch did not fail), then the stock split and rose again to more than $80 per share. I made about $240,000 from my $1,000 fantasy investment, equivalent to $1.5 million today.

The reason I bring this up is that recently, I was fortunate to attend a small meeting in Boston that focused on developments in the seemingly esoteric field of siRNA or “short interfering RNA” used to silence genes. The promise of this technology has rightfully created a significant buzz in the scientific and investment communities over for the last two to three years. And as I left this meeting, it occurred to me that in the next 10 to 20 years, siRNA, also called “RNAi”, will probably dominate drug development, with many successful drugs currently targeting specific proteins, like Genentech’s Herceptin and Imclone’s Erbitux, being replaced by RNAi-based drugs. Furthermore, many disease-causing proteins thought to be “undrugable”, like the metastatic biomarker L-plastin for colon, breast, melanoma, prostate, and bladder cancer, could now be targeted by RNAi drugs.

Andrew Fire, of Stanford, and Craig Mello, at the University of Massachusetts, discovered “gene silencing by double-stranded RNA” in 1998, earning them the 2006 Nobel Prize in Medicine. In 2001 companies started forming around RNAi. One of them, Alnylam Pharmaceuticals filed its S-1 registration with the SEC in February 2004, claiming $23,000 in cash assets and creating 3.2 million shares worth 28 cents each. Two years later, Alnylam went public with stock selling at $7.50 per share after an unprecedented short start-up time. Alnylam’s shares were selling on NASDAQ at around $16 per share in early July after hitting a 52-week high of $24.46 last December. By December or perhaps early winter, Alnylam will announce the outcome of its Phase II clinical trial on their lead product for treating the infant respiratory disease caused by Respiratory Syncytial Virus (RSV infections). Alnylam has multiple collaborations funded by Merck, and about 20 pipeline products. At the same time Merck bought Sirna Therapeutics, another RNAi company with strong IP for this technology. During the last year, in order to acquire additional RNAi-relevant IP, Hoffmann-La Roche bought 454, Sigma Chemicals bought Proligo, Alnylam bought Ribopharma, Acuity Pharmaceuticals merged with two other companies to form Opko, Dharmacon became part of Thermo-Fisher Scientific, and RXi Pharmaceuticals was spawned by CytRx. Also Pfizer, GlaxoSmithKline, Novartis, Bristol-Myers Squibb, and Abbott Labs have started R&D programs around RNAi.

Santaris Pharma, a Danish company formed in 2003, has a novel method for making and stabilizing RNAi and drug products in Phase II clinical development. Santaris is strategically partnered through licensing agreements with Enzon, a leading clinical research organization that is conducting clinical trials in the U.S. for many Santaris’ drug candidates. Santaris has completed Phase I/II clinical trials in Denmark, France, the U.K. and the U.S. for an RNAi drug for treating chronic lymphocytic leukemia (CLL) and Phase I trials for a second product treating renal and colon carcinoma and multiple myeloma. The CLL product should compete favorably with Genta’s BCL-2 antisense (RNA) product in development for over a decade, through phase III clinical development, and in pre-registration for CLL and malignant melanoma.

As an aside, it’s worth noting that several of these companies are Nerac clients.

RNAi therapy is not like stem cell therapy, which will take decades to develop. Approval of the first RNAi drugs is expected in three to five years. This is because stem cell therapy is complex and the science is still in its infancy. By contrast RNAi is well developed because of the advanced understanding of genetics and gene expression. In fact RNAi will be used to make stem cell therapy work.

The 1993 discovery of microRNA, a natural mechanism of gene regulation in all cells, accelerated understanding of how RNAi works. SiRNA is an exogenous synthetic version of the natural endogenous microRNA that takes advantage of the cellular machinery that normally processes and mediates the function of microRNA. Micro- or siRNA (RNAi) is targeted to inhibit a specific counterpart transcript (messenger RNA) that serves as a template for synthesis of an individual protein, the natural process of gene expression. RNAi is processed by a ribonuclease enzyme that binds to a larger precursor siRNA. The enzyme processes siRNA into a 21-nucleotide base-pair double stranded molecule. The specificity of RNAi is governed both by its ‘complimentarity’ to a particular messenger RNA nucleic acid sequence and also by a complex of proteins whose function is to mediate the binding of the RNAi to a target sequence on the messenger RNA, usually in the 3′-noncoding region of the messenger RNA. This binding event leads to a shut-down in synthesis of the protein encoded by the messenger RNA (called “knock-down”).

There is currently little mystery about how to design siRNA molecules and synthesize them, as this method is aided by readily available algorithms. In fact, Todd Woolf, CEO & President of RXi Pharmaceuticals, says, “Weeks instead of years to lead compounds.” This finely tunable technique of RNAi knock-down is also currently used in many academic research labs.

Finally, many studies have been completed including Phase I clinical trials that indicate the siRNA is essentially non-toxic. Conventional drugs have always required the balancing of efficacious doses with consideration of the drug’s negative side-effects.

Several companies and labs have shown siRNA conjugated with cholesterol or other lipid carriers will attach to cholesterol carrier proteins in the blood and transport to the liver rather than being excreted. If an siRNA is used that knocks down an enzyme involved in cholesterol production by the liver, then serum cholesterol levels can be diminished in mice by 30 to 40 percent without diminishing the good cholesterol (HDL) levels. The blockbuster statin drugs like Lipitor, which are well known to produce toxic side-effects in the liver, also reduce cholesterol levels in the blood by about 30 to 40 percent. In the mouse model, the cholesterol-reducing effects of one treatment with siRNA lasts three to four weeks.

In a mouse model for intestinal adenomatous polyposis, the mice develop a high density of benign polyps that ultimately block the intestines, subsequently leading to death. In humans, such polyps are precursors to malignant colon cancer. Johannes Fruehauf of Cequent Pharmaceuticals and Harvard Medical School described a novel method for delivering siRNA to the intestinal tract which targeted beta-catenin synthesized by polyp cells. Increased expression of beta-catenin is associated with proliferation of polyp cells but not by itself in the conversion of benign polyps to malignancy. Cequent has demonstrated that bacteria, such as E. coli, carrying about 100 copies of recombinant siRNA in a plasmid vector, can simply be fed to polyposis mice whose intestines are clogged with polyps.

Administration of these bacteria containing the siRNA copies killed the polyps and cleared up the problem completely; the histopathology pictures established clearly that the intestines were cleansed of the polyps. The explanation for this efficacy is that thousands of these bacteria were engulfed by the polyp cells by the natural process of endocytosis. The bacteria were dissolved in the endosomes, the plasmids carrying the siRNA insert were fragmented, and the liberated siRNA inhibited beta-catenin synthesis in the polyps. This last step causes the polyps to self-destruct by the natural mechanism of apoptosis, or programmed cell death.

The prospect for siRNA as a therapy seems unlimited in that any and every gene can become a target for this therapy. Before siRNA, many potential disease targets were considered “undrugable,” meaning that virtually every disease can be considered for siRNA therapy, including all forms of cancer, metabolic diseases like diabetes, and cardiovascular disease. One speaker at the meeting predicted that when the first siRNA proved its efficacy in a Phase III clinical trial, this event would lead to an explosion of interest in siRNA by Big Pharma and the investment community. It seems inevitable that this will happen in the not too distant future.

RNAI

Nowadays chemotherapy is found to be the best treatment to kill cancer cells. A combination of different drugs is used to destroy major number of cancerous cells. Some side effects like weight loss, memory loss, hair fall, nausea and so on may occur due to chemotherapy treatment and these drugs can also damage healthy cells.

There are various types of cancers and every type requires different drugs at different stages. Before going through chemotherapy treatment, drugs used in it should be tested in clinical trials to prove its effectiveness. It’s side effects also depend on other conditions like age and health of patient.

Following are the types of chemotherapy:
Alkylating medications: Alkylating agents block DNA replication of cancer cells, which can destroy cancer cells at any phase of cancer. These drugs are commonly used for cancer of ovaries, breast and lungs. Some alkylating agents are alkylsulfonates: busulfan, metal carboplatin, oxalipaltin, salts: cispaltin and many more are used in chemotherapy treatment. Anti-tumor antibiotics: These are natural products produced by soil fungus streptomycin. Anti tumor antibiotics work during the multiple phases of cancer cell cycle. Some examples of anti-tumor antibiotics are mitomycin, plicamyacin, dactinomycin etc. Antimetabolite medications: It effectively blocks the enzymes found within the cancerous cells. Antimetabolite medication works by interfering with DNA and RNA growth. These drugs are very effective during Synthesis phase of cell cycle. Anti-tumor Antibiotic medications: It works interfering with DNA of cancerous cell. This interference blocks the enzymes and changes the cell membrane of cancerous cells and also interrupts cell division. Plant alkaloids: These are naturally produced from herbs and shrubs. Plant alkaloids like vinca, taxanes, paclitaxel, docetaxel, etc are used to treat cancer cells. Anthracyclines: Anthracyclines interfere with enzymes required to reproduce the DNA. Some anti-tumor antibiotics and non-particular antibiotics are used to cure different types of cancer. Doxorubicin, bleomycin and mitomycin are examples of some drugs used for chemotherapy treatment. Topoisomerase inhibitors: It plays important role in controlling the exploitation of DNA structure. Topotecan, etoposide phosphate, ironotecan and teniposide are some examples of drugs used during this type of chemotherapy treatment.

RNA Interference

Even as the 2008 Olympics in Beijing are gaining momentum, the subject of doping is making its way into the coverage. That is to be expected. The prevalence of doping among athletes in professional, college and high school sports is well documented. And up till now, doping has always involved muscle-enhancing drugs such as steroids and recombinant growth factors.

Growth factors such as Human Growth Hormone, or HGH, and other new age drugs result from recombinant DNA technologies of the mid-1980s that a decade later led to drugs approved for human use to treat growth deficiencies.

In theory, these same growth-promoting drugs could be introduced into humans using gene therapy. However, gene therapy has been notoriously difficult to control, and once you introduce the gene, how do you take it back after its effect is no longer needed? After all, modern athletes who wish to cheat the system to achieve their athletic goals may wish to return to a normal life after athletic ambitions have been satisfied. With gene therapy there may be no way to reverse the unending effects of alien muscle-enhancing genes.

However, a new genetic solution is emerging that may solve the problem of uncontrollable long-term effects and offer a new, easier way to cheat the system.

In a 2004 Scientific American article titled, “Gene Doping,” H. Lee Sweeney describes the “Belgian Blue Bull” as the bovine version of the Incredible Hulk. The Belgian Blue Bull is a freak of nature because an inherited genetic mutation in the breed deactivates both copies of the gene that encodes myostatin, a protein that inhibits muscle growth so the organism can maintain a balance between muscles and skeleton. The absence of this protein not only allows unchecked muscle growth, it also inhibits fat deposition. As a result, this bull is incredible lean muscle bulk-a bigger, stronger, and, yes, faster bull.

In a recent paper in Trends in Genetics titled “Sprinting without myostatin: a genetic determinant of athletic prowess,” author Se-Jin Lee of Johns Hopkins University describes the occurrence of this myostatin mutation in mice, sheep and bully whippet racing dogs. In whippets, mutations in both copies of the myostatin gene lead to a dog with twice as much muscle mass. A mutation of only one copy of the myostatin gene results in about a 25 percent increase in muscle bulk with increased athleticism.

Among humans, a 2004 article in the New England Journal of Medicine reported on a child whose mutation affected both gene copies, meaning the child has no myostatin. The child’s mother, who was an accomplished sprinter, has one mutated copy of her myostatin gene. The child appeared extraordinarily muscular at birth and was noted to be unusually strong at seven months. At age 4 the child was monitored for cardiac function, but no cardiomyopathy was found.

Beyond naturally occurring mutations, the last five years have seen a new approach known as RNA interference to intentionally silence genes to treat diseases. The effectiveness of what is known as siRNA has been established for silencing genes , such as a gene in the liver of primates that causes high blood cholesterol.

Development of this technology has brought about rapid growth, creating a billion-dollar industry in just five years. In addition, large pharmaceutical companies such as Merck, GlaxoSmithKline, Novartis, Pfizer, and Hoffmann-La Roche are buying up or partnering with the smaller, innovative companies including Alnylam and Sirna Therapeutics, which own the patent rights to the siRNA technology.

It would take only a few weeks to design and synthesize an RNA interfering drug that could silence the gene that encodes myostatin, which is active only in muscle. Gene silencing of myostatin to produce a better athlete could, in theory, be accomplished by injecting siRNA into the area targeted for muscle building.

Indeed, researchers at Sirna Therapeutics have already produced siRNA’s that shut down myostatin expression, and Sirna has filed a U.S. patent application (US 20050124566) on the use of these compounds to increase muscle mass for increased strength, athleticism, bodybuilding, or cosmetic applications.

Targeting other genes has demonstrated lasting inhibitory effects of three to four weeks with a single siRNA injection. Since this is not classic gene therapy, this approach to muscle building can be reversed, avoiding problems associated with the life-long physiologic consequences of non-reversible myostatin deficiency.

A number of other human genes have also been mentioned as possible targets for gene doping in athletes. However, those muscle-enhancing genes would have to be introduced into the athlete with no guarantee of the lasting outcome. It seems more likely that siRNA will find its way to athletes who wish to cheat and the enablers who wish to exploit athletes to make money.

There may be no way to test for the type of genetic manipulation. Nevertheless, the US and International Olympic Committees should advocate for national laws to be enacted by all participating nations to make genetic manipulation of athletic traits unlawful. The ethical dilemma here is should athletes be denied the ability to acquire athletic traits that have been naturally acquired by others?

Biotech Websites

Serious Visual Side Effects Found With New AMD Treatment

A study in the August 2008 New England Journal of Medicine (NEJM) suggested that Dry AMD–a form of Age-related Macular Degeneration (AMD) found in eight to nine million Americans–may be associated with a gene in our body. The study also found that in individuals with this genetic variation, a currently practiced modern treatment for AMD may lead to serious adverse consequences, including blindness.

Researcher Kang Zhang and co-workers from the Shiley Eye Center at the University of California, San Diego, found that a key protein that alerts our immune system to the presence of viral infections–called Toll-like Receptor 3 (TLR3)–was linked with dry AMD. Zhang and co-workers also noted that if individuals with a genetic variant of TLR3 are treated with a modern treatment for AMD–called RNA interference (RNAi)–they could be at risk for serious adverse effects, including blindness. RNAi is a modern modality of treatment that is used to silence the genes related to various disease conditions.

The study links the occurrence of dry AMD with a genetic variation of TLR3, which indicates that some persons with this particular genetic variation will be more prone to develop dry AMD. Given that gene test is emerging as a new trend in personal health, genetic linkage of dry AMD may help people know–through gene tests–whether they’ve propensity for the disease. And this in turn may help them adopt proper preventive measures to stay away from the disease. The second component of the study has raised the question of safety in adopting modern treatments for AMD. It has cited the evidence that a new treatment approach for AMD–RNAi–may lead to serious adverse consequences, including blindness. This finding has reinforced the position of nutritional treatment in AMD, because treatment of AMD with nutritional supplements is safe and substantially effective.

Elderly People Remain in the Dark About Age-Related Macular Degeneration

Research released this month by the Toronto-based AMD Alliance International (AMDAI) showed that AMD ranked lowest among a list of conditions that are likely to affect the aging population, when participants in that study were asked how much they know about those conditions.

This study suggested that people lack knowledge and concern regarding AMD, and it is preventing them from taking critical steps to halt or slow the progression of the disease. According to the study, amid those who had a high propensity for loss of vision due to AMD, only 56 percent of the participants met an eye specialist once a year and more. That apart, when the participants were asked about their knowledge about conditions that are likely to affect the aging populations, AMD ranked lowest in the list.

The AMDAI spoke for the necessity of increased understanding about AMD. In the web document related to the study, the chair of the organization David Herman says, “This study clearly indicates that there is a low level of concern about AMD and many people aren’t seeking adequate eye care until the disease has reached more of an advanced stage.” As antioxidants help keep the eyes healthy (for example, by cutting the risk and slowing the progress of AMD)–regular intake of antioxidant-rich nutritional supplements may be of some practical help for people who avoid visit an eye doctor at regular intervals.

More Support for Biochemistry of Antioxidants in the Treatment of AMD

The Journal of Biological Chemistry (JBC), has reconfirmed that antioxidants substantially help combat AMD in a study published on September 9, 2008.

The study showed two damaging processes in retina that play an important role in the development of AMD. Conducted by researchers from Brigham Young University (BYU) and Cornell University, the research also found that antioxidants fight against AMD by significantly disrupting the link between those two processes (in retina) and extending the lifetime of the irreplaceable photoreceptors and other cells in retina. “The implication is that people at risk of macular degeneration could help prevent the disease by consuming antioxidants,” says, in a news release, Heidi Vollmer-Snarr, co-author of the study and a chemist at the BYU.

The authors explained the role that antioxidants play in tackling AMD. In the study, the researchers looked at a compound called A2E (which is a byproduct of natural cellular activity) and damage to mitochondria (the power plants present inside the cells). The researchers found that when oxidative stress is created on A2E, by light exposure, it disrupts the energy production in mitochondria. It results a shortage of energy inside the cells which in turn hampers the daily cleaning and maintenance of photoreceptors and other type of retinal cells. “The result is more A2E buildup, and the cycle of destruction hastens the death of these vital visual cells, which are not replaced when they die,” says a BYU news release associated with the study, adding, “The experiments performed with visual cells from rats, cows and humans showed that antioxidants could completely counter the damage.” Regarding the role of antioxidants in AMD, research in past suggested that antioxidants found in nutritional supplements (for example, Lutein, Zeaxanthin, Vitamin E and beta-carotene) work as scavengers for free radicals and protect the retina against damages caused by oxidative stress.

Genetic Assessment

Almost every child that enters high school in the United States has a cell phone. More than a third of the grade school kids carry them. Over eighty-two percent of all Americans own cell phones. The percentage would be higher, if it weren’t for the over sixty-five group, in which there are a large number of hold-outs. And one fifth of all US homes keep a cell phone with no land line at all.

For what reasons are people ridding themselves of land lines? They need to be plugged in day and night. Some feel they use more energy, but that is only true if you have backup batteries, or a cordless phone that needs recharging all the time. Land line phones are harder to recycle, but on the other hand, they do not wear out as fast, rarely break down, and you can keep them forever…unless you are looking for one that offers some new gimmick that your old phone hasn’t got.

For the most part, land line service, while it usually has a cheap base rate, charges extra for minutes used, long distance, call waiting, etc. and so forth. Most cell phone plans include more extras in the rates. While call for call they may be a bit cheaper, you have to factor in the original cost of the phone itself.

You will get a strong signal on a land line that is not affected by the weather, wind speeds, and the distance between towers. The number of users will not affect your ability to get through to your number. And reaching 911 in an emergency is far quicker and easier from your home phone.

While it makes sense, especially in these troubled economic times, to not pay for two telephone bills when you can make do with one mobile phone, there are other factors that are being ignored that most seriously need to be considered. What are cell phones doing to the environment, and how are they affecting your health?

Cell phones quickly become obsolete, and you are lucky if they last a couple of years. They are easily misplaced, lost, and stolen. Cell phone recycling centers may be fairly easy to find, but too few users bother to do so. Most cell phones become landfill.

These phones use toxic batteries that need frequent recharging. Most mobile phone users leave their chargers plugged in all the time, draining our natural resources even when the phone itself is not on the charger. A land line uses no energy when it is not being used, making it a lot friendlier to the environment. Don’t forget that the provider is using energy all the time to route calls over the network and towers.

Coltan, which is a metal ore mined in Africa is used in cell phones capacitors. The competition for buying this product has led to civil wars, smuggling, and the destruction of national parks in the Congo and other parts of Africa. Forests are destroyed to enable mining of the ore, displacing both humans and the endangered gorillas by eliminating their food sources in their natural habitats. It also makes it easier for poachers to get to the gorillas, a major cause of the 90% drop in the gorilla population of the Congo.

There is a lot of worldwide debate going on regarding the possibility that these phones are hazardous to your health. According to Mobile Telecommunications and Health, in a summary of the ECOLOG study for T-Mobile, 2000, it was found that the nervous systems of both humans and animals are affected by the magnetic fields emitted by cell phones.

In the Proceedings of the National Academy of Sciences, on August 24, 2009, Berenbaum noted that when cells removed from bees whose colonies and collapsed were studied, they were found to be full of fragments of ribosomal RNA. This indicated that genetic material was not being converted to functional proteins. It may be why the honey bee population is decreasing rapidly. The German research group, Verum, led by Franz Adlkofer offers cell phone usage as the reason for it.

Though mobile phones are still too new to accurately determine the long lasting effects of radio frequencies beyond doubt, there is some evidence that it can alter brain activity, and cause cancer and reproductive disorders. According to the WebMD Health News, on October 23, 2006, a link was found between men who wore their phones on their belts or in a pants pocket and a weaker sperm quality and even infertility. There have even been suggestions that cell phone use is more dangerous than smoking.

Interestingly, there are many who uphold that cell phones impair reaction time and memory. They believe that laws prohibiting holding a cell phone while driving will not alleviate the problem, since the mobile phones that are hands free emit more than ten times the interference to your brain wave activity!

In a study that was reported by Dr. Mercola, on September 22, 2007, he stated that researchers from the Weizmann Institute of Science in Israel found that changes in brain cells that led to cancer and cell division were triggered even by as few as five minutes on a cell phone.

As early as October 15, 1998, the BBC News reported that biologist Roger Coghill, believes that prolonged use of cell phones can cause fatigue, headache, dizziness, nausea, depression, and even arteriosclerosis. If calcium and serotonin levels are continuously disrupted by transmissions from a cell phone violence and even suicide can be the result.

Studies done all over the world showed a connection between increasing asthma related problems and deaths and heavy cell phone users. Heavy use triggers histamine production, which can cause bronchial spasms. Yes, more studies need to be done, but surely it is prudent to consider the implications.

Regarding land lines vs. cell phones, it would appear that, while mobile phones are wonderfully convenient, and have all kinds of extra gadgets, bells and whistles, it would be prudent to only use them when you are out and to continue the practice of using your land line when you are home.

Sources:

“Proceedings of the National Academy of Sciences”, August 24, 2009 (Berenbaum)

“Summary of the ECOLOG study for T-Mobile, 2000,” Mobile Telecommunications and Health
“WebMD Health News,” October 23, 2006
“Mercola.com,” September 22, 2007 (Dr. Mercola)
“BBC News,” October 15, 1998

Genetic Exam