ImmuneRegen BioSciences^® Reports Additional Positive Results From Study of Homspera^® in Treating Highly Pathogenic Influenza

New Data Reveal Homspera Reduced the Levels of Influenza Virus Particles in Infected Animals

SCOTTSDALE, AZ–(Marketwire – January 5, 2010) – ImmuneRegen BioSciences Inc.®, a wholly owned subsidiary of IR Biosciences Holdings Inc. (OTCBB: IRBS), today announced additional positive results from a recent study that evaluated its lead anti-influenza drug, Homspera®, in ferrets. Performed at a public University under the guidance of a world-renowned influenza expert, the study utilized a ‘real-world’ scenario of highly pathogenic influenza infection by a clade 2.2 H5N1 virus (A/Whooperswan/Mongolia/244/2005), and drug treatment beginning one day following influenza infection, coinciding with emergence of the first symptoms. These newly obtained data reveal Homspera treatment resulted in a decrease in viral titers (concentration of virus particles) at 5 days post-infection, indicative of an anti-viral effect of Homspera. Previously reported findings from this study revealed that Homspera treatment starting 1 day following influenza infection dramatically reduced symptoms of influenza infection and increased survival by 60% over infected controls.

“These new findings are exciting,” stated ImmuneRegen Vice President and Chief Scientific Officer Hal Siegel. “The reduction in viral titers in the Homspera-treated animals complements the reductions in symptom severity and increases in survival we announced previously and provides credence to the anti-viral mechanism of action of Homspera we’ve hypothesized. We previously showed reductions in nasal virus titer in cotton rats infected with seasonal influenza, and inhibition of the lung damage in mice and rats as is typically seen in influenza infection. These data from highly pathogenic influenza virus infection in ferrets provide further support that Homspera treatment reduces viral titers and improves recovery and survival in models of influenza infection. We are focused on ways to aggressively advance this program toward the clinic.”

About ImmuneRegen BioSciences, Inc.

ImmuneRegen BioSciences Inc., a wholly owned subsidiary of IR BioSciences Holdings, Inc. (OTCBB: IRBS), is a development-stage biotechnology company focused on the research, development and licensing of Homspera® and its derivatives. Homspera is an adult stem cell active compound that in study results has been shown to regenerate and strengthen the immune system and enhance wound healing. Viprovex®, a derivative of Homspera, is being developed for potential use against infectious diseases as a stand-alone or combination therapy and as a vaccine adjuvant. To advance its mission, the Scottsdale, Arizona based company has forged numerous study partnerships with industry and academic leaders, including Celgene Cellular Therapeutics, HemoGenix, Lovelace Respiratory Research Institute and Virion Systems. For more information, please visit www.immuneregen.com.

Statements about the Company’s future expectations, including statements about the potential use and scientific results for the Company’s drug candidates, science and technology, and all other statements in this press release other than historical facts, are “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933, Section 21E of the Securities Exchange Act of 1934, and as that term is defined in the Private Securities Litigation Reform Act of 1995. The Company intends that such forward-looking statements be subject to the safe harbors created thereby. These future events may not occur as and when expected, if at all, and, together with the Company’s business, are subject to various risks and uncertainties. The Company’s actual results could differ materially from expected results as a result of a number of factors, including the uncertainties inherent in research and development collaborations, pre-clinical and clinical trials and product development programs (including, but not limited to the fact that future results or research and development efforts may prove less encouraging than current results or cause side effects not observed in current pre-clinical trials), the evaluation of potential opportunities, the level of corporate expenditures and monies available for further studies, capital market conditions, and others set forth in the Company’s periodic report on Form 10-Q for the three months ended September 30, 2009 as filed with the Securities and Exchange Commission and report on Form 10-K for the year ended December 31, 2008 as filed with the Securities and Exchange Commission. There are no guarantees that any of the Company’s proposed products will prove to be commercially successful. The Company undertakes no duty to update forward-looking statements.

ImmuneRegen BioSciences® Summarizes Previous 9 Months of Advances as Homspera® Development Continues

SCOTTSDALE, AZ–(Marketwire – December 24, 2009) – ImmuneRegen BioSciences Inc.®, a wholly owned subsidiary of IR Biosciences Holdings Inc. (OTCBB: IRBS), ends 2009 with a significantly deeper understanding of the mechanisms underlying the demonstrated immunostimulatory activity of its development candidate Homspera®, and additional partners and advisory members who strengthen the Company’s efforts to bring Homspera into human testing.

Relationships forged over the past 3 calendar quarters have included those with investigators at the University of Rochester and the University of Pittsburgh, and the Company has entered into a joint licensing agreement with the latter in the area of cancer vaccine adjuvants. Both investigators have subsequently joined the Company’s Advisory Board and continue to support the Company’s research and grant submission activities.

With the support of those investigators as well as others, multiple grant submissions have been made to NIH and BARDA (Biomedical Advanced Research and Development Authority) , as well as through the Armed Forces Institute of Pathology and Walter Reed Army Medical Center through their Combat Wound Initiative Program. NIH-funded studies in areas related to Idiopathic Pulmonary Fibrosis, where the Company has filed its first IND (Investigational New Drug application) with the U.S. Food and Drug Administration (FDA), are being pursued at the University of Rochester. Also, additional studies in Avian Influenza (H5N1) as well as the currently pandemic Swine-originated Influenza A virus (H1N1) have shown Homspera’s efficacy in animal models in reducing the impact of infection with these potentially debilitating viruses.

Successful research studies have garnered the interest of potential partners, among them the world-renowned peptide manufacturerBachem Inc., at which Homspera is being manufactured in compliance with current Good Manufacturing Practice (cGMP) standards. This material will be used in the necessary safety studies that will be submitted to FDA to support advancement of Homspera into initial human testing, which is planned to begin in late 2010.

“We are quite pleased with the company’s progress over the past 12 months. Our team has worked extremely diligently to advance our work with Homspera with the hope this translates to great value for our shareholders,” said ImmuneRegen CEO Michael Wilhelm.

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About ImmuneRegen BioSciences, Inc.

ImmuneRegen BioSciences, Inc., a wholly owned subsidiary of IR BioSciences Holdings, Inc., (OTC BB:IRBS.OB – News) is a development-stage biotechnology company focused on the research, development and licensing of Homspera™ and its derivatives. Homspera is an adult stem cell active compound that in study results has been shown to regenerate and strengthen the immune system and enhance wound healing. Viprovex®, a derivative of Homspera, is being developed for potential use against infectious diseases as a stand-alone or combination therapy and as a vaccine adjuvant. To advance its mission, the Scottsdale, Arizona based company has forged numerous study partnerships with industry and academic leaders, including Celgene Cellular Therapeutics, HemoGenix, Lovelace Respiratory Research Institute and Virion Systems. For more information, please visit www.immuneregen.com.

Statements about ImmuneRegen’s future expectations, including statements about the potential use and scientific results for ImmuneRegen’s drug candidates, science and technology, and all other statements in this press release other than historical facts, are “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933, Section 21E of the Securities Exchange Act of 1934, and as that term is defined in the Private Securities Litigation Reform Act of 1995. ImmuneRegen intends that such forward-looking statements be subject to the safe harbors created thereby. These future events may not occur as and when expected, if at all, and, together with ImmuneRegen’s business, are subject to various risks and uncertainties. ImmuneRegen’s actual results could differ materially from expected results as a result of a number of factors, including the uncertainties inherent in research and development collaborations, pre-clinical and clinical trials and product development programs (including, but not limited to the fact that future results or research and development efforts may prove less encouraging than current results or cause side effects not observed in current pre-clinical trials), the evaluation of potential opportunities, the level of corporate expenditures and monies available for further studies, capital market conditions, and others set forth in ImmuneRegen’s periodic report on Form 10-Q for the three months ended June 30, 2008 and on Form 10-KSB for the year ended December 31, 2008 as filed with the Securities and Exchange Commission. There are no guarantees that any of ImmuneRegen’s proposed products will prove to be commercially successful. ImmuneRegen undertakes no duty to update forward-looking statements.

Contact:
Michael K. Wilhelm OR John N. Fermanis
ImmuneRegen BioSciences Inc.
Phone: 480-922-3926
E-mail: mwilhelm@immuneregen.com
E-mail: jfermanis@immuneregen.com

Would I like to see just how bad it is? Yes. So this morning I joined a police operation to ‘nab red light jumping cyclists’.Location posh Belgravia, junction of Ebury And Eccleston Streets, SW1, near Victoria Coach Station and Belgravia Police Station.

The concern here is the risk cyclists pose primary school children who have near misses crossing the road to reach Eaton Square School on the corner. Quite often cyclists sail straight through the red, without checking left or right.

I joined Sgt Herrett and PC Nigel Lewis who, with two other officers, was on a mountain bike. Two community officers were also on mtbs.

By 8.20 we had the junction staked out. Despite the six officers being highly visible in their bright yellow jackets the number of cyclists – and drivers – contravening traffic regulations had to be seen to believed.

Here’s what happened. The junction of Ebury St and Eccleston St is controlled by lights, but they have a rather short pedestrian phase. The junctions include a decent segregated cycle lane and advance stop lines. Eaton Square Primary School is on the corner. Opposite is La Bottega Delicatessen, where two guys taking coffee on the pavement outside watch the operation.

And we’re off.  At 08.20 and 10 seconds a gent in neat shirt and tie, pressed trousers with cycle clips and riding a fold up has jumped a light and is stopped by yellow-jacketed police officer.He’s given a talking to and when the officer fills out a form the rider makes mobile phone call.

Meanwhile, another rider in Ebury street is checked for crossing the white line, as a bunch of 11 riders all queue up at the red, eyes darting right and left, clocking the cops.

Then a woman runs the red and turns left. When stopped, she says I always do that there because it’s safe, but not at the next junction where it’s not safe. At 08.23. Another rider jumps the light to cross Eccleston Street – straight through until: “Oi”. Booked.

“On any given day between 8.30 and 10.30 I could book 20 or 30 here,” Sgt Herrett tells me, shaking his head and smiling at the wonder of it all. I make notes and look up to see two more cyclists stopped, being dealt with by four officers. While this is going on, two vans cross the junction and a woman cyclist makes a dash for it against the red, gets clean away.

The driver of a 4×4, which pulls into advance stop line box, finds a policeman knocking on his side window. Another talking to. Yet another car does same thing in Ebury Street, the driver looking indignant at being scolded, told to back up.

A spokeswoman for Eaton Square School was greeting children as they arrived. She told me: “We welcome the police doing this. But cyclists are only part of the problem. The green man phase on the lights is too short.”

I tell Sergeant Herrett and we both timed the light. When the green man lit up an adult started to cross and got halfway before losing the green. Imagine attempting that with a child in a pushchair, another dragging their heels?

There’s no end to the action. A girl on a smart Danish bike cut through on the wrong side of keep left sign and is stopped, given  a warning. She  looked bemused. Across the road another bloke is stopped – insisting it was green. It was red, the police tell him. The fella ribbed the police for not doing more important police work, like chasing robbers!

Police Sgt Herrett told me: “On any given day, between 8.30 and 10.30, I could book 20-30 cyclists…

“Local people tell us that there main concern is not with serious crime, but little things, like dog fouling, cycling on the pavement, through red lights, inconsiderate driving….”

The operation was timed out at 09.30. We went back to the police station for coffee, stopping on the way to enquire of a lorry driver whose truck was blocking a side road. He moved it a bit, created a bit more room and we strolled on.

PC Nigel Lewis read out the results of the morning’s work. “10 people were stopped and spoken to about contravening the red light and three people were given a fixed penalty.”

“Some people didn’t realise they had to stop on a white line, at the red light. Some went straight thro, made no attempt whatsoever to stop.”

Will policing cyclists at junctions become a routine? “We’ll be doing this monthly. We do on a daily adhoc basis when we see it. I imagine other (police) teams will do so as well.”

He says the hope is that by doing so, they will educate cyclists. “I think it’s a large proportion of cyclists doing this. In  a 10-hour shift, I will certainly see 50 doing it.

“At that particular junction, up until we started this quite recently, people would just ride straight through. Whole groups of 10 at a time, just going straight through.”

What about drivers stopping in the cycling box, they looked a bit knarked when you spoke to them. “Yes, because they are contravening the white line, the first one, the primary one, which means they then go into the cyclists place.

“And this is another reason why cyclists – they say – are getting ahead of them. So everyone is getting ahead of each other. Everyone is being pushed forward and forward and forward.”

One of the cyclists stopped this morning was Bill. He preferred not to give me his full name. Bill, 28, tee shirt and shorts, riding black Cannondale mtb with discs and slicks. What happened there, then? Why do you think you were stopped?

“Because the PC’s here I’m not going to say I went through a red light. To my eyes the light was green as I approached it. Someone was in the way so I rang my bell … and I was stopped, in my mind, slightly unfairly.” (Slightly?)  “I can understand why the police are doing this, there are some reckless cyclists out there. (But not me)

“In that instance I think it was in my favour but I’m not going to contest it.” So you say the light was green, the police say it was red. “Yep.”

“I think what the police are doing here is giving a short sharp shock to cyclists. I think it’s a good idea on the whole but in this (my) case I disagree with what they said.”

Bill, who rides eight miles to work and has done so every day since he was 18 (about 10 years) showed me his battle scars. Dark spot on arm, scars on legs. “Sent sprawling on the floor by a bad driver.”

So, to sum up. Clearly nearly everyone is in too much of a hurry. Men and women of all ages on all sorts of bikes. Fold ups, mtbs, hybrids, big wheel Dutch bikes, road bikes, fixies. Oddly enough, those stopped looked really intelligent. Clearly, they have thought this through and decided that red lights, white lines are a barrier to progress to be treated as advisory or ignored. Ditto everyone else on the road if they so much as cause him or her the slightest delay.  Inconveniences on the conveyor belt of life.

www.bicyclecomicjokes.blogspot.com

Also, I watch people driving IN the bike lane and often pull them over to tell them.

I am obnoxious, but they NEED to know. They MUST know and it is my job to tell them.

“However, current epidemiologic evidence from European populations for a role of these genes in CRC risk is scarce. In addition, it is not clear whether these genes may modulate CRC risk independently or by interaction with blood vitamin D concentration wild-type bb, the BB genotype of the VDR BsmI polymorphism was associated with a reduced risk of CRC [RR, 0.76; 95% confidence interval (CI), 0.59-0.98). The association was observed for colon cancer (RR, 0.69; 95% CI, 0.45-0.95) but not rectal cancer (RR, 0.97; 95% CI, 0.62-1.49). The Fok1 and CASR genotypes were not associated with CRC risk in thisand level of dietary calcium intake. A case-control study was conducted nested within the European Prospective Investigation into Cancer and Nutrition. CRC cases (1,248) were identified and matched to 1,248 control subjects. Genotyping for the VDR (BsmI: rs1544410; Fok1: rs2228570) and CASR (rs1801725) genes was done by Taqman, and serum vitamin D (25OHD) concentrations were measured. Conditional logistic regression was used to estimate the incidence rate ratio (RR). Compared with the study. No interactions were noted for any of the polymorphisms with serum 25OHD concentration or level of dietary calcium,” wrote M. Jenab and colleagues, World Health Organization.

The researchers concluded: “These results confirm a role for the BsmI polymorphism of the VDR gene in CRC risk, independent of serum 25OHD concentration and dietary calcium intake. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2485-91).”

Jenab and colleagues published their study in Cancer Epidemiology Biomarkers & Prevention (Vitamin D Receptor and Calcium Sensing Receptor Polymorphisms and the Risk of Colorectal Cancer in European Populations. Cancer Epidemiology Biomarkers & Prevention, 2009;18(9):2485-2491).

For more information, contact M. Jenab, IARC, Lifestyle & Cancer Group, WHO, 150 Cours Albert Thomas, F-69008 Lyon, France.

Publisher contact information for the journal Cancer Epidemiology Biomarkers & Prevention is: American Association Cancer Research, 615 Chestnut St., 17TH Floor, Philadelphia, PA 19106-4404, USA.

But questions remain on how aggressively to treat this cancer. The October issue of Mayo Clinic Women’s HealthSource lays out the issues and treatment choices.

DCIS occurs when abnormal cells multiply and form a growth within a breast’s milk duct. The cells are considered cancerous but have remained in place within the milk duct. “In situ” means “in place.”

More than 62,000 cases of DCIS are diagnosed in the United States annually, making it the most rapidly increasing type of noninvasive cancer. The majority of DCIS cases — about 90 percent — are discovered during routine mammograms. DCIS usually has no outward signs or symptoms.

DCIS isn’t considered life threatening, but, if not detected and treated, it can progress to a more serious form of invasive cancer. The best treatment approach is still being debated.

Lumpectomy or mastectomy: Most women with DCIS are good candidates for a lumpectomy, where a portion of breast tissue is removed. However, there’s a slightly higher chance that the cancer will return after a lumpectomy than after a mastectomy, which involves removal of breast tissue, skin, areola and nipple.

Mastectomy is commonly recommended when the area of DCIS is large or in several parts of one breast. Women may choose this option if they can’t have or don’t want radiation. Some women choose to have both breasts removed to prevent recurrence or a new cancer.

Radiation therapy: Radiation therapy is almost always recommended after a lumpectomy. Research has shown that it significantly reduces the chances that DCIS will recur or progress to an invasive form of cancer. Radiation is usually given five days a week for five to six weeks. Some research has questioned whether this approach is overly aggressive, particularly for older women with small, slow-growing tumors.

Tamoxifen therapy: Tamoxifen is a synthetic hormone that can be used to help treat or prevent the development of breast cancers. It’s approved as therapy after surgery or radiation to prevent recurrence of DCIS or a new cancer in the opposite breast. But, some doctors don’t recommend it because no evidence shows that tamoxifen improves long-term survival with this type of cancer. Taking tamoxifen can result in side effects such as hot flashes. And tamoxifen may increase the risk of blood clots and cancer of the uterus.

Researchers are attempting to better understand which women with DCIS are at highest and lowest risk of recurrence. That information would help in determining the most appropriate treatment. In the meantime, patients and their care providers should discuss the pros and cons of all treatment approaches.

More so than many illnesses, chronic fatigue syndrome (CFS) frustrates those who suffer from it and those close to them, due to its nebulous assembly of symptoms, along with continued controversies over its etiology, diagnosis, treatment and even its nomenclature. Now, the discovery of a familiar retrovirus in many CFS patients could bring new energy to the field—and fresh hope for more specific medical care.

Chronic fatigue is in part a misnomer. The syndrome often has more to do with immune system abnormalities than pervasive tiredness—although the two can go hand in hand. The symptoms range from exhaustion to muscle pain, giving CFS a reputation among some as a “wastebasket diagnosis”. The slipperiness of the syndrome is in part because “it’s diagnosed based on exclusion,” says Judy Mikovits, director of research at the Whittemore Peterson Institute for Neuro-Immune Disease in Reno, Nev., and co-author of research on the retrovirus findings published online today in Science. Doctors often apply the label if no other explanation can be found for a patient’s symptoms, which may be part of the reason it seems to pop up in everyone from overworked career women to continually sick children.

Roughly 17 million people worldwide are thought to have CFS, but given current diagnosis methods, the true number could be much higher or lower. Having a specific virus to look for would make for much more robust tests and possibly even be a step toward treatment. Mikovits’s team thinks they have found just such a candidate.

The xenotropic murine leukemia virus–related virus (XMRV), a type of gammaretrovirus, has recently been linked to strong cases of prostate cancer. Like CFS, this cancer involves changes in an antiviral enzyme (RNase L). The prostate cancer discovery, described last month by Ila Singh, an associate professor of pathology at the University of Utah in Salt Lake City, et al. in the Proceedings of the National Academy of Sciences (PNAS), along with a traditionally high incidence of cancer in CFS patients, got Mikovits and her team thinking: Would they find the same retrovirus in people with CFS?

After analyzing biological samples from more than 100 CFS patients for the retrovirus, two thirds of them were found to test positive for the virus—compared with 3.7 percent of 218 healthy volunteers who were screened.

To find the retrovirus, Mikovits and her team studied documented cases, such as CFS outbreaks in a symphony orchestra in North Carolina and in Incline Village, Nev. “We found the virus in the same proportion in every outbreak,” she says. But how are people getting this retrovirus? “Ila’s work shows that everyone’s susceptible,” Mikovits says of the PNAS paper by Singh that illustrates the link between prostate cancer and XMRV and shows that the virus is not linked to a genetic mutation.

Experiments in Mikovits’s lab proved that the retrovirus can be transmitted via blood by infecting healthy cells drawn from volunteers with material from XMRV-positive CFS patients. Mikovits hopes to soon have a better understanding of how the virus might be transferred in the real world, especially among families. If it, for instance, is like human T-lymphotropic virus type 1 (HTLV-1), it may be communicable through breast milk or if it’s like a herpes virus that is common in CFS, it may be passed along to offspring.

Precisely how this virus is related to chronic fatigue, however, remains a mystery. One of the problems with tracking down CFS is that it may not be a single ailment. “We think that the problem is that CFS is a collection of many, many different diseases even though it has similar symptoms,” says Brigitte Huber, a professor of pathology at Tufts University’s Sackler School of Graduate Biomedical Sciences in Boston. She and others suspect that the retrovirus may be unleashing other underlying conditions and viruses in the body.

“This new retrovirus may be able, through infecting human cells, [to] induce a transcription of an endogenous virus,” says Huber, who has been studying the presence of an ancient retrovirus (HERV-K18) dormant in most people but active in patients with CFS and multiple sclerosis. “We’ve already shown that Epstein-Barr virus can do exactly this.”

Even in their testing for the XMRV retrovirus, Mikovits says, “We could see a human endogenous virus at the same time” as XMRV. “There are a number of old diseases that seem to be rising at an infectious rate,” she says. Although this background noise of various viruses may be difficult to sort though, it brings clues to help researchers find the root cause of CFS. “It’s possible, downstream, that this will all feed into the same mechanism,” Huber says.

Even before the precise mechanisms are found, work toward finding treatment proceeds. Animal model testing is already underway, and Mikovits notes that her team is looking into some reverse transcriptase inhibitors that have already been approved by the U.S. Food and Drug Administration for other uses.

“Now we have a drug target and a marker,” Mikovits says. “If we treat them with a drug and they get better, we win.”

In the meantime, her team has been making quick strides toward a simple diagnostic test that doctors could use to check for the virus. Tests have been running smoothly in the lab, she notes, with some diagnostics companies already interested in the technology. She predicts a test will be available in less than six months. Mikovits adds that she is “excited that we will actually have some causes…rather than just building a better wheelchair.”

The 2009 Nobel Prize in Physiology or Medicine will go to three Americans who discovered telomeres, the genetic code that protects the ends of chromosomes, and telomerase, the enzyme that assists in this process, findings that are important in the study of cancer, aging and stem cells.

Announced this morning in Stockholm, the three geneticists—Elizabeth Blackburn, a professor of biology and physiology at the University of California, San Francisco, Carol Greider, a professor in the department of molecular biology and genetics at Johns Hopkins University School of Medicine in Baltimore, and Jack Szostak, a professor of genetics at Massachusetts General Hospital in Boston, who are all previous Scientific American authors—will split the award of 10 million Swedish kronor (about $1.4 million), along with the prestige and honor.

The work for which they received the award illuminated key aspects of the DNA replication process. As genetic material is copied from the chromosome during cell division, the whole DNA strand must be duplicated from end to end, otherwise, portions of genetic information will be lost. Until the 1980s, it was a mystery as to how the chromosomes could be reliably copied the whole way through without missing bits and pieces at the very end of each strand. Work completed by this year’s laureates demonstrated how, if parts of the end-cap telomeres were missing, DNA would eventually be shortened and cut off in the replication process.

Blackburn and Szostak, who had been studying the ends of chromosomes and minichromosomes respectively, met at a conference in 1980, after which they began collaborating. Two years later, they demonstrated in a paper published in Cell that the telomere sequence could be isolated, inserted into another organism and still serve the same function. Working with Blackburn, Greider helped in 1989 to identify the RNA-based telomerase—the enzyme that creates the crucial telomeres—in a paper published in Nature. (Scientific American is part of the Nature Publishing Group.)

The findings have since been applied in studies of aging, stem cells and cancer. Early research by Blackburn and Szostak showed that if telomeres were shortened it would lead to slower cell division and premature aging in yeast—and later in human cells. Since the early discoveries, defective telomeres have also been found to play a role in some forms of inherited anemia, as they affect the division of bone marrow stem cells. Cancer may also be in part a disease of telomere dysfunction. Given the rapid rate of division among cancer cells, they have been a more recent target of telomere research. Treatments taking advantage of this new knowledge are in clinical trails—the data from which are still outstanding—noted the Nobel Committee.

Although findings related to this research have been generating much excitement in the field of cancer research—as well as that of aging—those issuing the award note that much study remains to be done.  “Now it will be very important to figure out what is real, what is mechanism and what is statistical noise,” said Goran Hansson, a professor of cardiology at the Karolinska Institute and member of the Prize Committee, said during the announcement press briefing.

For the researchers, much of the early discoveries were driven by general curiosity about the workings of chromosomes and DNA replication. “We had no idea when we started this work that telomerase would be involved in cancer, but were simply curious about how chromosomes stayed intact,” Greider said in a statement after winning the Lasker Award in 2006 for some of the same research. “Our approach shows that while you can do research that tries to answer specific questions about a disease, you can also just follow your nose.”

Jeremy Berg, director of the National Institute of General Medical Sciences was pleased to see an example of general research chosen for the prize. He calls it “A great example of a curiosity-driven process.” The selection of telomeres research was not a surprise to many in the field, he says, as the research has “been moving along steadily under its own power…[and] everybody had known how important it was. “Nevertheless, there are some large questions that remain to be answered about the workings of telomeres and the associated telomerase—in addition to results from the ongoing clinical trials. From an evolutionary standpoint, for example, the similarities between telomerase and the reverse transcriptase in retroviruses and living telomereless knockout mice beg for further study, Berg notes.

This is the first time in the prize’s 108-year history that more than one woman has been awarded the prize in medicine in a single year. Only eight other women have won the medical Nobel. Last year’s Nobel Prize in Physiology or Medicine was shared by Harald zur Hausen—for his work discovering the link between the HPV (the human papilloma virus) and cervical cancer—and Francoise Barre Sinoussi and Luc Montagnier—for their joint discovery of HIV (the human immunodeficiency virus).

Editor’s note: We are posting the main text of this article from the February 1996 issue of Scientific American for all our readers because the authors have won the2009 Nobel Prize in Physiology or Medicine. Subscribers to the digital archive may obtain a full PDF version, complete with artwork and captions.

Often in nature things are not what they seem. A rock on the seafloor may be a poisonous fish; a beautiful flower in a garden may be a carnivorous insect lying in wait for prey. This misleading appearance extends to certain components of cells, including chromosomes—the strings of linear DNA that contain the genes. At one time, the DNA at the ends of chromosomes seemed to be static. Yet in most organisms that have been studied, the tips, called telomeres, are actually ever changing; they shorten and lengthen repeatedly.

During the past 15 years, investigation of this unexpected flux has produced a number of surprising discoveries. In particular, it has led to identification of an extraordinary enzyme named telomerase that acts on telomeres and is thought to be required for the maintenance of many human cancers. This last finding has sparked much speculation that drugs able to inhibit the enzyme might combat a wide array of malignancies. The research also opens the possibility that changes in telomere length over time may sometimes play a role in the aging of human cells.

Modern interest in telomeres and telomerase has its roots in experiments carried out in the 1930s by two remarkable geneticists: Barbara McClintock, then at the University of Missouri at Columbia, and Hermann J. Muller, then at the University of Edinburgh. Working separately and with different organisms, both investigators realized that chromosomes bore a special component at their ends that provided stability. Muller coined the term “telomere,” from the Greek for “end” (telos ) and “part” ( meros ). McClintock noted that without these end caps, chromosomes stick to one another, undergo structural changes and misbehave in other ways. These activities threaten the survival and faithful replication of chromosomes and, consequently, of the cells housing them.

It was not until the 1970s, however, that the precise makeup of the telomere was determined. In 1978 one of us (Blackburn), then working with Joseph G. Gall of Yale University, found that the telomeres in Tetrahymena, a ciliated, single-cell pond dweller, contained an extremely short, simple sequence of nucleotidesÑ TTGGGG —repeated over and over. (Nucleotides are the building blocks of DNA; they are generally denoted as single letters representing the chemical bases that distinguish one nucleotide from another. The base in T nucleotides is thymine; that in G nucleotides is guanine.)

Since then, scientists have characterized the telomeres in a host of creatures, includinganimals, plants and microorganisms. As is true of Tetrahymena, virtually all telomeres—including those of mice, humans and other vertebrates— contain repeated short subunits often rich in T and G nucleotides [see "The Human Telomere," by Robert K. Moyzis; SCIENTIFIC AMERICAN, August 1991]. For instance, human and mouse telomeres feature the sequence TTAGGG; those of roundworms feature TTAGGC. ( A stands for adenine, C for cytosine.)

In Search of Telomerase

The telomerase enzyme that is the object of so much attention today was found when comparisons of telomere length suggested such an enzyme could resolve a long-standing puzzle in biology. By the early 1980s investigations had revealed that, for some reason, the number of repeated subunits in telomeres differs between organisms and even between different cells in the same organism. Moreover, the number can fluctuate in a given cell over time. (Every species, however, has a characteristic average. In Tetrahymena, the average telomere has 70 repeats; in humans, 2,000.) The observed heterogeneity led Blackburn, who had moved to the University of California at Berkeley, Jack W. Szostak of Harvard University and Janis Shampay of Berkeley to propose a new solution to what has been called the end-replication problem.

The problem has to do with the fact that cells must replicate their genes accurately whenever they divide, so that each so-called daughter cell receives a complete set. Without a full set of genes, a daughter cell may malfunction and die. (Genes are those sequences of nucleotides that give rise to proteins and RNA, the molecules that carry out most cellular functions. The genes in a chromosome are scattered throughout the large expanse of DNA that is bounded by the chromosome’s two telomeres.)

In 1972 James D. Watson, working at both Harvard and Cold Spring Harbor Laboratory, noted that DNA polymerases, the enzymes that replicate DNA, could not copy linear chromosomes all the way to the tip. Hence, the replication machinery had to leave a small region at the end (a piece of the telomere) uncopied. In theory, if cells had no way to compensate for this quirk, chromosomes would shorten with each round of cell division. Eventually, the erosion would eliminate the telomeres and critical genes in some generation of the cells. These cells would thus perish, spelling the end of that cellular lineage. Clearly, all single-cell species subject to such shortening manage to counteract it, or they would have vanished long ago. So do germ-line cells (such as the precursors of sperm and eggs), which perpetuate the species in multicellular organisms. But how do such cells protect their telomeres?

For Blackburn, Szostak and Shampay, the observed fluctuations in telomere length were a sign that cells attempt to maintain telomeres at a roughly constant size. Yes, telomeres do shorten during cell division, but they are also lengthened by the attachment of newly synthesized telomeric subunits. The researchers suspected that the source of these additional repeats was some undiscovered enzyme capable of a trick that standard DNA polymerases could not perform.

When cells replicate their chromosomes, which consist of two strands of DNA twisted around each other, they begin by separating the double helix. The polymerases use each of these “parent” strands as a template for constructing a new partner. The special enzyme the workers envisioned would be able to build extensions to single strands of DNA from scratch, without benefit of an existing DNA template.

In 1984 the two of us, working in Blackburn’s laboratory at Berkeley, set out to discover whether this putative telomere-lengthening enzyme—telomerase —actually existed. To our delight, we found it did. When we mixed synthetic telomeres with extracts of Tetrahymenacells, the telomeres gained added subunits, just as would be expected if the proposed enzyme were present.

Within the next several years we and our colleagues learned much about how telomerase works. Like all polymerases and virtually all enzymes, it consists mainly of protein, and it requires that protein to function. Uniquely, though, it also includes a single molecule of RNA (close cousin to DNA) that contains the critical nucleotide template for building telomeric subunits. Telomerase places the tip of one strand of DNA on the RNA, positioning itself so that the template lies adjacent to that tip. Then the enzyme adds one DNA nucleotide at a time until a full telomeric subunit is formed. When the subunit is complete, telomerase can attach another by sliding to the new end of the chromosome and repeating the synthetic process.

Telomerase and Human Aging

In 1988 Greider left Berkeley for Cold Spring Harbor Laboratory, and later our groups and others found telomerase in ciliates distinct from Tetrahymena, as well as in yeast, frogs and mice. In 1989 Gregg B. Morin of Yale also discovered it, for the first time, in a human cancercell line—that is, in malignant cells maintained for generations in culture dishes. Today it is evident that telomerase is synthesized by nearly all organisms with nucleated cells. The precise makeup of the enzyme can differ from species to species, but each version possesses a species-specific RNA template for building telomeric repeats.

The importance of telomerase in many single-cell organisms is now indisputable. Such organisms are immortal in that, barring accidents or geneticists meddling in their lives, they can divide indefinitely. As Guo-Liang Yu in Blackburn’s research group demonstrated in 1990,Tetrahymena needs telomerase in order to retain this immortality. When the enzyme is altered, telomeres shrink and cells die. Blackburn’s team and others have similarly demonstrated in yeasts that cells lacking telomerase undergo telomere shortening and perish. But what role does telomerase play in the human body, which consists of a myriad of cell types and is considerably more complex than Tetrahymena or yeast?

Surprisingly, many human cells lack telomerase. Greider and others made this discovery in the late 1980s, when they pulled together the threads of research that investigators in Philadelphia had initiated more than 25 years earlier. Before the 1960s, human cells that replicated in the body were thought to be capable of dividing endlessly. But then Leonard Hayflick and his co-workers at the Wistar Institute demonstrated unequivocally that this notion was incorrect. Today it is known that somatic cells (those not part of the germ line) derived from human newborns will usually divide 80 to 90 times in culture, whereas those from a 70-year-old are likely to divide only 20 to 30 times. When human cells that are normally capable of dividing stop reproducing—or, in Hay- flick’s words, become “senescent”—they look different and function less eÛciently than they did in youth, and after a while they die.

In the 1970s a Soviet scientist named A. M. Olovnikov linked this programmed cessation of cell division to the end-replication problem. He proposed that human somatic cells might not correct the chromosomal shortening that occurs when cells replicate their DNA. Perhaps division ceased when cells discerned that their chromosomes had become too short.

We were unaware of Olovnikov ’s ideas until 1988, when Calvin B. Harley, then at McMaster University, brought them to Greider’s attention. Intrigued, Greider, Harley and their collaborators decided to see if chromosomes do get shorter in human cells over time.

Sure enough, most normal somatic cells they examined lost segments of their telomeres as they divided in culture, a sign that telomerase was not active. Similarly, they and Nicholas D. Hastie’s group at the Medical Research Council (MRC) in Edinburgh found that telomeres in some normal human tissues shrink as people age. (Reassuringly, Howard J. Cooke, also at the MRC in Edinburgh, had shown that telomeres are kept intact in the germ line.) These results indicated that human cells might “count” divisions by tracking the number of telomeric repeats they lose, and they might stop dividing when telomeres decline to some critical length. But definitive proof for this possibility has not yet been obtained.

Could the reduction of telomeres and of proliferative capacity over time be a cause of human aging? It is probably not the main cause. After all, cells can usually divide more times than is required in a human life span. Nevertheless, the functioning of the older body may at times be compromised by the senescence of a subset of cells. For instance, local wound healing could be impaired by a reduction in the number of cells available to build new skin at a site of injury, and a reduction in the number of certain white blood cells could contribute to age-related declines in immunity. Further, it is known that atherosclerosis typically develops where blood vessel walls have been damaged. It is conceivable that cells at repeatedly injured sites could finally “use up” their replicative capacity, so that the vessels ultimately fail to replace lost cells. Then damage would persist, and atherosclerosis would set in.

The Cancer Connection

Some investigators suspect that the loss of proliferative capacity observed in human cells lacking telomerase may have evolved not to make us decrepit but to help us avoid cancer. Cancers arise when a cell acquires multiple genetic mutations that together cause the cell to escape from normal controls on replication and migration. As the cell and its offspring multiply uncontrollably, they can invade and damage nearby tissue. Some may also break away and travel to parts of the body where they do not belong, establishing new malignancies (metastases) at distant sites. In theory, a lack of telomerase would retard the growth of tumors by causing continually dividing cells to lose their telomeres and to succumb before they did much damage. If cancer cells made telomerase, they would retain their telomeres and would potentially survive indefinitely.

The notion that telomerase might be important to the maintenance of human cancers was discussed as early as 1990. But the evidence did not become compelling until recently. In 1994 Christopher M. Counter, Silvia Bacchetti, Harley and their colleagues at McMaster showed that telomerase was active not only in cancer-cell lines maintained in the laboratory but in ovarian tumors in the human body. Later that year groups led by Harley, who had moved to Geron Corporation in Menlo Park, Calif., and by Jerry W. Shay of the University of Texas Southwestern Medical Center at Dallas detected telomerase in 90 of 101 human tumor samples (representing 12 tumor types) and in none of 50 samples of normal somatic tissue (representing four tissue types).

Even before such evidence was obtained, however, researchers had begun exploring some of the details of how telomerase might contribute to cancer. That work suggests telomerase probably becomes active after a cell has already lost its brakes on proliferation.

The first clue was an initially mystifying discovery made independently by Titia de Lange, now at the Rockefeller University, and by Hastie’s group. In 1990 these investigators reported that telomeres in human tumors were shorter than telomeres in the normal surrounding tissue—sometimes dramatically so.

Studies by Greider’s, Bacchetti’s and Harley’s laboratories explained why the telomeres were so small. The teams had induced normal cells from humans to make a viral protein causing cells to ignore the alarm signals that usually warn them to stop dividing. The treated cells continued to proliferate long after they would normally enter senescence. In most of the cells, telomeres shortened drastically, and no telomerase was detected; eventually death ensued. Some cells, however, persisted after their siblings died and became immortal. In these immortal survivors, telomeres were maintained at a strikingly short length, and telomerase was present.

These outcomes imply that telomeres in cancer cells are small because cells synthesize telomerase only after they have already begun to replicate uncontrollably; by then, the cells have presumably lost a substantial number of telomeric subunits. When the enzyme is finally activated, it stabilizes the severely clipped telomeres, allowing overly prolific cells to become immortal.

These findings and others have led to an attractive but still hypothetical model for the normal and malignant activation of telomerase by the human body. According to this model, telomerase is made routinely by cells of the germ line in the developing embryo. Once the body is fully formed, however, telomerase is repressed in many somatic cells, and telomeres shorten as such cells reproduce. When telomeres decline to a threshold level, a signal is emitted that prevents the cells from dividing further.

If, however, cancer-promoting genetic mutations block issuance of such safety signals or allow cells to ignore them, cells will bypass normal senescence and continue to divide. They will also presumably continue to lose telomeric sequences and to undergo chromosomal alterations that allow further, possibly carcinogenic mutations to arise. When telomeres are completely or almost completely lost, cells may reach a point at which they crash and die.

But if the genetic derangements of the pre-crisis period lead to the manufacture of telomerase, cells will not completely lose their telomeres. Instead the shortened telomeres will be rescued and maintained. In this way, the genetically disturbed cells will gain the immortality characteristic of cancer.

This scenario has generally been borne out by the evidence, although, once again, things may not be entirely as they seem. Some advanced tumors lack telomerase, and some somatic cells—notably the white blood cells known as macrophages and lymphocytes —have recently been found to make the enzyme. Nevertheless, on balance, the collected evidence suggests that many tumor cells require telomerase in order to divide indefinitely.

Prospects for Cancer Therapy

The presence of telomerase in various human cancers and its absence in many normal cells mean the enzyme might serve as a good target for anticancer drugs. Agents able to hobble telomerase might kill tumor cells (by allowing telomeres to shrink and disappear) without disrupting the functioning of many normal cells. In contrast, most existing anticancer therapies disturb normal cells as well as malignant ones and so are often quite toxic. Further, because telomerase occurs in numerous cancers, such agents might work against a broad array of tumors.

These exciting possibilities are now being actively explored by pharmaceutical and biotechnology companies. Nevertheless, a number of questions must be answered. For instance, researchers need to determine which normal cells (beyond the few already identified) make telomerase, and they need to assess the importance of the enzyme to those cells. If telomerase is crucial, drugs that interfere with it might in fact prove unacceptably toxic. The shortness of telomeres in certain tumor cells may obviate this problem, however. Telomerase- inhibiting agents might cause cancer cells to lose their telomeres and die well before normal cells, with their much longer telomeres, lose enough of their telomeres to suffer any ill effects.

Investigators must also demonstrate that inhibition of telomerase can destroy telomerase-producing tumors as expected. Last September, Harley, Greider and their co-workers showed that an inhibitory agent could cause the telomeres of cultured tumor cells to shrink; the affected cells died after about 25 cycles of cell division. Blackburn, now at the University of California at San Francisco, and her group have found, however, that cells sometimes compensate for the loss of telomerase. They repair their shortened ends by other means, such as by a process called recombination, in which one chromosome obtains DNA from another. If activation of alternative, “telomere-salvaging” pathways occurs frequently in human tumors, therapy targeted to telomerase would fail.

Studies of animals should help resolve such concerns. They should also help reveal whether inhibitors of telomerase will eliminate tumors in the living body and whether they will do so quickly enough to prevent cancers from injuring critical tissue.

To develop agents that will block telomerase in the human body, investigators must also have a sharper picture of exactly how the enzyme functions. How does it attach to DNA? How does it “decide” on the number of telomeric subunits to add? DNA in the nucleus is studded with all manner of proteins, including some that specifically bind to the telomere. What part do telomerebinding proteins play in controlling the activity of telomerase? Would altering their activity disrupt telomere elongation? Within the next 10 years we expect to learn a great deal about the interactions among the various molecules that influence telomere length.

Research into the regulation of telomere size could also yield benefits beyond new therapies for cancer. A popular approach to gene therapy for various diseases involves extracting cells from a patient, inserting the desired gene and then returning the genetically corrected cells to the patient. Frequently, though, the extracted cells proliferate poorly in the laboratory. Perhaps insertion of telomerase alone or in combination with other factors would temporarily enhance replication capacity, so that larger numbers of therapeutic cells could be delivered to the patient.

Modern research into telomeres has come a long way from the initial identification of repetitive DNA on the ends of chromosomes in a unicellular pond dweller. Elongation of telomeres by telomerase, initially considered to be merely a “cute” mechanism by which some single-cell creatures maintain their chromosomes, has proved, as ever, to be other than it seemed. Telomerase is, in fact, the predominant means by which nucleated cells of mostanimals protect their chromosomal end segments. And, now, study of this once obscure process may lead to innovative strategies for fighting a range of cancers.

In the early 1980s scientists would not have set out to identify potential anticancer therapies by studying chromosome maintenance in Tetrahymena. The research on telomerase reminds us that in studies of nature one can never predict when and where fundamental processes will be uncovered. You never know when a rock you find will turn out to be a gem.