Interview with Expert in Receptor Biology Dr. Robert Lefkowitz and Nobel Prize Winners Dr. Joseph Goldstein and Dr. Michael Brow

Expert in Receptor Biology Dr. Robert Lefkowitz joined JCI's Executive Editor Dr. Ushma Neill  in our studio for a conversation with Geneticists Dr. Joseph Goldstein and Dr. Michael Brown, as part of the Conversations with Giants in Medicine video series. Those videos, produced in collaboration with the Journal of Clinical Investigation and hosted on their Web TV, show interviews with Nobel Prize winners and renown scientists.

Robert Lefkowitz is known for his seminal discoveries in understanding G protein-coupled receptor function. He's a Professor of Medicine at Duke University and received the National Medal of Science in 2007.

Joseph Goldstein and Michael Brown won the Nobel Prize in Physiology of Medicine in 1985 for describing the regulation of cholesterol metabolism. Their findings led to a better understanding of the mechanism of action of statin drugs, the cholesterol-lowering compounds used by 16 million Americans. It is the most prescribed medications in the United States.

Goldstein is a member of the Boards of Trustees of the Howard Hughes Medical Institute and The Rockefeller University, and a member of the U.S. National Academy of Sciences.

Brown serves on the Prix Galien USA Committee, the equivalent of the Nobel Prize in his field.

In this interview, they talk about their careers and how they found their scientific inspiration. The discussion also focuses on the topic of mentoring and being a celebrity and the scientific world.

PWC Report Shows Decrease in Life Sciences Venture Capital Funding; Still Cause for Hope

A recent report released by PwC’s Pharmaceuticals and Life Sciences Industry Group indicates that life sciences venture capital funding has shrunk for the fourth straight quarter.

On medcitynews.com, contributor Arundhati Parmar writes that “the decline was 39 percent in amount invested and 22 percent in number of deals in the second quarter from the same quarter in 2011. Total money invested in the sector that includes biotechnology and medical devices was $1.4 billion in the second quarter and the number of deals fell to 174. What’s more, the results show a four quarter slide.”

He continues,

“Both biotech and medical device venture funding took a hit. A total of 84 deals brought in $800 million for the medical device industry, but the numbers represent drops of 11 percent in deal volume and 17 percent in amount invested year over year. Biotech took a much bigger hit with a 52 percent decline in funding to $697 million and a 30 percent drop in number of deals to 90 deals in the second quarter.” Read more at medcitynews.com.

However, there is still cause for hope. As global managing partner of the venture capital practice at PwC US Tracy T. Lefteroff explained,

“The pace of venture-backed exits we saw for life sciences companies during 2011 should encourage investors. If M&A activity picks up during the second half of this year, investors should continue to see a clearer path to returns, which potentially could attract more money to be invested in this sector.

“Additionally, the new Jobs Act could spur more confidential IPO filings, creating the opportunity for more exits. This act makes it easier for start-ups with under $1 billion in annual revenue to go public by relaxing Sarbanes-Oxley requirements for five years.”

He continued,

“Finally, the recently passed user fee legislation contains some incentives for companies to develop breakthrough therapies for infectious and rare diseases. These include extended market exclusivity for qualified infectious disease products and expedited FDA review for therapies that address unmet medical needs to treat rare and life-threatening diseases and conditions. Such incentives could pique the interest of investors in companies developing innovative products that might have a shorter path to market.”

Read the full report here. 

Nobel Prize Winning Scientists Brown and Goldstein Interviewed by Robert Lefkowitz at Film Annex

For the second episode of Conversations with Giants in Medicine, hosted by the Journal of Clinical Investigation's Ushma S. Neill and Howard Rockman, Film Annex Studios welcomed three of medicine’s most charismatic giants, Robert Lefkowitz, Joseph Goldstein and Michael Brown.

In this episode, Lefkowitz, Goldstein, and Brown interview each other about their backgrounds, how they got started in medicine, where they got their scientific inspiration from, how to be a good mentor, and how to deal with scientific celebrity. Goldstein and Brown together won the 1985 Nobel Prize in Physiology and Medicine for their discovery of the LDL cholestoral receptor and its role in the regulation of cholestrol metabolism. 

One of the interesting discussions revolved around the difference between being a physician versus being a scientist. The three talked about their first discoveries, their Eureka moments, their time at NIH, and the sense of wonder they felt, which led to a never-ending passion for science. 

Another remarkable topic that is discussed in the interview is the legendary, 40-year old scientific partnership between Goldstein and Brown. The duo talk extensively about how they met at the emergency room at Mass General when they were interns, their common interest in metabolism, and how they kept building on their relationship till this day. Lefkowtiz describes the partnership between Goldstein and Brown as a "remarkable mind-meld," and Brown says that he has the most priviledged existence, because every morning, Goldstein gives him a complete digestive of scientific literature from the night before.

The interview is fascinating and inspirational not only for those with scientific interests, but for anyone with a passion. In this 48-minute conversation, there's so much to learn about science, partnership, hard work, dedication, and curiousity.

-- Eren Gulfidan

DARPA Awards $3.8 Million Contract to CytoSorbents Corporation (CTSO)

CytoSorbents Corporation (OTCBB: CTSO) is a publicly-traded, critical care focused therapeutic device company using blood purification to treat life-threatening illnesses. Its purification technology is based on biocompatible, highly porous polymer beads that can actively remove toxic substances from blood and other bodily fluids by pore capture and surface adsorption. Each polymer bead contains millions of pores and channels that can be modified to remove substances as small as drugs, to substances as large as antibodies.

The Company has announced that it has been awarded a technology development contract worth up to $3.8 million by the Defense Advanced Research Projects Agency (DARPA). The contract would be over a period of five years as part of the company’s Dialysis-Like Therapeutics (DLT) program to treat sepsis, pending satisfactory achievement of key milestones. 

DARPA is the U.S. Department of Defense agency responsible for funding cutting-edge programs such as the internet, the global positioning satellite system (GPS), and robotic surgery. In this case, it is funding the development of a portable, artificially intelligent blood purification system that can detect and remove, in real time, substances that can contribute to sepsis, including cytokines, toxins, biowarfare agents, pathogens, and activated cells. The goal is to save the lives of injured warfighters and civilians afflicted with sepsis, where approximately one in every three patients die today, even with the best medical treatment.

Under the terms of this contract, CytoSorbents will develop next-generation broad-spectrum, porous polymers capable of removing cytokines, toxins and certain biowarfare agents from whole blood, with $1.5 million in funding designated for the first year, based upon the achievement of pre-determined milestones.

Dr. Phillip Chan, Chief Executive Officer of CytoSorbents, stated,

"We are delighted to officially begin working with DARPA on this exciting project and are honored to have had our unique core blood purification technology selected for funding. We are one of the industry leaders in the area of blood purification to treat sepsis and other critical care illnesses, with our first-in-class CytoSorb® cytokine filter currently approved and commercialized in the European Union. That being said, under this DARPA program, we are looking to significantly advance our polymer technologies to not only remove cytokines, but also a wide variety of toxins, and do so with little to no anti-coagulation in both high flow and microfluidic systems. The excessive production of cytokines, or 'cytokine storm,' is common in the worst forms of sepsis, and triggers massive inflammation that can lead to organ failure and infection -- the two leading causes of death in the ICU. Meanwhile, toxins produced by bacteria, viruses and other pathogens play an additional devastating role on the body, poisoning or killing cells, leading to widespread tissue destruction and worsened inflammation and sepsis. And the threat of a biowarfare attack with toxins such as ricin and botulinum remains a perennial concern. Our porous polymers are ideally suited to achieve the broad spectrum removal that is needed to counter most of these agents."

Dr. Chan continued,

"Because of the maturity of our technology, we are confident in our ability to meet DARPA's timetable for technology development and strict performance metrics. Over the past several months, we have also collaborated with some of the leading potential systems integrators, to include our technologies into their integration proposals, under a separately funded DARPA DLT solicitation. The role of the systems integrator is to put together the best detection, separation and predictive modeling technologies into a single blood purification system and guide it to human clinical trials within 4 to 5 years. These partnerships are mutually beneficial and will help to contribute to the success of the overall program."

Dr. Chan concluded,

"Just within the recent past, we have seen many high-profile cases of sepsis here in the U.S. including a young woman injured from a fall from a broken homemade zip-line who developed sepsis from a 'flesh-eating' bacterial infection, and a 12-year-old boy who died of unrecognized sepsis after cutting his arm during a basketball game. Unfortunately, these cases are not unusual, with thousands of patients dying silently from sepsis every day in hospitals around the world. The number of sepsis cases in the U.S. alone has doubled in the past decade, and continues to climb due to increased antibiotic resistance, a high rate of hospital-acquired infections, and an aging baby boomer population that is prone to infection due to age, diseases such as diabetes and cancer, and the use of implantable medical devices such as artificial hips and knees. There are currently no approved therapies to treat sepsis in the U.S. or in the European Union. Therapies like CytoSorb® and the device being proposed by DARPA are sorely needed and we are proud to be part of this worthy effort."

Read the full press release here. 

Clinical relationships: The Film Annex and The Journal of Clinical Investigation

The Journal of Clinical Investigation is a top-tier venue for critical advances in biomedical research. The JCI combines a 2011 Impact Factor of 13.069 with immediate free access to its research articles to produce an ideal venue for authors seeking the widest possible audience for their most important work. The journal is headed by Editor in Chief Dr. Howard Rockman and an Editorial Board of peer scientists at Duke University Medical Center, the University of North Carolina, Duke-NUS, and Sanford-Burnham Medical Research Institute whose depth and experience ensure fair and competent peer review.

In addition to the high-impact research that the JCI has always published, the journal accepts submissions in two other categories: Brief Reports and Technical Advances (see list). Brief Reports are discrete, highly significant findings reported in a shorter format. Technical Advances report new and important research tools and techniques with broad impact; these submissions should include application of the technique to a specific question relevant to understanding or treating a disease.

In this film, Ushma Neil talks about its growing relationship with Film Annex and JCI's "Conversations with Giants in Medicine."

The Crushing Cost of Care @ The Wall Street Journal (CTSO)

In a recent Wall Street Journal article, journalists Janet Adamy and Tom McGinty tell the story of Scott Crawford, a young father who had been healthy his whole life until he was diagnosed with idiopathic dilated cardiomyopathy at age 26. That diagnosis signalled the beginning of a long, painful journey through medication, transplants, surgery, therapy, amputation, and nearly chronic pain, which ended with his death in late 2009. Estimates from Johns Hopkins Hospital in Baltimore, where Mr. Crawford was receiving treatment, put the cost of his Medicare claims at the staggering total of $2.7 million, $766,919 of which remains unpaid. Read the full article here. 

Adamy and McGinty use Mr. Crawford's story as a springboard to discuss Medicare and the shockingly high cost of care in the US. However, something very compelling stands out in Mr. Crawford's story: The frequent mention of sepsis, defined as an overzealous response to a severe infection, as a leading culprit in his downward spiral.

For example, deputy administrator and director for Medicare Jonathan Blum commented that for Mr. Crawford, "a lot of the costs were driven by complications that could have been avoided," citing an early infection as an example. Additionally, after 2 heart transplants, Mr. Crawford developed a severe infenction and had to have his leg above the knee amputated. Shortly before he died, sepsis was again identified as the condition that was overwhelming his system. 

Mr. Crawford isn't the only patient who could have been spared years of pain by catching and treating sepsis early. According to a 2011 brief by the CDC, "an estimated $14.6 billion was spent on hospitalizations for septicemia [In 2008], and from 1997 through 2008, the inflation-adjusted aggregate costs for treating patients hospitalized for this condition increased on average annually by 11.9%. Despite high treatment expenditures, septicemia and sepsis are often fatal. Those who survive severe sepsis are more likely to have permanent organ damage, cognitive impairment, and physical disability. Septicemia is a leading cause of death." Read more here. 

When a person develops sepsis, the body frequently overresponds to the threat by producing a massive excess of cytokines, called cytokine storm. While cytokines normally help the body cope with injury, a cytokine storm "is toxic to the body, driving severe inflammation and a cascade of dangerous changes in the body that cause cell damage, organ failure and often death. It follows that reduction of cytokine storm may limit this cascade of events, thereby reducing the severity of illness, and helping patients recover and survive. Until recently, however, there were no effective ways to reduce cytokine storm broadly."

CytoSorbents Corporation (OTCBB: CTSO) is one company working on a solution, that has until recently has not been possible to do.  Its flagship product, CytoSorb®, is a blood filtration cartridge that works to modulate the immune system by removing excess cytokines in critically-ill patients.  If left unchecked, these inflammatory toxins can lead to deadly inflammation, multiple organ failure, immune dysfunction, and often death in common illnesses such as sepsis, trauma, burn injury, acute respiratory distress syndrome, and pancreatitis. CytoSorb® has demonstrated statistically significant reductions in mortality in septic patients at high risk of death and is now available for sale in Germany for the treatment of critical care illnesses with availability in other E.U. countries planned in the future, assuming adequate and timely funding, and continued positive results from its clinical studies. Read more at cytosorbents.com. 

Unnoticed infection turns unstoppable @ The Irish Times (CTSO)

Rory Staunton was a happy, friendly 12-year old boy who wanted to be a pilot when he grew up. He lived with his parents and younger sister in New York. He was quite healthy until he dove for a basketball in his school gym one day and cut his arm. The next day, he was feverish and vomitting. Two days later, he was dead.

Rory died from Strep A Toxic Shock Syndrome, a commonly misdiagnosed condition. In The Irish Times, journalist Jim Dwyer chronicles the dismaying story of how the severity of Rory's condition could escape the notice of his pediatrician as well as the emergency room at NYU Langone Medical Center. 

He writes,

On the first day of his illness, "partially camouflaged by ordinary childhood woes, Rory’s condition was, in fact, already dire. Bacteria had gotten into his blood, probably through the cut on his arm. He was sliding into a septic crisis, an avalanche of immune responses to infection from which he would not escape."

The rest of the story includes doctor miscommunications, inaccurate diagnoses, and even a 12-minute gap between symptom observation and doctor recommendation that could have caught the sepsis early:

"A screening tool in the Stop Sepsis program, used when a patient first arrives in the emergency room, calls special attention to a person with three symptoms of a possible eight. At the hospital, Rory showed two: he was breathing 20 times per minute and his pulse was 143. 

Two hours later, though, he had three: his temperature had risen to 102, his pulse was 131 and his respiration rate was 22. But by the time those vital signs were recorded, at 9.26pm, they had no bearing on his treatment. In fact, the doctor had already decided that Rory was going home. Rory’s 'ExitCare' instructions, signed by his father, were printed 12 minutes before those readings." Read more at The Irish Times. 

Rory's story serves as yet more evidence that sepsis is a looming health problem for the country, and also that it remains underdiagnosed. In addition to correctly diagnosing the illness, it is also crucial to ensure that solid treatment options are available once sepsis is diagnosed. CytoSorbents Corporation (OTCBB: CTSO) is one company making gains in this space. CytoSorbents Corporation is a critical-care focused therapeutic device company using blood purification to modulate the immune system and fight organ failure in life-threatening illnesses, including sepsis. CytoSorbents is developing novel and advanced blood purification therapies designed to actively prevent, mitigate, or reverse the development of organ failure and infection, thereby potentially reducing illness severity and helping patients to heal and recover faster. Ultimately the goal is to improve patient outcome and save healthcare costs. 

CytoSorbents’ purification technology is covered by 29 issued patents and is based on biocompatible, highly porous polymer beads that can actively remove toxic substances from blood and other bodily fluids by pore capture and adsorption. The technology has been selected for funding by both the U.S. Army and DARPA (Defense Advanced Research Projects Agency) in a Phase I SBIR grant for trauma, and DARPA’s “Dialysis-like Therapeutics” program for the treatment of sepsis, respectively. The technology is also the basis of the Company’s two lead programs, CytoSorb™ and HemoDefend. Read more at cytosorbents.com.

The Coming “Sepsis Boom" and How to Avert it (CTSO)

In the Medical Labratory Observer, contributor Mark H. Oltermann, MD, writes that due to a variety of factors, the generation known as "the Baby Boom is about to become the Sepsis Boom."

He explains,

"We're seeing an unmistakable increase [in sepsis rates] among all age groups, but particularly among the elderly. There are many factors contributing to this trend. Three of the most dynamic are the aging population, underlying conditions that lead to immunosuppression, and the increase in antibiotic resistance."

Coinciding with the increasing rates of sepsis among the elderly is the actual increasing number of elderly Americans relative to other age groups: 

"We are on the front end of an enormous bulge in the population of Americans who will be 65 and older. The first U.S. Baby Boomers [turned] 65 in 2011, inaugurating a rapid increase in the older population during the 2010 to 2030 period. The older population in 2030 is projected to be double that of 2000, growing from 35 million to 72 million...

In fact, this study shows that the trend of the older population growing at a faster pace than the total population will accelerate dramatically from 2010 to 2040. Whereas the total population of the U.S. is expected to increase by nearly 20% in the two decades between 2010 and 2030, the population of U.S. residents 65 years of age and older will increase at nearly four times that rate (78%) in the same time period."

The bottom line is this: In 2030, nearly 1 in 5 Americans will be aged 65 and older, compared with about 1 in 8 in 2010. Of those elderly Americans, many more will be at risk for sepsis than would have been in previous generations. 

However, not all hope is lost. Oltermann proposes 2 changes to be made that could stem the tide of sepsis cases in the coming years:

"The first [is] to require hospitals to make sepsis one of the core measures that would push for standardizing protocols and reporting of mortality rates. Until that happens, sepsis will be one of hundreds of problems competing for scarce resources and priority status. The second step toward improvement would be to adopt screening tests for sepsis such as lactate and procalcitonin as standard blood tests for all elderly patients who are admitted to the hospital. As noted earlier, this population is at increased risk, and they also may not always display the classic SIRS (systemic inflammatory response syndrome) criteria because of comorbid conditions and concomitant medications." Read more here. 

Though not mentioned in the article, a third step to take would be to ensure that there are solid, reliable treatment options available to help treat sepsis once it is diagnosed. In this space, CytoSorbents Corporation (OTCBB: CTSO) is one company making remarkable gains. CytoSorbents Corporation is a critical-care focused therapeutic device company using blood purification to modulate the immune system and fight organ failure in life-threatening illnesses, including sepsis. CytoSorbents is developing novel and advanced blood purification therapies designed to actively prevent, mitigate, or reverse the development of organ failure and infection, thereby potentially reducing illness severity and helping patients to heal and recover faster. Ultimately the goal is to improve patient outcome and save healthcare costs. 

CytoSorbents’ purification technology is covered by 29 issued patents and is based on biocompatible, highly porous polymer beads that can actively remove toxic substances from blood and other bodily fluids by pore capture and adsorption. The technology has been selected for funding by both the U.S. Army and DARPA (Defense Advanced Research Projects Agency) in a Phase I SBIR grant for trauma, and DARPA’s “Dialysis-like Therapeutics” program for the treatment of sepsis, respectively. The technology is also the basis of the Company’s two lead programs, CytoSorb™ and HemoDefend. Read more at cytosorbents.com.