Bird flu: to fear and not to fear

I find it frightening when new strains of bird flu emerge somewhere in the world. Perhaps it's the combination of having two boys, knowing enough science to realize that a global pandemic is possible and having seen too many disaster movies like Contagion, Children of Men and Outbreak.

The Wall Street Journal reports that, as of last Saturday night, there were 120 confirmed cases of the latest strain of bird flu, H7N9, which has caused 23 deaths so far in mainland China. Last week, the virus spread for the first time outside of the Chinese mainland, with one case diagnosed in Taiwan. The virus is probably just a few small changes away from becoming a global threat, and yet the chances of that happening are very small. It makes for an odd mix of comfort and dread.

The Mix asked Ming Luo, Ph.D., professor in the Department of Microbiology within the UAB School of Medicine, to answer some common questions about bird flu, and about why its jump from birds into humans makes it dangerous. He also updated us on his work seeking to design new drugs against flu viruses. Bottom line: a vaccine for the new bird flu would take 6-10 months to get ready, and new classes of antiviral treatments are years away. Researchers will probably one day come up with a vaccine that protects us against all flu viruses, but until then I get jumpy as each strain emerges.

Q. Why are bird flu viruses so deadly when they jump into humans?

A. When humans are infected by a virus from another species, the human immune system has had no chance to develop any immunity against it, said Dr. Luo. Our immune cells do not recognize the new invader,and so cannot quickly ramp up a massive counterattack against them. The new flu virus is also dangerous because it appears to make copies of itself very quickly once inside human cells, and to cause more severe lung damage than does a typical flu virus.

Q. What are the chances that the new virus becomes a global pandemic?

A. This new H7N9 flu virus is closer to a human flu virus than all previously known avian flu viruses, which makes it easier for the virus to jump from birds to humans, Dr. Luo said. Should a few more mutations, small random genetic changes, occur in the virus, it could result in a virus that is passed from person to person worldwide. The last such pandemic happened in 1918. That said, the spread of current H7N9 virus has largely ceased, or has at least greatly slowed down. In its current form, it is very unlikely to become transmissible from human to human, Dr. Luo said.

Q. Why are poultry versions of influenza viruses spreading now as opposed to 20 years ago?

A. Researchers see more cases of human infections by avian flu viruses because of increased density of the human population, more global travel and more consumption of live poultry in large cities in places like China.

Q. How would you rate the current government/health care surveillance systems designed to catch and isolate new cases of new flu viruses to prevent their spread?

A. The global surveillance system worked very efficiently in this latest case. Within weeks of the first infection, the new H7N9 virus was identified, and the information was shared globally so that any new case could be identified around the world. Authorities in places like Hong Kong are shutting down and sterilizing live poultry markets, and health authorities are watching for and isolating cases.

Q. What kind of birds are spreading the virus to humans?

It looks like chickens as opposed to migrating birds, which are often the vectors that spread viruses through poultry populations.

Q. What advances have been made in the field that promise to deliver new treatments in time to prevent an influenza pandemic?

A. To develop a H7N9 vaccine will take 6-10 months, said Dr. Luo. There is always a long delay in developing a flu vaccine against a new strain. Preliminary efforts are underway to develop a universal flu vaccine, but it may take years.

A. Antiviral drugs will, in the future, represent another effective alternative to prevent and treat flu infection. Preliminary tests showed that this H7N9 virus is sensitive to currently available drugs in the class called neuraminidase inhibitors, including Tamiflu, Relenza and Peramivir, the latter of which was developed in a partnership between UAB and the company BioCryst. Many governments participate in antiviral drug stockpiling programs in case of pandemic infection.

Note: BioCryst and UAB have had a close relationship since BioCryst was founded. Former BioCryst CEO, Dr. Charles E. Bugg, was also a past director of the UAB Center for Macromolecular Crystallography. Former BioCryst CEO, Dr. J. Claude Bennett, was previously UAB President. Several of BioCryst's early drug development programs originated at UAB. Currently, BioCryst has research agreements in place with UAB focused on influenza neuraminidase and complement inhibitors.

Q. What is neuraminidase, and why do current antiviral drugs seek to inhibit it?


A. Neuraminidase is a viral enzyme located on the surface of flu virus particle. Neuraminidase inhibitors are drugs that bind to neuraminidase tightly and shut it down, which stops the ability of flu viruses to spread from cell to cell.

Q. I understand you are working to develop antiviral therapies that block the ability of influenza to fuse with and enter a human cell on the way to turning human cells into virus factories?  What progress are you making in that design effort, and what’s next?

A. Neuraminidase inhibitors target a viral protein called neuraminidase, but this protein regularly changes shape in quickly evolving viruses. These shape changes could eventually enable flu viruses with mutated proteins to become resistant to all current neuraminidase inhibitor drugs. Thus, the field is striving to develop drugs that target different viral proteins as a backup.  Dr. Luo's lab is working on fusion inhibitors that target a viral protein called hemagglutinin, and by blocking it, take away the ability of a virus to enter into human cells. In the lab, our fusion inhibitors block cell infection by many strains of influenza virus, including those already resistant to neuraminidase inhibitors. We are testing this class of novel inhibitors in animal studies.

Q. How would the viral fusion inhibitors you are working with complement neuraminidase inhibitors?

A. Our studies already showed that influenza viruses that are resistant to neuraminidase inhibitors are sensitive to our fusion inhibitors. The two classes of inhibitors target two unrelated viral proteins so changes in one may not affect the other. When two drugs target a disease process via independent mechanisms, they can in some cases be combined in potent antiviral drug cocktails.

Note: the H7N9 name of the newly emerged bird flu strain refers to the versions of hemagglutinin (H) and neuraminidase (N) found to be specific to the virus, and more precisely, to the fragments of those proteins that trigger our immune systems to respond to them.

Q. How long before human testing can start with your clinical candidate drugs?

A. We are testing these fusion inhibitors in animal models now. If it works in an animal model, it will still take years before human testing can begin for the new drugs. We need to begin studies of new drugs long before new threats of pandemic flu appear.

For the most recent updates on bird flu, see the Disease Outbreak News bulletins from the World Health Organization.

Goal: keep your transplanted organ permanently

Unless you have an identical twin, needing an organ transplant comes with a serious problem even beyond the fact that you need a transplant. Assuming the surgery goes well, the minute the new organ is grafted into your body, your immune system will recognize it as foreign, akin to invading bacteria, and seek to destroy it.

Taking the kidney for an example, there was a time 25 years ago when half of kidney transplant recipients lost their transplant due to immune rejection. The field of transplant immunology has in recent years become very good at preventing this during the first year after transplant using drugs that turn down the immune response, but long-term rejection remains commonplace.

The immune systems of many organ recipients eventually destroy transplanted kidneys over ten to 15 years. Worse yet, patients live through those years with a suppressed immune system; making them vulnerable to viral infections, some of which cause cancer.

Research efforts to solve these thorny, remaining problems in transplant immunology continue, but the field is under duress thanks to cuts in federal research funding, says UAB's Rosyln Mannon, M.D., director of research at the UAB Comprehensive Transplant Institute and a kidney transplant specialist. She was among the organizers of a recent transplant immunology symposium held by the institute.

Dr. Mannon sat down with The Mix to talk about research frontiers in transplantation, including efforts to design drugs that precisely turn down the activity of immune cells involved in transplant rejection, while ignoring those that fight infection.


Show notes for the podcast:

1:05  As we develop in the womb, special proteins are built on the surfaces of all our cells that serve as tags that say "self," and thus keep our immune cells from attacking them.  A transplanted organ obviously has different cell-surface, protein labels.

1:31  When surgeons put in a transplanted organ, the proteins labels on the organ surfaces are picked up and carried by immune cells to nearby lymph nodes, where they trigger the building of an army of cells designed specifically to attack the new organ. Several sets of immune cells are swept up into the effort to destroy the transplanted organ (also called a graft), including T cells and antibodies, two workhorse cells of the adaptive immune system.

1:47 Thus, the response to a transplanted organ that immunologists must deal with when preventing transplant rejection includes a mix of proteins, including antibodies that glom onto and remove foreign cells,    and cells that swarm to the transplant site and release destructive chemicals (e.g. cytokines).

3:15 The field of transplant immunology has been "incredibly successful" at preventing acute transplant rejection in the first year after the transplant using a subtle, powerful mix of drugs that damp down the immune system to protect transplanted organs.

3:39  The average person who receives a kidney this year from a diseased patient can expect the graft to last ten years. If the organ came from a living donor, the transplant may continue to function for 15 years, and especially if the organ came from a well matched family member. Despite these advances, all patients see their transplants fail eventually. About half of them "fail" because the patient dies, some from heart disease. Others organs fail because the medicines taken to suppress immune systems leave patients vulnerable to infection.

4:20 Physicians typically take a biopsy of a failing kidney to see why it has failed after working well for so long. In some cases, the slides will reveal that the immune system finally overcame immunosuppressive drugs to recognize the transplant as foreign and attack it. Interestingly, sometimes it will be one part of the immune system that finally tracks down the organ (e.g. antibodies), and sometimes another (T cells).  In still other cases, the biopsy may reveal that a longtime, undetected viral infection has destroyed the organ, or maybe it was fibrosis, the wear-and-tear scarring that comes with age.

5:15 The failure of organ transplants many years after implantation for these varied reasons is the central, remaining problem facing transplant immunologists and their patients.

5:43 The drugs used to suppress the immune system on the way to protecting a transplanted organ have evolved. In the old days, transplant recipients received steroids like prednisone (an anti-allergy drug) and drugs called anti-metabolites. In the mid-1980s, a set of drugs called calceneurin inhibitors arrived, including cyclosporin and then later Prograf. Most patients in those days got large doses of drugs like these, some of which themselves scar the kidneys. Other risks of such therapy included knocking the immune system thoroughly enough to encourage viral infections like the Epstein-Barr virus, cytomegalovirus and related cancers viruses.  The latter make random genetic changes in the cells they infect, some of which accidentally cause the abnormal growth seen in cancer. Presentations at the recent symposium talked about ways of fine-tuning immunosuppressive treatments to minimize damage related to their use.

7:47 Newer FDA-approved treatments appear to have fewer side effects, but still have the same problem as older drugs: they knock down the immune system broadly instead just the cells attacking the new organ. All physicians can do is gradually reduce the dose of immune suppressing medications over time under the assumption that the immune system has come to see the transplant as self, but doing so may result in the late-stage rejections currently observed five and ten years down the line.

8:53 Frontiers in the field include research efforts to design therapies that influence only the subsets of immune cells most associated with transplant rejection. Certain kinds of immune cells "remember" they have encountered a foreign protein, for instance.  Therapies may destroy most of those cells, but those that remain eventually become capable of re-launching the attack on the transplant.  On the other hand, one subset of T cells, called Tregs, are known to damp down the immune response in a careful way. What if engineers were able to deploy a person's own Tregs to damp down response to specific proteins on the surfaces of transplanted tissue?

10:11  Research efforts looking suppressing specific immune mechanisms, while the future of the field, are still in the early phases. Dr. Mannon hopes they suppress more surgically than the global suppression seen with older drugs.

10:45  The recent UAB transplant immunology symposium was timely, said Dr. Mannon, because UAB has been working to establish a collaborative consortium of transplant centers in the Southeast. UAB is one of the largest clinical transplant centers in the country, as is its partner in this symposium, the Emory Transplant Institute. Vanderbilt and the Medical College of South Carolina also have a strong interests in this area. The symposium was the first forum to identify and discuss the central, remaining problems in transplant immunology, and to launch joint efforts to solve them.

11:15 Among the research frontiers discussed was how best to arm patients with the ability to fight off infections without jeopardizing their transplants. One way may be to harness the bacteria that live in the human gut. What role do the bacteria that permanently colonize the body have in the immune system and transplant rejection? Can the interaction between our gut bugs and antibiotics for instance be manipulated to improve long-term outcomes of transplant patients by damping down system-wide inflammation?

14:24  Dr. Mannon is the newly elected president of the American Society of Transplantation, the second president in a row to come from UAB after Dr. Robert Gaston, M.D.  UAB has for years been recognized across the Southeast for the large volume of clinical transplant procedures done here, but having the presidency sends a message to the nation about the strength of the basic and translational research underway.

15:45 The society has been very active on Capitol Hill in terms of lobbying for the support of related research, and that stance will continue during Dr. Mannon's term. As for the group's legislative agenda, they have been trying for 12 years to get a bill passed that would provide coverage for immunosuppressive therapy for the life of those with kidney transplants. Currently, Medicare pays for such medications for three years after the transplant, after which medications the become prohibitively expensive for those without private insurance. Another bill would ensure that those who donate a kidney to another person cannot have their coverage dropped by an insurer after they give the gift of life.

Image post 1: brain message superhighways

While most posts from The Mix feature a science story, we also wanted a forum to share powerful images coming out of UAB research. Regular image posts will be accompanied by a brief description, including how the image depicted might soon be important to science or medicine. The post will also link to the creator of the image.

Above is a face view of a brain’s white matter created by UAB graduate student Meredith Reid using an MRI technology called diffusion tensor imaging (DTI). The strands running through the image are axons, long extensions of nerve cells that form pathways carrying messages between the parts of the brain. The colors represent the spatial orientation of the axons, with one color for those running left to right, another for those running back to front, etc. Certain qualities of such images give researchers a measure of the integrity of white matter axon fibers, which promises to improve understanding of neurological disorders like schizophrenia. The work was done in the lab of Adrienne Lahti, M.D., professor in the Department of Psychiatry and Behavioral Neurobiology within the UAB School of Medicine. On a final, related note, it's also worth checking out the Human Connectome Project run by the National Institutes of Health.  

Note: if you have an amazing UAB research image you would like to share, please email mwindsor@uab.edu.

Showcasing Alabama's biotech future at BIO

Perhaps the largest delegation in Alabama's history heads off this week to the annual meeting of the Biotech Industry Organization (BIO) annual meeting in Chicago. The group will include the leadership of the UAB Research Foundation, the Birmingham Business Alliance and Innovation Depot, the UAB-affiliated incubator, as well as experts from universities and companies from across the state.

As a group, most of those heading off to BIO are members of BioAlabama, the organization that works to foster life sciences here by creating the right scientific, business and legislative climate. The meeting will provide its members the opportunity to form new relationships with the biotech industry, hopefully as a first step toward new ventures.

We thought BIO made for a good occasion for the The Mix to break from its usual focus on research, and to instead consider the potential for research-driven economic development in the state. We sat down with David Winwood, Ph.D., CEO of the UAB Research Foundation, to talk about his goals for the BIO meeting and what's next for the Alabama economy. The foundation helps to manage discoveries by UAB researchers (e.g. patent protection), while finding partners that can help them form companies.

The BIO meeting comes just as the foundation is integrating these traditional functions into an larger effort to found more tech-based companies and create an entrepreneurial culture under the auspices of the newly founded UAB Institute for Innovation and Entrepreneurship.

The ultimate goal: see more inventions save and improve lives while serving as a basis of new companies that spread prosperity. This notion is at the core of  the UAB strategic plan, the new UAB branding campaign and recent remarks by the new UAB President, Ray L. Watts, who will be headlining BioAlabama's science symposium in May.

Show notes for the podcast

1:22 The UAB Research Foundation operates at the center of a world renown, half-billion-dollar research enterprise in UAB, said Dr. Winwood, which features a collaborative group of clinicians, basic science researchers, engineers, etc.  This makes it a great place for those seeking to help students and researchers found new companies. The UAB Research Foundation has helped to create 55 start-up companies since its inception.  

2:19  Despite economic hard times in recent years, Alabama research universities have held their own in fiercely competitive areas in terms of winning grants from from the National Institutes of Health, the National Science Foundation and the agencies and foundations that support engineering.

2:52 Just a few blocks from UAB's campus in the Innovation Depot, which is Birmingham's UAB-affiliated technology incubator. It has attracted more than 90 high-growth companies, many of them led by UAB faculty, which makes it among the largest incubators of its kind in the Southeast.

3:39 In terms of an economic forecast for Alabama's tech-driven economy, Dr. Winwood said the overall outlook is positive, with Alabama's manufacturing sector on somewhat of a recovery path. One shining example is the recent decision by aircraft manufacturer Airbus to invest $600 million to build a new plant in Mobile, Alabama. This represents a stamp of approval of the state's ability to manufacture highly complex engineering products, and the investment will have impact across the state and lead to collaborations with UAB engineers.

4:44 Big challenges remain in the federal budget, making it difficult for UAB to chart its course. UAB researchers have been extraordinarily successful in winning federal research grants, which has helped the school have a $5 billion economic impact on Birmingham. Budgets for agencies like the National Institutes of Health is in jeopardy, however, unless representatives in Congress can agree on how to stabilize financial support for medical research. Huntsville, Alabama, is also dependent on federal dollars that flow through that city's aerospace and defense industries. For these reasons, Dr. Winwood said he is very careful about creating realistic expectations surrounding economic growth in the state.

5:55  Along with biotech strength, UAB and Birmingham have some amazing capabilities in terms of advanced materials design for defense and civil engineering applications, as well as a strong capability in simulation, including the creating of simulated battlefields and surgical suites for training.

7:58  Beyond catch phrases, UAB is uniquely collaborative across science disciplines, Dr. Winwood said. Some of the most exciting spin-off companies out of UAB research have represented combinations, for instance, of neurosurgery, materials design and bioinformatics. This spirit has spilled over from science into commercialization efforts, leading to the emergence of a new model of tech transfer. In the old model, a research got some funding, did the research and eventually told the research foundation so they could file for a patent. With support from the UAB Office of the Vice President for Research & Economic Development, UAB now embeds technology transfer officers in research functions earlier in projects, which better positions them to the watch for nubs of ideas that could evolve into companies.

10:08 As far as big UAB economic development news expected in the coming months, Dr. Winwood talked how the UAB Institute for Innovation and Entrepreneurship will be up and running shortly. The institute will expand on what the research foundation has been doing for 20 years, but also incorporate more services that accelerate the process by which scientists turn discoveries into new businesses. Some of the new services will be delivered in partnership with the Birmingham Business Alliance, which has a volunteer cadre of business leaders in place to help guide fledgling biotech businesses (market opportunities, financial models, etc.). Beyond economic development, the institute will help to launch a new set of educational initiatives as well that seek to encourage the entrepreneurial spirit in students.

12:35 Dr. Winwood is a member of BioAlabama, which represents more than 550 bioscience entities in Alabama, including those from the pharmaceutical, agriculture, devices and testing industries. BioAlabama had done a nice job recruiting delegates from across the state to attend BIOM, many of which are going for the first time.

12:46 Dr. Winwood thinks the large size of the state's BIO delegation this signifies a growing recognition of the potential economic impact on Alabama of the founding of new biotech companies and of forming new partnerships between Alabama and the biotech industry. This industry sector can have a broad impact on the state's economic well being, and well beyond Ph.D.s and M.D.s. If managed properly, growth is the area could create a large number of manufacturing jobs and change the profile of industries thriving in the state. Beyond medicine, the BIO meeting represents opportunities to meet with companies focused on the advanced agriculture, food and energy industries.

14:44 BIO is where the world's biotech industry gathers and represents a broad collection of technologies that are the subject of research at most colleges, universities and institutes in Alabama. The BIO meeting has perfected a matchmaking system by which the 17,000 attendees can easily find and meet with those interested in the same business and technical areas.

15:35 It often surprises observers from outside Alabama that there are more than 700 technology companies in the Birmingham greater area that represent an unusual capability in specialty manufacturing. In addition, the UAB Center for Biophysical Sciences and Engineering is renowned for its expertise in building miniaturized, electronic components, many of which are currently in use on the international space station.

18:48  While the BIO meeting represents a great opportunity to meet with industry, Dr. Winwood is working with the leadership of the new UAB institute to create a permanent, two-way online industry portal. UAB researchers will use it to find industry partners, and industry, to review technologies it may want to invest in, and long after BIO ends.

19:50 For those interested in learning more about commercialization efforts or tech transfer in general, resources include the BioAlabama, BIO meeting and the Association of University Technology Managers (AUTM) websites.

For those on site at BIO, please visit the Southern Research Institute / BioAlabama Booth (#4422A).

Faster-acting drugs meant to counter depression and prevent suicide

A vexing problem in psychiatry has been that intense suicidal feelings must be countered within minutes, and traditional antidepressant drugs like Prozac take weeks to work.

The good news is that, after decades of work, scientists are zooming in on the precise areas and chemical pathways in the brain that control emotion, and that malfunction to cause severe depression. As understanding of the central mechanisms grows, researchers are identifying targeted drugs that work faster and faster.

Specifically, drugs that target the brain signaling chemical glutamate within nerve networks now work quickly enough to be useful in patients on suicide watch in emergency rooms.

A recent article by our Bob Shepherd talked about how Richard Shelton, M.D., professor in the UAB Department of Psychiatry, Division of Behavioral Neurobiology, is leading clinical trials at UAB that look to combat intense, immediate depression with drugs that alter glutamate signaling.

Among the drugs is ketamine, an anesthetic used since the 1970s to put people to sleep during surgery, but increasingly recognized as useful against depression at lower doses. Work with ketamine set the stage for the precision design of newer glutamate-targeting drugs like Glyx-13, also being tested here because it works like ketamine but may have fewer side effects. Dr. Shelton sat down with The Mix to talk about how his field is unraveling the mechanisms of depression.


Show notes for the podcast

1:25 We have long heard about how depression may be caused by problems with nerve pathway signaling chemicals like serotonin, norepinephrine and dopamine. Older drugs that target serotonin include Prozac, Luvox, Paxil and Celexa. Wellbutrin blocks influences dopamine and norepinephrine signalling, while Cymbalta, Effexor, and Remeron affect both norepinephrine and serotonin. A growing research focus in recent years, however, has been on glutamate and the mechanisms by which it interacts with nerve cells. They all appear to influence depression, but which one operates at the heart of the matter?

1:35 Over twenty years, first in animal studies and then in human studies, it became clear that ketamine blocks the interaction between glutamate and a protein receptor on nerve cells called NMDA, which stands for N-methyl-D-aspartate. When glutamate docks into a receptor like NMDA, like a key into a lock, it changes shape such that a biochemical message is passed on inside the nerve cells to create a strong and very quick anti-depressive effect.

2:25 Dr. Shelton leads a first-of-its kind clinical study in that its seeks to test whether or not ketamine can help people with depression so severe they have come to a hospital emergency room to report a strong urge to kill themselves.

4:07  Glutamate is one example of a neurotransmitter, a chemical released from one nerve cell in signaling pathway that floats across space to the next nerve cell to trigger reactions that pass on the message. They regulate not only the passing on of messages but also the growth and connection of nerve cell networks that control, among other things, emotion.

4:53 As is the case with many cellular mechanisms, the binding of glutamate to NMDA opens a channel in the outer membrane of a nerve cell. In through this channel flow charged calcium ions that act like an electric switch kicking on cell processes.

Note: As I understand it (disclaimer), cell signalling is based in part on atomic theory, where atoms are among the basic units making up all matter, and these in turn are made up of electrons, protons and neutrons. Atoms with more positively charged protons have an overall positive charge; those with more electrons carry a negative charge.  Whatever charge is (it is undefined), like charges repel and opposites attract, and pulling apart two particles attracted to each other (separation of charge) creates potential energy that can be put to work. Cells have harnessed charge to drive life processes by pumping charged molecules into or out of cells. The buildup of charged particles on one side of a cell membrane means those particles will rush back if given the chance. That chance comes, under carefully regulated circumstances, with the opening of channel proteins that enable charged particle flow.

5:03 Precise regulation of calcium entry into nerve cells is extremely important because calcium signaling has a great many functions throughout the cell, and the glutamate/NMDA partnership regulates the flow. Studies over many years have revealed that when calcium ions flow through NDMA, it shuts down the stimulation of nerve cells to sprout outgrowths that connect them to other nerve cells.  These connections are regulatory in nature, helping cells act in concert to better regulate complex processes like the formation of emotions.

5:44 Depression associated with suicide happens when such processes are no longer regulated properly and run out of control thanks to an abnormally low number of connections between nerve cells. Nerve cells start sprouting connections the minute you block glutamate signaling and calcium influx through the NMDA receptor channel with a drug like ketamine, said Shelton.

6:08 High doses of ketamine just put people to sleep. At low doses, Shelton said, it acts as a strong antidepressant within about 15 minutes. A person in terrible distress will not be helped by older antidepressant drug classes like the selective serotonin re-uptake inhibitors that take weeks before they start to work.

7:02 Calcium flow into cells regulates the activity of enzymes and groups of cooperating proteins called complexes. Among the calcium-regulated complexes is nerve cells is MTOR, which calcium shuts down. Among MTOR's functions is to encourage the growth of connections between nerve cells.  Ketamine blocks calcium influx, thus preserving the ability of nerve cells to form networks.

8:16 Ketamine is given to patients by infusion, where the medication is delivered via an intravenous line directly into the bloodstream, which leads to a rapid effect. In a typical setting, patients receive ketamine in a higher dose given over 40 minutes of infusion. In the emergency room scenarios seen in Shelton's clinical trials, where a patient is in extreme crisis, his team has been testing whether or now a lower dose given over five minutes can avert suicidal urges.

9:11 The current study by Shelton and colleagues seeks to confirm that treatment with ketamine, if physicians do nothing else, protects patients against sever depression and suicidal urges for five to seven days.  Specifically, the current study is looking at what happens when you give the infusion ketamine, and then let physicians take whatever next steps they think best as continuing treatment (counseling, other drugs, etc.).  Initial evidence suggest that the combination of ketamine and the physician's choice for continuing treatment sustains the benefit of the ketamine even longer.

10:17 Another study led by Shelton is looking at whether or giving patients a series of ketamine infusions can maintain the protection against severe depression over a period of months.

11:32 It has become clear, said Shelton, that traditional antidepressants act though changing the activity of serotonin and norepipinephrine produce antidipressent effects slowly, and that most people taking them get better but never fully well. Another set of patients gets better but then relapses. Ultimately, these older approaches are not ideal for controlling the emotional state because their effect is indirect and incomplete.

12:16 Researchers believe that somewhere in signaling pathways downstream of serotonin and norepinephrine there is the central set of mechanisms in control of depression that all antidepressant drugs must act on, the mechanism that controls the formation of connections between nerve cells.

12:45 Shelton believes this central mechanism is closely related to the action of glutamate, which comes with about with the blockage of NDMA receptor signalling via ketamine. The effect of drugs that adjust glutamate activity is stronger, faster and more sustainable than the effect of traditional antidepressant treatments. .

13:13   Researchers seek to catch patients in the emergency room, and then prevent them from again becoming acutely depressed again through a series of interventions. They also need new solutions for patients that are chronically depressed and for whom many treatments have failed.

15:02 In the past, and at its traditional dose as an anesthetic, ketamine has been identified as a drug of abuse.  A heavy dose puts people to sleep. A lighter, pre-anethesia dose makes people hallucinate. The lower dose used in the current study should not create euphoria or hallucinations. Still, a drug like ketamine is best administered in a clinic, said Shelton, versus sending it home with people.

16:56 A third trial underway at UAB is testing a compound called Glyx-13, produced by Naurex, Inc.  Glyx-13 may produce similar results as ketamine by blocking an amino acid called glycine, which works in tandem with glutamate. Glycine regulates glutamate signaling, so it is like an added layer of fine-tuning. When glycine and glutamate bind to NMDA together, the calcium ion channel opens widely. Blocking glutamate with ketamine can reduce the release of calcium. Blocking glycine with Glyx-13 may achieve the same result, but more subtly and with fewer side effects.