The bane of biofilms: Bacteria bound together in a protective matrix tend to resist viral attack. But Lu’s virus produces an enzyme that breaks up these biofilms. When it infects the bacteria on the biofilm’s surface, they burst and release viruses that infect those underneath, soon exposing even deeply embedded bacteria to infection. Graphic Credit: Bryan Christie Design

MIT Technnology Review, August 25, 2010 — At Harvard Medical School, many of Timothy Lu’s patients were being attacked by carpets of microbial goo. They had “really bad infections,” Lu says. “Patients with cystic fibrosis, people getting infections in their catheters. All caused by biofilms.”

Lu, age 29, who is now an assistant professor at MIT, began researching how to destroy biofilms. But unlike those who had previously attacked the problem, he took advantage of the new tools of synthetic biology. He engineered a type of virus, known as a phage, to destroy biofilms and sabotage their defenses against antibiotics. His accomplishment could produce synthetic biology’s first big commercial success by attacking the biofilms that infest industrial equipment.

When bacteria settle on a surface, they spew out molecules that bind the entire population together and cover it in a protective shield. Bacteria in these biofilms are up to 500 times more resistant to antibiotics than free-floating microbes are. Normally, viruses have a hard time penetrating the dense layers of a biofilm. But Lu stumbled across an enzyme produced by oral bacteria that can break up biofilms. He inserted the gene for the enzyme into a phage called T7 so that when the virus infects a microbe, it makes as much of the enzyme as possible.

When the engineered T7 is unleashed on a biofilm, it invades the top layer of bacteria. These bacteria soon burst open, spilling out enzymes and new phages. Aided by the enzyme, the viruses then penetrate the next layer of bacteria, repeating the cycle until the biofilm is destroyed. Lu and his colleagues have also found other ways to turn phages into effective weapons against biofilms, such as creating versions that can shut down the genes that bacteria use to defend themselves against antibiotics.

Last year Lu cofounded Novophage (now called Ascendia Biotechnology) to develop commercial applications for the phages. The company is initially concentrating on biofilms that Lu says can corrode water pipes and block heat transfer in heating and cooling systems, decreasing energy efficiency by up to 80 percent. Conventional industrial attempts to deal with biofilms have involved scrubbing pipes, applying chemicals, or exposing the films to ultraviolet light, but these treatments are not very effective, can damage piping, and are toxic to humans and the environment. A small injection of phages into a water pipe, however, could clean an entire system, with the phages replicating themselves as they consume the biofilm. –Carl Zimmer

The bane of biofilms: Bacteria bound together in a protective matrix tend to resist viral attack. But Lu’s virus produces an enzyme that breaks up these biofilms. When it infects the bacteria on the biofilm’s surface, they burst and release viruses that infect those underneath, soon exposing even deeply embedded bacteria to infection.
Credit: Bryan Christie Design

Visit Dr.Timothy Lu’s lab to see how he destroys biofilms using engineered viruses.

Today – Genzyme Partners With Isis

FORBES.com, 01.09.08 – Genzyme will pay $325 million upfront — and as much as $1.9 billion — for worldwide rights to the cholesterol drug being developed by Isis Pharmaceuticals. Isis will keep a share of at least 30% of the profits, or more if sales are good. I reported that a deal between the companies looked likely in November.

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Back in Nov 2007 Genzyme Eyes Isis Drug

FORBES.com, by Matthew Herper, 11.09.07 – Isis Pharmaceuticals, developer of a promising anti-cholesterol injection that produces unprecedented drops in heart-attack causing gunk in the blood, has said it needs to sign up a marketing partner before beginning a big trial next year.

The obvious choice would be any of the drug giants who dominate the $28 billion market for cholesterol-lowering drugs. Pfizer, for one. Merck. Maybe AstraZeneca. But a surprising entrant is taking a long, hard look at Isis’ drug, previously known only as 301012 and now called mipomersen. It’s Genzyme, the biotech giant best known for selling very expensive treatments for rare and deadly genetic diseases.

Cambridge, Mass.-based Genzyme has approached cardiologists with questions about the drug’s prospects, and that the biotech giant, which has sales of $3.2 billion and a market capitalization of $20 billion, seems to be taking a keen interest in mipomersen. These doctors say Genzyme has discussed mipomersen’s prospects with them at length.

Isis says it is talking to lots of potential partners, but can’t comment on whether it is talking to any particular company. Genzyme said it would not comment on speculation about marketing deals.

But a Genzyme-Isis tie up to distribute mipomersen makes a great deal of sense. For one thing, mipomersen will at first be aimed squarely at the kind of market Genzyme understands best: an inherited genetic disease. And both companies are on the prowl for a partner. Isis needs one in order to start a large and expensive clinical trial testing its drug in patients who have high cholesterol that is not caused by a genetic defect.

Genzyme, for its part, has made acquisitions a key part of its growth strategy, with sales from products bought in from the outside generating 38% of total revenue in 2006, not to mention 50% of revenue growth, according to a research note by biotech analyst Geoffrey Porges at Sanford C. Bernstein. He counts 15 major deals going back to 1997, and he expects acquisition to remain a “core strategy.” But Porges doesn’t think Genzyme will want to spend on another major acquisition before the second half of 2008.

Thursday, Isis announced trials that could get mipomersen approved in the rare genetic disease familial hypercholesterolemia (FH). The worst form, caused by having two bad copies of a particular cholesterol gene, afflicts only a few hundred people. Their cholesterol levels can soar to six times the normal level and cause heart attacks in patients who are in their 20s.

Some 600,000 Americans have the more common form of FH, which is caused by a single bad copy of the cholesterol gene and causes levels of cholesterol that are just above the upper limit of normal. A study of both kinds of FH could be completed and filed with the U.S. Food and Drug Administration sometime next year.

Genzyme is used to selling drugs to small groups of patients for quite a lot of money. It has become one of the biggest biotech firms thanks to a series of rare diseases. Cerezyme, Genzyme’s first drug, treats a disease that afflicts fewer than 10,000 patients globally. Yet it generated $1 billion in total sales last year. Three other medicines sold by the company treat diseases that occur in just a few thousand people.

This model is so successful it is often imitated. Biomarin and Alexion have launched drugs for orphan diseases. Amicus and Shire teamed today to address some of the same markets that Genzyme targets. But Genzyme has also been moving into broader markets. The drug Renagel, for kidney dialysis, brings in $500 million a year. It already sells a drug to treat FH, Cholestagel, in Europe.

But Isis would offer Genzyme a bigger opportunity: a chance to launch a drug into a far broader market. One reason Isis needs money is the company plans to launch a study next year in patients with garden-variety high cholesterol. This study will need to be far bigger and more expensive than one in patients who suffer from FH. And while existing medicines like Lipitor, Vytorin and Crestor aren’t enough for some FH patients, they work well for most patients with run-of-the-mill high cholesterol.

There’s no guarantee that just because Genzyme is looking at Isis that it will come through with a deal. Another partner could swoop in and sign up marketing rights to mipomersen. But the companies fit nicely. Food for thought as Isis prepares to hold an analyst meeting in New York on Nov. 13.

Target Health Inc. is proud to be a contributor to The Millennium Villages project, supported by The Earth Institute at Columbia University, Millennium Promise, the United Nations Development Programme, and the UN Millennium Project. Columbia University’s Professor Jeffrey Sachs MD is the Head of The Earth Institute.

NEW YORK, June 15, 2007 – A new initiative from Columbia University Medical Center will be the first to target chronic oral health problems in sub-Saharan Africa, where the vast majority of chronic diseases are left undetected and untreated. The initiative is the result of an anonymous $1.5 million gift to support the Millennium Villages, which aims to fight extreme poverty and related challenges such as disease, hunger and lack of access to water and sanitation though scientifically sound and sustainable interventions. A third of the gift will be devoted to supporting the oral health program.

Dr. Syrop in Ethiopia

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Dr. Steven Syrop and a patient in Koraro, Ethiopia

Chronic diseases will soon become the leading cause of health problems in the developing world, and oral health conditions are one of the most common chronic disorders, according to the World Health Organization. Initial Columbia research in the village of Koraro, Ethiopia, found that more than half of the population complained of oral pain. The generous donation will fund the first extensive initiative, led by Columbia’s College of Dental Medicine, to directly target oral health problems in sub-Saharan Africa with a sustainable prevention and treatment program.

“Oral health is important to total health, so it’s essential that efforts to improve the lives of impoverished communities include a dental component,” said Ira Lamster, DDS, dean of the College of Dental Medicine at Columbia University Medical Center. “The faculty and students of Columbia’s College of Dental Medicine are committed to addressing the global epidemic of chronic oral health problems through treatment and prevention programs.”

“There is currently no access to dental care whatsoever in the remote villages of the world,” said Steven Syrop, DDS, associate clinical professor of dentistry at the College of Dental Medicine, who is leading the dental component of the Millennium Villages. “There are only 48 dentists in the entire country of Ethiopia, and most are in the capital, Addis Ababa. We’re going to bring dental care to villages where there are no dentists.”

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Dental student Jeff Laughlin and Dr. Syrop in Koraro, Ethiopia

The health component of the Millennium Villages grew out of the United Nations Millennium Project and the World Health Organization Commission on Macroeconomics and Health, both of which showed the direct link between improving public health and economic growth. Those reports explained that health improvements can only happen through a broad range of inter-related public health reforms.

The Millennium Villages project, supported by The Earth Institute at Columbia University, Millennium Promise, the United Nations Development Programme, and the UN Millennium Project, currently includes 12 sites in 10 sub-Saharan countries. It reaches more than 400,000 people with plans to increase its reach over time. The project empowers the local health care sector by supporting basic health interventions, building or upgrading clinics, and expanding the pool of community or village health workers. The participating villages are integral partners in the project and take responsibility for the interventions.

In addition to the oral health initiative, the new funding will support Columbia-led interventions to address chronic cardiovascular and mental health disorders in the region.

The dental component of the project is the result of research by Dr. Syrop and his team, who traveled to Koraro, Ethiopia, in the fall of 2006 to assess the oral health situation in the village of 5,100 people. In addition to the common complaint of oral pain, the team found a high incidence of hardened plaque (calculus) and gingival bleeding. Ninety-five percent of the people they examined had significant dental erosion because of the presence of sand in their food as a result of the arid environment and lack of water for rinsing crops.

“We were surprised by the extent of the oral health crisis in Ethiopia,” said Dr. Syrop. “In an area where the population has little access to sugary food and fermentable carbohydrates, we didn’t expect the problem to be as bad as it is. Developing a sustainable oral health program is an essential ingredient to improving the lives of these people.”

Teams of five or so Columbia faculty, staff and students will travel this fall to sub-Saharan countries, including Tanzania, Rwanda and Senegal, to collect data and assess the population’s oral health needs. They will use the data to develop a program for three or four villages initially, and then ultimately incorporate oral health as an integral component of improving health care at all of the Millennium Village sites.

The Columbia teams will train local health care workers to provide basic essential dental care, including extractions and control of infections. Additionally, the teams will introduce a comprehensive prevention program in the schools and the overall community by working with local teachers to develop a curriculum that is appropriate and sustainable for the individual village. They also will develop a prevention program to educate mothers about caring for the oral health of their young children.

“Treating and preventing oral health problems is one spoke in the wheel of improving conditions in sub-Saharan Africa,” said Dr. Syrop. “By improving their health, we enable this population to be more productive, helping them to improve their economic situation and lift themselves out of poverty.”

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Columbia University Medical Center provides international leadership in pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, nurses, dentists, and public health professionals at the College of Physicians & Surgeons, the College of Dental Medicine, the School of Nursing, the Mailman School of Public Health, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. www.cumc.columbia.edu

Target Health Inc. continues to donate $$ to Millennium Promise, an organization pledged to wipe out
global poverty by the year 2020. Millennium Promise was created by Jeffrey Sachs, head of The
Earth Institute at Columbia University and in partnership with the United Nations. Target Health urges readers to contribute, even $7 which will buy mosquito netting for one bed, and help to fight malaria in that way.