Technological leaps make multiple, kidney-swapping surgeries more common

Chronic kidney disease affects 26 million American adults, with millions of those affected unaware because there are no symptoms until the disease is severe. When a person’s kidneys fail, they can go on dialysis or try to get a kidney transplant, which provides a better quality of life. The latter options requires that a friend or family member be willing to donate one. Otherwise, they face many years on a waiting list. 

But what if you have a donor who is not a match, which means the donated organ will be rejected by your immune system?  

The answer in Birmingham is UAB’s paired exchange and incompatible transplant programs. Ann Marie Reynolds, Gwendolyn Goldsmith and Frank Peters each needed a kidney and had a donor lined up that turned out to be incompatible. The swapping enabling them to be entered into a database that made all participants more likely to get a kidney, and this powerful story by UAB’s Tyler Greer describes their recent three-way transplant surgery.   

Their multiple, living-donor transplant has made it possible for each patient to live free of the constraints of dialysis for what doctors hope will be at least a decade and maybe two. Each of those who donated the kidney did so even though they knew their organ would be going to someone other than their family member or loved one. By the end of 2013, UAB is expected to complete perhaps 30 kidney swap transplants as part of the program.

A team of UAB surgeons, physicians and researchers in UAB’s Kidney/Pancreas Transplant Center has assembled and developed the technologies needed to make the multiple surgeries successful. We thought to talk to one of the UAB surgeons who oversaw the three-way transplant that day, Dr. Jayme Locke, and to ask her about this emerging field and what it means for patients. 

Show notes for the podcast:

1:52  The kidneys filter the blood, divert waste into urine and return useful proteins to the bloodstream. but can be damaged by diabetes, high blood pressure and cancer. 

3:00 As diseases progress, the kidneys become less and less able to function until they fail, at which points patients either go on dialysis, a mechanical system that filters the blood, get a kidney transplant or die. 

3:51 The field has shifted over the years from implanting kidneys from a stranger who recently died to organs donated by living people known to the recipient. In the United States there are about 100,000 people waiting for a kidney, but only 10,000 and 15,000 transplants done a year. The need far outweighs the supply, and those who have a family member willing to donate a kidney instead of going on a waiting list (ten-year wait in Alabama for some) has a tremendous advantage.  

5:12 It is important to note that about 35 percent of people who come forward and volunteer to donate a kidney to loved one are found to be incompatible with their would-be recipient. They have a blood type that means the recipient's immune system will immediately attack the donated organ and prevent it from functioning. Another 11 percent of willing donors will be found to be tissue incompatible. So almost half of would be donors cannot donate to their intended recipient. 

6:10  Paired exchange and incompatible transplant programs were born to address this problem, and to make it possible for many to get kidneys that would not otherwise happen.

6:37:  Paired exchange programs started in single hospitals, and now national databases have begun.  At UAB, the list of would be donors and patients is so large that the database locally is effective at making swaps possible in Alabama.

7:37: Ann Marie Reynolds, one of three patients in the transplant swap described above, has had three kidney transplants over the last 25 years. Some patients need more than one transplant because of rejection (sometimes years later) or because a systemic disease comes back in the new organ. Getting a second transplant is more difficult than the first because patients become sensitized. 

8:44 We all have labels on our cells that say self (made of a protein called human leukocyte antigen or HLA). Our immune system looks for this tag and spares self-labelled cells from immune attack, whereas those with other tags like bacteria are targeted. Thus, the goal is to find a transplanted organ made up of cells with an HLA that matches pretty closely with the patient's own tags. In the last ten years, researchers have developed the technology that enables patients to overcome some degree of mismatch if their blood and tissue types are close enough.  

10:30 Dr. Locke discussed the work of UAB's Dr. Roz Mannon, whose specialty is keeping the immune system from attacking a transplanted organ over the long term. While the field has gotten very good at preventing transplant rejection in the first year, gradual damage can cause the organ to fail five years later.

11:10 One approach to preventing long-term rejection, says Dr. Locke, is to find people better blood and tissue matches in donated organs in the first place. By carefully testing the expanded pool of potential donors and recipients in a swapping system, the chances increase that each patient will not only get a kidney, but a better matched kidney.  

11:45 The transplant researcher community also continues to work urgently to improve immunosuppressive medications such that they stop immune attack on a transplanted organ without making patients overly vulnerable to infections. UAB is a national leader in this regard, participating in several, ongoing clinical trials. 

12:57 A unique team at UAB makes multiple swap transplant operations possible. In some cases, six operations are underway at the same time, which requires skilled support by teams of nurses, anesthesiologists, pharmacists, etc., both in preparation and follow up to surgery. This tremendous and coordinated effort by UAB Nursing is led by people like Katie Stegner who runs the operating rooms and Debbie Sparks, the nurse manager on the kidney floor. 

15:35 The living donors that make the swapping system possible are willing to sacrifice part of themselves for their loved ones, a choice that has Dr. Locke's respect. Beyond that are those that chose to donate an organ into the system in honor of a family member or friend, hoping the swap system can give an organ back to that loved one. 

17:28  Dr. Locke would like to see a truly national swapping system develop, one that was not for profit. The huge size of such a database would make a great difference for many more patients in need of transplant. 

 

Damaged hearts may be healed by their own stem cells

Thanks to stem cells, each of us develops from a single-celled embryo into a fetus with hundreds of different cell types. Stem cells multiply and specialize until they become heart muscle, bone, nerves, etc. Tissues like skin keep pools of stem cells on hand into adulthood, activating them as needed to replace worn out cells in a constant turnover.

But not the heart. Cardiologists believed for a long time that you get one set of heart cells for life. If you lost a bunch in the wake of heart attack, you had to live with whatever was left. In recent years, however, researches have revised that view. There is cell turnover in the heart, albeit as a much slower pace than that seen in other tissues.

The existence of such replenishing mechanisms suggested that it may be possible to coax them into action to regenerate heart muscle damaged by disease. Results of early human trials have been positive, although there is still work to do before such treatments become part of clinical practice.

It may be no surprise then stem cell-based therapies were a focus of the recently held UAB Comprehensive Cardiovascular Center’s Annual Symposium. We sat down with Sumant Prabhu, M.D., director of the center and symposium organizer to talk about the promise of regenerative medicine.



1:32 Dr. Prabhu said he organized the symposium with this theme at this time because his team wanted to focus on the next wave of science and therapeutics in cardiology. He believes that stem cell-based, genetic and tissue regeneration therapies will dominate the field in the coming years, just as drugs and devices did in during eras past. The symposium was designed to foster new collaborations in these areas among leading researchers.

3:19 Several symposium presentations were dedicated to stem cells that are present in the heart, and on attempts to manipulate them such that the become needed replacement cells in damaged hearts. Over the last ten years, clinical trials have examined the value of stem cells taken from the bone marrow or blood to repair damaged hearts, but a more recent thrust is the use of stem cells in the heart itself.

4:37 Joshua Hare, M.D., from the University of Miami, described in his presentation the use of mesenchymal stem cells, which can become bone, cartilage or fat cells, and how they showed "incredible promise" in clinical trials.  The studies looked at whether they could repair heart tissue after heart attack, and heart failure, the loss of pumping efficiency, seen in the wake of heart attacks. While these studies are promising, the field still has a long way to go before stem cell treatments become part of standard medical practice.

5:35 Harvard's Piero Anversa, M.D., delivered the keynote lecture for the symposium on the topic of stem cells in the heart, their discovery, their use in animal studies to repair hearts damaged by heart attack. In particular he described strong, early results in the Phase I human Scipio trial. In this trial, researchers removed stem cells from the hearts of patients as they underwent coronary bypass surgery. The research team then reinfused each patient's stem cells into their hearts after the surgery, where they proved to be safe, to improve pumping function and to lessen the amount of dead tissue in the heart.

6:39 Stem cell therapies target tissue that forms scar when damaged by a heart attack. Scar tissue is made of structural cells instead of functional muscle cells, and scars interfere with the hearts ability to pump blood (heart failure). Dr. Prabhu said there are often pockets of live tissue within the scarred area.  The hope is that added stem cells will receive signals from the surviving areas that turn them into the kind of cells that either improve the remaining tissue or build new tissue.

9:04 It was actually the dawn the nuclear era that made possible the discovery of the slow stem-cell led turnover of heart muscle. Heart cells exposed to low level of radiation from power plants, for instance, could the be carbon dated to show cell turnover. There is not much turnover, but over a lifetime it makes hearts more durable. After a heart attack, the process of stem-cell based tissue replacement seems to kick up a notch, said Dr. Prabhu, but obviously not enough to counter the massive damage caused by a heart attack. What if researchers could temporarily pump up this natural response? Would more the presence of more stem cells mean more rebuilding of tissues in of damaged areas?

10:28 Whether injected stem cells themselves bring about cardiac repair or whether they trigger some chain reaction that brings about repair is a matter of debate. How much heart muscle for instance that grows back in damaged hearts after stem cells are infused has varied considerably from study to study. What has been shown in animal studies is that stem-cell driven regeneration can be manipulated to improve cardiac function. Human studies are seeking to confirm that now.

Nobel Prize focused on life-giving cellular cargo delivery system

A Nobel Prize was recently awarded to three researchers who discovered bubbles within bubbles that have tentacles. Award winners James Rothman, Randy Schekman and Thomas Südhof were pioneers in the study of vesicles, which are like bubbles inside human cells whose outer layers are made of the same stuff that separates cell insides from the outside world. Because the bubbles’ insides are kept separate from the rest of the cell’s interior, they can store, organize and deliver highly reactive biochemicals and proteins, releasing them only when and where they’re needed.

Electron microscope images of vesicles near Golgi complex in a cell.

Furthermore, the outer membranes of vesicles can fuse to outer cell membranes or to the membranes surrounding other cellular machines. This lets them take in contents from one compartment, move them to another walled-off area, and deposit them there. It also lets a cell start manufacturing a hormone or an antibody in one spot, truck it somewhere else for finishing, move it to the cell's surface, and secrete it to do a job elsewhere in the body.

To ensure that it dumps its contents into the right compartment, each vesicle has “tentacles,” squiggly proteins that “taste” the surface of other vesicles to make sure they have reached the right destination. Without vesicle formation and fusion, cells could neither live nor signal to each other as part of complex tissues. Vesicles are so central to cellular function that they are most likely involved in almost every disease when things go wrong, although we don’t yet know their role.

For his share of the prize, Dr. Rothman, a professor at Yale, discovered a protein complex that lets vesicles fuse with membranes to deliver their molecular cargo. He has a UAB connection in his former student, Dr. Elizabeth Sztul, Ph.D., professor in the UAB Department of Cell, Developmental and Integrative Biology and a vesicle expert in her own right. Dr. Sztul said she was “thrilled” to see vesicle research be recognized in the form of a Nobel Prize, and we thought to ask her why her field deserves notice.

Show notes from the podcast

1:56  A Nobel Prize win for vesicle research underscores just how vital basic scientific research is, along with the fundamental importance of vesicles in human life, said Dr. Sztul. Cells are made of compartments, and the prize went to the three-scientist team for discovering how proteins and genes work together to move key substances from one compartment to another.

3:02  Vesicular traffic has implication for all of life. Genetic mistakes that occur in genes that control this delivery system mean that an embryo does not often survive, and if so, with severe disabilities. The Nobel Prize winners designed tests that identified the cogs (proteins) that make possible the machinery behind vesicle formation and transport.

4:15 Specifically, Dr. Rothman, a biochemist, identified the proteins required for vesicle transport and then re-created vesicle trafficking in a test tube. Dr. Schekman identified some of the genes that control vesicle transport, and that have done so throughout evolution. He works one-celled organisms like yeast that share vesicle pathways with human cells. Dr Sudhof, a neurobiologist, showed how vesicles deliver proteins, not just to the right place, but also with perfect timing, to make cellular life possible. Together, the pioneers outlined how a vesicle "knows" where to go and when to fuse.

5:47  Genetic mutations, random changes in that occur in genes as they constantly get copied, are usually fatal within a few days when they occur within the central machinery proteins of vesicle trafficking in a human embryo. Dr. Stzul describes one key vesicle protein type as snares, which help a vesicle grab on to the outside of another compartment they want to fuse with. Genetic defects in snares are fatal, but people are born with genetic changes in less essential machinery related to vesicles and survive.

6:22 For instance, proteins on the sides of vesicles that are nicknamed tethers or tentacles, touch and "sample" the outer membranes of surrounding vesicles to determine which they should target for fusion.  A mutation in one these protein tentacles causes a very serious, rare disease called congenital disorder of glycosylation. Tethers and snares represent two ways that any vesicle chooses a specific vesicle that it will deliver its cargo into.

8:40 There are many types of payloads delivered by vesicle in human cells. The immune system uses them to swallow invading bacteria, and then to deliver chemicals to that vesicle that destroy the bacteria.  Nerve cells use them to deliver signaling molecules to the next cell in line as a nerve message runs along a nerve pathway. After you eat a meal, cells in your pancreas packs digestive enzymes into vesicles and ship them off to the gut.

10:38 Vesicle delivery of proteins by cells is tightly regulated and very precise, Dr. Sztul said. Even small genetic errors in the genes that make the vesicle proteins can cause disease, including one called craniofacial disorder. These patients have bones that don't form properly because the structural protein collagen, which makes the lion's share of skin and bones, is not delivered properly by vesicles.

12:37  Dr. Sztul's lab is trying to figure out all of the steps needed to move all important proteins in the cell from where they are made, through every required vesicle stop along the way and to a final destination.  Each stop in this journey involves a web of interacting proteins, and Dr. Sztul would like to map all of these interactions precisely in time and space. She believe that this map, once complete, will reveal links between mutations in vesicle trafficking genes and many diseases, both common and rare. These patterns will emerge, she said, as more and more patients routinely get their DNA sequenced as part of personalized medicine.

15:00 With the map in place, researchers will have a basis for the design of treatments that compensate for problems with specific vesicle proteins. At least theoretically, every protein that regulates trafficking will become targets for drug design. In cancer for instance, vesicles may be used by tumors to deliver proteins that cause cancer cells to spread or that encourage the growth of blood vessels that feed tumors. Drugs might be designed to keep vesicles from making these harmful deliveries.

18:15 The field is working to invent imaging technologies that can track the movement and action in a living cell, not just of a couple of interacting proteins at a time, but that can watch perhaps 60 vesicle trafficking proteins at work during one stage of trafficking. Also on the horizon, an in-depth understanding of the interaction between vesicle trafficking and outer key cellular actions. How do hormones effect vesicle trafficking in cells that secrete hormones? How vesicles in immune cells become filled with antibodies when the body senses that it has been infected with a bacterium or a virus, or in response to a vaccine?

Chimerism: not being yourself has medical implications

Science has demolished another idea that researchers once knew to be "true" about genes, the chains of molecules that encode the blueprint for the human body. The consensus a few years back was that every cell in each person's body has the same genetic signature, the same set of DNA unique to that person. It is a pretty important concept if you think about it.

Researchers determine things like paternity, genetic risk for disease and presence at crime scenes by examining just a few of the trillion cells in each a person.This practice is based on the assumption that the few cells taken accurately represent the genes in the rest of that individual.

But what if one person had different sets of genes, or genomes, in different cells? Some people, it turns out, have patches of cells with genetic changes in them not found in other parts of their bodies. Some have cells with genes that came from other people.

Such variety is called chimerism or mosaicism, depending on the details, both of which were the subject of a recent article by writer Carl Zimmer in the New York Times. We used the occasion of the article to ask Bruce Korf, M.D., Ph.D., chair of the UAB Department of Genetics, for his thoughts on the implications of these ideas for medicine. 

Show notes for the conference: 

0:35 To recap, the blueprint for the human body is encoded in genes, many of which hold the information necessary for the building of one or more proteins. Gene expression is the process by which information stored in genes is converted into proteins, the workhorse molecules that make up the body’s structures and carry its signals.

1:38 The dogma for decades in genetics was that all cells in one person, having all come from the same original cell (the embryo), had copies of the same genetic material throughout life. That belief was correct to a point, but did not tell the whole story, said Dr. Korf. Each person does indeed have a unique genome, a set of genetic material made up of about 3 billion bases, the “letters” that make up the DNA code, but changes in that code occur every time anyone our trillions of cells divides and multiplies. So mutations are underway constantly, with different changes building up in different groups of cells. Furthermore, several events, some of them more common that once thought, can inject other people's cells into our bodies.

6:35 Chimerism is the presence of two or more genetically different cells occurring in the same body. While we are taught the a fetus results when one sperm fertilizes one egg, more pregnanices than once thought may result from multiple fertilization events. More than one sperm fertilizes more than one egg in the womb get mixed to form one body. Beyond the number of twins born, researchers now suspect that many single baby pregnancies started as twins. One of the embryos then died early on, but not before sharing blood and cells with its twin. Thus you have one baby with the genomes of two babies mixed together. In other cases, two fertilized eggs may fuse together with no evidence they were once two individuals. Obviously, people who get an organ transplant are chimeras as well, as are most mothers, who absorbed their some of their babies' cells while pregnant.

8:15 Chimerism, which happens during conception, is different from the changes in genes that arise from constant small changes in genetic code underway in every human cell over a person's lifetime, a concept called mosaicism. Most of us have patches of cells in our body that have different genes than patches growing elsewhere. While the overall differences are small, mounting evidence suggests they may be meaningful. In the UAB Medical Genomics lab led by Dr. Korf,  the team studies many genetic orders that proceed from mosaicism. In many cases, a patient will have a genetic change that has caused cancer just in one patch of skin, instead of a change across the entire body.

11:06  When a person has two sets of different DNA in their cells, one set will greatly predominate with the other in relatively few cells. Until recently, DNA technologies often could not capture the less frequently occurring genome, losing it in the vast background of the majority. Next-generation sequencing technologies, however, can now identify rare cells that have a different genotype than most of the cells in a person, a capability which may explain why this topic has been more in the news lately. According to the Times article, recent cases have featured genetic test results that found a mother was not the mother of one of her children, and that a sexual assault suspect did not have the same genetic signature in his sperm as in his saliva. The fact both were chimeras threw the tests off.

12:56 While we don't yet know whether cells with different DNA have a big impact on say hearth disease risk, they are known to have a profound role in cancer. Whether the DNA is atypical from chimerism or mosaicism, it is possible the change may affect a cell's ability to divide and multiply, perhaps leading to abnormal growth. Cancer is a disease of mosaicism, said Dr. Korf, because a cell comes to include a small changes in its DNA that remove normal growth limits to create tumors.

16:45  We don't really know how many different genomes we have in the cells in our body. If you look at it one way, we have as many different sets of genetic material as we have cells, since small, unique and random changes slip in as each cell divides and multiplies into two more. Most of the changes have no impact on healthy function, but some do, and the trick is to pick out trillions the few that do.

17:22  Cells with slightly different DNA sequences obviously play a role in cancer, but the remaining question is whether or not small numbers of cells with differing genomes different play a role in other major diseases, like heart disease or Alzheimer's. Is it possible that chimerism or mosaicism in the heart can cause rhythm disorders or that such changes in the pancreas bring about diabetes?

Goal of next massive decades-long cancer study: reduce cancer to a nuisance

Before the first cancer prevention studies run by the American Cancer Society between 1952 to 1955, and again between 1959 and 1972, Americans had no idea that smoking causes cancer. Before the Cancer Prevention Study II, which started in 1982, physicians and patients didn't fully understand the link between nutrition, obesity and cancer.

The University of Alabama at Birmingham just became the largest enrolling center in the next study in this series, Cancer Prevention Study-3, or CPS-3, with a record 1,209 people signed up to participate at UAB. Nationally, the study will follow the health of 300,000 people for decades in hopes of making the next great leap in the understanding of what causes cancer.

Specifically, the study will track the lifestyle, environments, diet and genetics of people not previously diagnosed with cancer in hopes of understanding what causes or prevents cancer for each person in the coming decades. The ultimate goal is to turn cancer from a major killer into a manageable, chronic disease (a nuisance) or stop it before it starts.

We thought to ask Edward Partridge, M.D., director of the UAB Comprehensive Cancer Center, about the science behind massive, long-term studies like CPS-3, and about why they reveal clues about diseases that other studies miss. 

Show notes for the podcast:

1:06 Population-based studies like this are especially important because they enroll large numbers of people who are well at the beginning of study. Researchers can they see who gets sick over time, and go back to indetify which factors were associated most closely with disease. Sadly, a good many of the people in the study will develop cancer in the coming years, Dr. Patridge said. Was it a certain kind of food, or a certain certain of a gene that created risk? This is a different type of approach than studies that look at whether a drug will work in people who are already sick.

3:14 Massive, decades-long studies reveal patterns where other studies cannot because of the detailed tracking of so people and so many factors for so long. In addition, what the study designers decide to track in each patient is based on many studies in recent years that offered new clues about what to track. Participants take an original survey, which includes trying to recall what their lifestyle was like in their youth, and then repeat the survey every two years. The first of the CPS-3 study results might come out within a year, with more results will then continuing to come out for decades.

4:38 Importantly, this is the first large cancer prevention study that is taking a blood sample from every participant. That will enable researchers to study genetic factors, and their combination of withf other diseases, medications taken. diet, etc., over time.  The research team will also be able to look at epigenetics, the small chemical changes that turn genes on or off in reaction to the environment. In the future, this may enable the field to recognize future cancer risk from a blood sample taken from a perfectly healthy person and in time to intervene.

6:09  The CPS study before the current one, CPS II, led to a publication in 2001 that found obesity to be a major contributor to cancer. Today, some make the arugment that obesity has overtaken tabacco as the major cause of cancer.  In 1970, four percent of children between the ages of six and eleven were obese. Today, that number is 20 percent, a five-fold increase. Children who are obese are much more likely to become obese adults, and public health experts fear that a wave of obesity-related cancer is on its way. CPS-3 will include the largest percentage of obese people of any cancer prevention study so far, and the obesity-cancer link will be closely tracked. 

7:41 Other burning questions in cancer research that CPS-3 will help to answer are, for instance, what is the molecular basis of the increase in cancer risk related to obesity. Researchers will also be looking at what the drop in smoking has meant in terms of reduced risk. Researchers are also keen to study for the first time many of the pharmacuetical drugs taken now taken by so many Americans for large portions of their lives. For instance, what are the long-term effects of a drug like metformin, taken for Type 2 diabetes, on cancer risk?  It may actually reduce cancer risk and the study may explain why. 

9:23 Among the most exciting things about the study is the combination of taking blood samples and the fact that researchers have now mapped the human genome, the complete set of genetic material. That will enable researchers to see which deviations from normal genes are associated with cancer. Dr. Partridge said that he believes this study, and related efforts worldwide, will have eliminated cancer as a major public health threat half-way through the study, say by the year 2050.  By then, the field will detect and eliminate cancers before they become a health threat, or will be turning them into a chronic, manageable conditions, the way drug cocktials have enabled many AIDS patients to live normal lifespans. 

12:19  In a sign of the challenges involved in curing cancer, our society has not yet fully made use of the knowledge and data collected by cancer prevention studies that finished up decades ago, said Dr. Partridge. We all know that smoking causes cancer, and yet 22 percent of Americans still smoke, and even more Alabama. We know that colorectal cancer and mammography saves lives, and yet 40 percent of people with insurance don't opt for these tests. The new study will reveal many insights as well, but making the cultural changes needed to realize their value will be a larger task.

13:45 The fact that so many enrolled locally here in Birmingham says great things about the community, Dr. Partridge said.  He found it particularly gratifying that so many UAB employees enrolled. UAB is a major employer here, and to see nurses, staff, physicians and researchers, many of whom conduct research for a living, becoming participants in research.

14:54 Local enrollment in CPS-3 is closed, but folks can still visit the CPS-3 website to see what the 
nearest enrolling center is. The study will finish up enrolling nationally by December 2013.

Alcohol throws off circadian clock to damage liver

Having evolved to keep time with our planet's rhythms – day and night, light and dark – we are wired at the genetic level to sleep at night and to wake and eat during the day. Research in recent years revealed that genetic and protein feedback loops – or clocks – operate in 24-hour cycles in every human cell. The clocks signal to thousands of genes, many of which speed up our ability to make and use energy from food during the day and turn it down at night.

Bucking those patterns – say by working the night shift – has been shown to increase a person’s risk for heart disease, diabetes, cancer, depression, etc.

In a new twist, Shannon Bailey, Ph.D., associate professor in the Division of Molecular and Cellular Pathology within the UAB School of Medicine, just published a study that found chronic alcohol use may interfere with the genetic clocks in liver cells to accelerate liver damage. Dr. Bailey is a longtime liver disease expert with a new research focus on the role of circadian clocks in alcohol-related liver damage.

We thought to ask her whether too many martinis can throw off molecular clocks and, from a circadian point of view, what the healthiest hour is to drink a glass of wine.



Show notes for the podcast:

1:51 Genes are long chains of molecules that encode instructions for the building of the proteins, the workhorse molecules that make up bodily structures and signals. Interestingly, the process of turning genes into proteins proceeds at a certain rate, so it has become the basis of a system that keeps time like a clock. To achieve a biochemical balance necessary for life, many genes are part of pathways that sense when there enough of any given protein, and sends signals to shut down the building process: so-called feedback loops. The twenty or so genes and proteins that make up the human circadian clock happen to perform these loops in a roughly 24-hour cycle, and so evolution favored them. Creatures that happened to align their metabolism to these clocks became one with their environment and were more likely to survive. Thus, the cells making up most life on earth today -- bacteria, plants, animals, etc. -- include genetic clocks.

3:44 In a larger sense, the clocks show the ability of genes to adjust their action in the face of changing environment. Genetic changes in energy use also occur after meals whenever they occur, and during the flight or fight response.

4:35 One of the functions of the circadian clocks in every human cell type is to turn off metabolic pathways that produce cellular energy from food when we don't need them. While obviously vital to life, highly active metabolic pathways create byproducts like free radicals that tear apart sensitive cell components and cause cells to self-destruct as part of many diseases, including major ones related to energetics: diabetes and heart disease. Shutting them down at night may help us to live longer.  

5:33  A major focus of Dr. Bailey's research is the mitochondria, sub-compartments of human cells that convert sugar from food into cellular energy by using oxygen.  She is especially interested in the role of mitochondria in liver disease. Overproduction of free radicals by mitochondria in liver cells damages other parts of the same cells, and shutting down these pathways at night may give cells a chance to repair the damage. A key emerging question is how not circadian clock genes in the nuclei of liver cells signal to mitochondria to control energy production.

6:39  While most studies look at the effect of staying up at night on circadian biology, Dr. Bailey wanted to look at the effect of alcohol on circadian clocks. Some of her interest stems from the fact that neuroscientists have been exploring in recent years whether or not circadian clocks in nerve cells in the brain may contribute to the forming of addictions. Up until the current study, only a few studies had looked at the effect of alcohol consumption on peripheral cells (gut, heart, liver, etc.). It's really starting to take off, says Dr. Gohlke.

8:43 As whole, the body’s circadian clock is regulated by a part of the brain called the suprachiasmatic nucleus, which drives daily physiological and behavioral rhythms. The newest frontier, embodied by Dr. Bailey’s study, is the effort to understand the role of the circadian clock in each cell type, and what happens when the cell-specific clocks are out of sync with the central clock in the brain. The liver is the organ in the body most responsible for regulating system-wide energy needs and is charged with holding steady levels of sugar supplied to cells by the bloodstream. Studies have shown that molecular clocks in the liver help keep the blood sugar level constant as we eat and fast, sleep and wake., largely through adjusting levels of the hormone insulin. If we throw the clocks off, we throw our blood sugar off and contribute to the development of diabetes.

9:54  The liver also plays a prominent role in the amount of cholesterol and fat in the blood, as well as the breakdown of drugs in the bloodstream.  Should the clocks be shown to regulate those pathways and alcohol affects them, then chronic drinking hardens arteries, the leading cause of heart attacks and strokes, and contributes to obesity.

10:32 To study the effect of alcohol on circadian clocks, Dr. Bailey and her team separated mice into two groups, one that received a healthy diet, and a second that had the same diet plus a steady supply of alcohol (ethanol). They then collected brain and liver samples for both mice to look for changes in clock genes patterns. They found that expression of metabolic genes that normally up and down  in 24 hours cycles no longer do so with chronic alcohol use. It also looked like metabolic pathways that normally operate in sync became disjointed.

13:35 In a healthy individual, certain clock genes in liver cells are expressed three hours after the same genes are expressed in the brain. One theory holds that the time lapse is a temporal signal between the systems that monitor how much energy we need, and those that supply the right amount of energy in response.  If alcohol throws off the liver cell clocks, they may no longer proceed in sync with the brain clock. Such a loss of synchrony represents a potential disease mechanism in heart disease, diabetes and obesity.

15:56 Fatty liver disease, which is very common in the United States, is the earliest stage in the progression toward much more serious liver diseases like cirrhosis. It is also seen people in pre-diabetes or obesity. Healthy people store their fat in their fat cells, their adipose tissue, and not their liver cells. Dr. Bailey is interested in whether or not disruption of liver clocks contributes to this build up of fat in liver cells.

17:31 As the understanding of molecular clocks grows, researchers will seek to influences parts of the clock that contribute to disease. Research teams have already shown that some drugs, at least in animal models, can fine-tune clocks to counter weight gain. Dr. Baily is looking forward to testing whether such drugs can counter the contribution of clock genes, under the action of alcohol, to liver damage

18:03 Dr. Bailey's study did look at whether the expression of proteins that break down alcohol fluctuate with time of day, but not at how active those proteins are. She has proposed a series of studies that will seek to determine what time of day is best for that glass of wine. The studies so far at least suggest that there may be times of day when the liver is more or less vulnerable to the toxic effects of alcohol.

Mechatronics: from minivans that predict crashes to unmanned battlefield rovers

Remember the Subaru ad about how its cars "transfer power from the wheels that slip to the wheels that grip"?  Behind and beyond that jingle is an emerging field of engineering described by technical terms like mechatronics and agile vehicle dynamics.

Foxhound Vehicle. Courtesy UK Ministry of Defense.

The field seeks to design intelligent vehicles that adjust power distribution to the wheels, suspension stiffness and traction control with extreme speed in the face of changing road conditions. When perfected, such "agile" vehicles will make proactive decisions to avert crashes as the wheels begin to spin.

Systems that transfer power to the gripping wheels are also a must for vehicles meant to operate on loose soil for farming, construction, emergencies or military operations. Agile, unmanned vehicles, for instance, will soon negotiate the chaotic terrain of battlefields and disaster zones, making their own decisions while climbing out of ravines or driving over downed power poles.

We thought to talk with Vladimir Vantsevich, Ph.D., a specialist in vehicle design, as he gets set to host the UAB “agile vehicle” symposium Sept. 8-11, 2013, at the Hilton Birmingham Perimeter Park Hotel. The event will be the first to assemble experts in the specialty from around the world, and it will explore ground vehicle dynamics, energy efficiency and performance in severe environments.


Show notes for the podcast: 

1:17 Dr. Vantsevich earned his Ph.D. and Sc.D., the highest degree in the former U.S.S.R., from Belarusian National Technical University. Belarus is an independent country and home to several automotive design companies. In 1997, he received an assignment to work the deputy permanent representative from Belarus to as for the United Nations, where for the years he worked on issues related to the protection of intellectual property rights as part of the U.N. Commission on Science and Technology. After three and a half years there, he took a facutly position at Lawrence Technical University in Michigan, where he built automotive engineering programs for 11 years, before coming to UAB a year ago.

2:10  Dr. Vantsevich is a pioneer in the design of systems that distribute power between the wheels. What may seem like a technical detail has everything to with the ability of a passenger car to achieve traction on a wet road, not to mention its fuel efficiency

3:33 Dr. Vantsevich holds 30 certified inventions and is well known in the American Society of Mechanical Engineering, with most of his innovations concerned with slip differentials. A differential is a set of gears that enable wheels to rotate at different speeds as the engine applies power to them and as road conditions vary. When a car turns for instance, the wheel travelling around the outside of the turn must roll farther and faster than its counterpart on the inside. A limited slip differential is a gear arrangement that, in an off-road environment, senses when one wheel if off of the ground or has hit a patch of ice and transfers power to the wheels still in contact with the ground.

6:30 Alabama's reputation is growing internationally as a center for automotive engineering, and now is a great time to gather leaders in Birmingham to decide on next steps for the field. The symposium promises to have a positive impact on UAB and local automotive companies as well, potentially helping them to recruit talent to the area, Dr. Vantsevich said.

8:58 The symposium also focuses on dynamics, the study of what happens when you apply forces to a moving body, say a vehicle. What happens to a car when you combine the forces transmitted by the engine to the wheels with those applied by the wheels to the ground combined with a strong side wind?

12:14 Many ads about luxury cars talk about the "active safety features" available in new cars today.  Your car might issue a warning if you attempt to change lanes into space already occupied by another car.  It might tell you if you're about to back out of parking space into an oncoming car. Despite these wonders, there is still tremendous potential to improve these systems, Dr. Vantsevich said. To realize their potential will require researchers to develop theoretical and analytic foundations, the agile dynamic underpinnings of future systems. The symposium in Birmingham will launch some of those efforts.

14:48 There also may be value in creating unmanned vehicles that are autonomous, with no need for remote control as they go about their mission and stream intel back to headquarters. Such "ground drones" may save many soldiers lives, but only if they are capable of negotiating extreme terrain. If their mission requires them travel long distances, such vehicles must also be fuel efficient, and especially in the case of autonomous rovers deployed to the surface of Mars.

16:52  Furthermore, such unmanned vehicles would often have a "mission-related payload," like a robotic arm on top. Experts in mechatronics would have to consider how the weight and motion of the arm changed the agile vehicle dynamics and performance.as a rover drove up a steep slope.

18:54 While cars started out as mechanical systems, like wind up clocks based gears and mechanisms but no electricity, they have become something else, said Dr. Vantsevich. Cars today might have five computers, which is more than the space shuttle had. The interplay between mechanical, computer and electrical systems of any device, from a smart phone to a car, is the province of mechatronics. It's not just a combination of separate mechanical, electronic and computer systems, but an approach where different sets of physics become one.

23:55 In recent years, car designers have added many electronic devices to cars in seeking to improve their performance and fuel efficiency. An unintended result is that today's car has two kilometers of wires running though it that together weigh 30 kilograms. That weight that costs the car in fuel efficiency and handling, and mechatronics-minded engineers are seeking to reduce that burden.

28:02 Dr. Vantsevich seeks to develop a world class program in mechatronics at UAB, which will include courses at the bachelor's, master's and Ph.D. level. Newly offered courses include "introduction to mechatronics, design of robots and design of hybrid vehicles, the latter in partnership with The Southern Company. As electricity producers, power companies like The Southern Company have taken an interest in charging stations for electric cars and in the cars themselves.

29:07  The symposium starts on Sept. 8 and is formally titled The Agile Ground Vehicle Dynamics Energy Efficiency and Performance in Severe Environments International Engineering Symposium. It will be hosted by the UAB School of Engineering and Department of Mechanical Engineering, Barber Motorsports, Southern Company, the Birmingham Chapter of American Society of Mechanical Engineers and the International Society for Terrain Vehicle Systems.
                                                    
Speakers will include:

• Thomas Gillespie of Mechanical Simulation Corp.
• Japan’s Masato Abe of Kanagawa Institute of Technology; 
• Donald Margolis of University of California, Davis; 
• Jianbo Lu of Ford Motor Company; 
• Delbert Tesar of University of Texas, Austin
• Lev Barakhtanov of Nizhny Novgorod State Technical University and others.

Other symposium participants will include Ford Motor Company, General Motors, John Deere and Volvo.
Conference registration is $250 for students and professionals from developing countries, $550 for professionals and $750 for exhibitors. Registration discounts are available to local companies and academic institutions. UAB students, faculty and staff may attend workshops at no cost, but must pay to attend the banquet. For more information, contact Dr. Vantsevich at vantsevi@uab.edu or 205-975-5855.

Scratch-and-Sniff test for Parkinson's disease

Many of us grew up with iconic scratch-and-sniff technology. Maybe kids in your class had stickers that smelled like berries or popcorn when scratched. Mom's fashion magazine offered pungent samples of the latest perfume. According to its Wikipedia entry, everything from Nintendo video game packaging to a smell guide promoting the movie Spy Kids to Katy Perry's album Teenage Dream (cotton candy) have featured micro-fragrance coatings. Apparently, 3M came up with it by accident in the '60s during experiments on a copying technology.

Given the technology's pop-culture history, I was surprised to read a recent story in the Birmingham News that it is now being used to test people for early signs of Parkinson's disease. The story features video of David Standaert, M.D., Ph.D., chair of the Department of Neurology within the UAB School of Medicine, demonstrating the test. We asked him to talk about the science behind the test, as well as his team's involvement in a related study funded by the Michael J. Fox Foundation.



Show notes from the podcast: 

1:15 While the credit for the discovery of microfragrance coatings goes to 3M, it was the University of Pennsylvania that spent years developing the standard, scientific method for testing a person's ability to smell. Penn researchers must have had their reasons for including in the test certain smells -- dill pickle, grass, smoke, peach, turpentine, etc. -- but an explanation will have to wait for another post.

1:51 Researchers have known for years that people with Parkinson's disease lose their ability to smell, but not why. Neither did anyone make a connection between scratch-and-sniff technology and Parkinson's diagnosis for many years. Researchers first noticed the change because Parkinson's patients typically lose weight. Without the ability to smell, food loses it taste.

2:23  Old theories had it that Parkinson's disease, by interfering with muscle movement, meant that patients could not sniff as well. That idea was debunked by the work of German neuroanatomist Dr. Heiko Braak in 2003. His painstaking study revealed that among the first brain regions damaged as Parkinson's disease develops is the olfactory center.

4:07. People also lose their sense of smell after head trauma or exposure to harsh chemicals. This led to the major questions in the field like "what does it mean to lose your sense of smell?" and "can smell tests accurately reveal a change in the brain that points to pre-symptomatic, Parkinson's?" If you take a group of people who have lost the ability to smell and follow them through the years, what does that reveal?

4:40  The classic indicator that someone has Parkinson's disease is that their limbs begin to shake (tremor). In recent years it became clear that such a person's dopamine neurons have already lost about 70 percent of their function. An earlier warning sign is a must.

5:05 The damage of caused by Parkinson's to dopamine neurons probably starts a decade before hands start to tremble. Researchers once that the death of such nerve cells was the first thing to happen in the disease process, but not believe it happens in the middle.

6:10 So what happens first? Over the years, researchers had noted that people who would later go on to develop Parkinson's disease first suffered from a strange group of symptoms: sleeplessness, constipation and of course, loss of the ability to smell. With these symptoms so disparate, researchers did not realize for many years that they are influenced by buildup of the same protein, called alpha-synuclein, in the nervous systems of Parkinson's patients.

6:46 Those taking the Parkinson's sniff tests scratch a series of smell pads and answer questions about what they smell. Dr. Standaert's team tests people over 60 years of age, with thee expectation that about a third of them, if they have a sufficiently abnormal sense of smell based on a standard numerical score, will turn out to be in the early stages of Parkinson's disease. So if you are over 60 and can no longer smell normally, you have 66 percent chance of not having Parkinson's and a 33 percent chance of having it (up from 1 or 2 percent risk for the general population).

8:15 Another major thrust of the team's work is to study how nerve cells and nerve pathways that employ the major signaling chemical dopamine to pass on messages are different in people who have lost their sense of smell due to Parkinson's disease. It if turns out that people with with smell loss have a corresponding drop in dopamine function, the team will follow them over several years in hopes of revealing further details on early disease-causing mechanisms in Parkinson's disease.

11:00 Many labs are rigorously pursuing experimental drugs meant to slow the progression of Parkinson's disease. Should one or more of them be approved for use in the relatively near future, one can envision the creation of smell test screening programs for everyone as they turn 60. Those that do poorly, would then be referred for further testing, and preventive treatment could begin much earlier. In terms of a public health intervention, it would be relatively low cost because you could mass mail the sniff test cards with return postage, and people could mail them back in.

Those interested in more information or in participating in future trials should look up the Parkinson’s Progression Marker Initiative, or the Michael J. Fox Foundation survey. Those interested in local trials in Birmingham call also email Stephanie Guthrie at slguth@uab.edu.

3D printing: bones, buildings and burgers

I first saw 3D printing at work in the movie Mission Impossible II starring Tom Cruise, which debuted 13 years ago. It seemed like at every turn, some spy was printing out a life-like 3D facial mask to impersonate his enemies.

Action flicks tend to preview near-future technologies, and 3D printing has gone from science fiction to an over-hyped but cutting edge research area since MI 2. The printers in question print 3D objects out of plastic or concrete instead of flat images on paper using ink. To show why the subject seems to have captured popular imagination, here is a short list of objects that may be printed in the near or distant future, according to recent articles:

• Replacement teeth, ears, skin, heart valves and fingers 
• Buildings (by teams of mobile printers)  
• Burgers and pizza on long space flights. 
• Robotic octopus suckers to help robots grip

Our guest for this podcast is Kenneth Sloan, Ph.D., professor in the Department of Computer and Information Sciences within the UAB College of Arts and Sciences, and director of UAB’s 3D Print lab. As described in an article by UAB Magazine's Matt Windsor, 3D printing may have applications in areas as diverse as medical implants, gaming, archeology and crime fighting. As Dr. Sloan says, there may soon be a 3D printer in every kitchen, and available in designer colors, but who knows what we will use them for.

Show notes for the podcast

1:25 Instead of ink, one kind of 3D print head pushes out extremely thin layers of superheated material that instantly cool to hold a desired form. Most of the 3D printers at UAB lay down layers of melted plastic 1/100th of an inch thick. They then move the print head up a bit and do it again, until the 2D layers stack up into a 3D object.

2:27  A second kind of 3D printing cures material in layers. You start with a box full of powder, and the printer lays down liquid in layers that hardens the power in the desired pattern. What you end up with is a box full of powder, with the desired object inside of it.  You open the box, grab the object and shack of the lose, uncured powder.  Interestingly, since concrete is hardened by combining liquid with powder, this has enabled researcher to 3D print objects in concrete.

3:30 An important challenge in 3D printing is that engineers must often design and print out a framework right alongside the target object so that the object doesn't collapse have way through being printed.

4:13 3D printing technology has been available for 20 years, but the computational power is just arriving now to make it useful and available to all. The advent of cloud computing meant that most researchers can now afford to program complex combinations of objects and supporting frameworks. Otherwise, 3D printers are made of standard tinkerer elements like small electric motors, sprayers and heating elements that have been around since the 1950s.  

4:38 What makes 3D printing require computing power are the calculations about where to lay down solid material in space as you build the object in layers, as well as the translation of spatial relationships from a 3D model to a series of 2D slices.

6:05 For many years, engineers have looked at 3D graphical displays on computer screens when designing prototypes. They work through a series of rapid design changes for an invention, testing and rethinking versions along the way. 3D printing allows engineer to print out the object at each stage in rapid prototype design. They can test fit it against other parts of whatever they are creating. They can roll it around in their hands. 3D printing allows for the fast manufacture of quick, cheap, multiple versions of a prototype invention in plastic to solve problems before fabricating it from an expensive metal for instance.

7:03 3D printing enables the creation of complex objects that no other process can create. There are several examples on Dr. Sloan's website that you cannot take apart, and that you could not assemble out of pieces in the first place. By printing interlocking pieces in layers, the final product is made of moving pieces that cannot be assembled or dis-assembled.  Picture a door that is one solid piece with it hinges. The door swings on the hinges, but you can't remove the hinges. Fun examples of this kind of object include puzzles. Dr. Sloan mentioned that one MIT student had even designed a 3D-printed a Rubik Cube, a single, interlocking movable puzzle as opposed to the original, made of separate pieces that snapped together.

9:24 Plastic and concrete were the first materials used in 3D printers because they are easy to melt or harden quickly into durable materials. Plastic melts easily and can be shot through a print head. Concrete starts as a powder and object can be shaped by selectively getting it wet. The interesting thing is that any substance that meets either of these criteria might eventually be 3D printed, from ceramics to metal to glass to chocolate.

11:08  Dr. Sloan's original area of expertise was in computer graphics.  The field had delivered tremendous value to engineers by developing the capability to display 3D digital images of desired objects on computer screens. That said, researchers had long wished that they could cheaply 3D print digital designs. With every decade, a "zero has been chopped off the price" of 3D printers, and now most labs can afford one.

12:13 Beyond assembling equipment, Dr. Sloan has reached across UAB to offer a 3D printing service of sorts to researchers in many disciplines. With a main mission of educating students in 3D printing, his lab might have been satisfied with using "hobby level" printers, or with sending out big jobs to specialty "print farms."  By hatching collaborations across campus, he has been able to centralize equipment costs and expertise to offer more advanced 3D printing to many research efforts that couldn't do it alone.  By making this offer, his lab has enjoyed a steady flow of inquiries from researchers proposing to use 3D printing in wasy he never could have imagined. Meanwhile, his student now have unparalleled access to real world design projects.

Lamina cribrosa

14: 26 An example of an interesting, unexpected project was the 3D printing lab's collaboration with the UAB Department of Ophthalmology. The lab was able to 3-D print a computer model designed by eye researchers of part of the optic nerve, the lamina cribrosa, known malfunction in the development of glaucoma. Apparently, our eyes our sealed, with a certain pressure maintained inside. This is complicated by the need for the optic nerve to pass through the outer membrane of the eye as it carries information about images from the lens into the brain for processing. Making this possible is the lamina cribosa, a web-like mesh through which the optic nerve fibers can pass out of the eye without losing pressure. This feature of the anatomy is about two millimeters across, but Dr. Sloan's team was able to 3D print an eight-inch version. This enabled the research team to pick it up, look through it and roll it around in their hands for the first time. Since then, Dr. Sloan has watched as a series of eye researchers, including his wife, UAB anatomist, Christine Curcio, Ph.D., have picked up the model, spun it around and said,"...interesting, I never realized that XX."

16:59 Dr. Sloan also highlighted the ability of 3D printing to be useful to bioengineers seeking to design scaffolds. The body has an amazing ability to regrow skin, bone or muscle lost to injury or disease, but it often needs help. His lab is involved in current UAB research projects seeking to design of mats or scaffolds or weaves of material that act as a guide and support for tissue trying to grow back together in an orderly fashion. 3D printing may be especially useful in creating scaffolds out of biodegradable materials. That would enable surgeons to implant a scaffold that aids in tissue regeneration without requiring a second surgery to remove the scaffold later. It would simply dissolve about the time it was no longer needed. Dr. Sloan's lab has one printer that prints in a biodegradable, nontoxic material, and there has been a steady stream of researchers from the medical end seeking to build it into research projects.

18:32 3D printing will be valuable to regenerative medicine for the same reason it is useful in rapid prototyping. It lends itself to creating a single custom implant for each patient, versus technologies that require mass production of one-size-fit -all implants to break even.

19:32 Dr. Sloan believes that it will be possible in the next five years for biotechnicians to 3D print skin to cover wounds and burns, knee cartilage and heart valves. These are examples of the more straightforward, uniform tissue types that lend themselves to current 3D printing technologies. Unfortunately, he said there is also a great deal of hype surrounding 3D printing right now, and stories that predict the imminent arrival of printed, complex organs with intricate cellular structure are not realistic. These structures would require technologies that 3D print with a nanoscale resolution, and are still a long way off.

21:50 Beyond medicine, a recent article in Discover Magazine talked about how 3D printers may one day print out meals for future astronauts on long spaceflights. Dr. Sloan said burgers and pizza would be on the 3D printing menu, but not steak. The reason for this are the same ones that determine the field's ability to print out skin but not a brain. Burgers and pizza be printed out of somewhat homogeneous, simple materials that hold their form in layers as they are printed and then cooked. A pizza printer might have five printer cartridges that spew layered shapes that bake into a pizza. Steak is tissue, with a complex microstructure beyond the reach of current technologies.

24:40  Dr. Sloan this week attended the Inside 3D Printing Conference in Chicago, which included an exhibit of 30-foot high concrete sculptures made using 3D printers. He is currently seeking collaborations with artists and sculptors who wish to 3D print fantastical forms by curing concrete out of powder. Layer-by-layer printing may make possible the creation of interlocking, complex sculptures that would fall apart in mid-assembly if made any other way.

26:06 Moving from art to architecture, Dr. Sloan said he has seen reports of researchers experimenting with the idea of 3D-printed buildings. If one can print a 30 ft by 30 ft sculpture, it may be possible to print a 300 ft by 300 ft building. Furthermore, builders may one day dispatch a team of mobile robots with built-in 3D printers to assemble different parts of a building at the same time. The same idea goes for shooting robots to the moon that could mine local materials and and then 3-D print a moon base before the people even arrive. An advantage of large-scale 3D printing would be that you no longer have to build a structure out of pieces (nails, beams, etc.). That leaves the architect free to design any structure that will stand once complete.

28:23 Dr. Sloan hesitated to predict how we might use 3D printers in the future. He said he is old enough to remember when personal computers were just a pipe dream. As their advent approached, articles mistakenly predicted that we would use them to store our recipe files and to tell us what to make for dinner based on what was in the fridge. "Who knows how we will use 3D printers around the house?" If it gets cheap and useful enough, people will invent their uses for it.

Here are a few more, recent 3D printing articles from around the web:

New Scientist: Windows aims to open 3D printing to the masses

CNBC: How 3D printers are reshaping medicine

Time: Chicago 3D print shop open for business

AHA president: genetics will revolutionize heart disease treatment, but for now, eat better

Cardiologists are increasingly checking patients’ unique genetic profiles as a first step in caring for them. This may partly explain why the American Heart Association last year elected a UAB genetic epidemiologist as its president in Donna Arnett, Ph.D. As her term ends this week, we thought to talk to her about her year in office and what's next in the treatment of massive, global health problems like high blood pressure.

Within the UAB School of Public Health, Dr. Arnett is chair of the Department of Epidemiology, the science that examines patterns in populations, including who is at risk for major diseases and why. She leads several nationwide studies looking at whether genetic variations in each person make them more at risk for heart diseases – or less likely to respond to commonly used anti-cholesterol or anti-inflammatory drugs.

What came across is her passion for scientific inquiry and determination to find better treatments for the families at higher risk for heart disease thanks to their genes. At the same time, she is the first to recommend that Americans get some exercise and eat better, rather than depend on genetics to eventually yield cures.

Show notes for the podcast:

1:40  Dr. Arnett began her career as a clinical research nurse working in a veterans hospital, and proceeded to become a leading genetic epidemiologist in cardiology and AHA president. Much of her inspiration has come from her strong curiosity, a need to ask questions. Early in her career at the veterans hospital, she wanted to know, for instance, why African Americans with the same level of high blood pressure as whites often had more serious kidney damage. Why were African Americans also more likely to have left ventricular hypertrophy. It's a thickening of the muscle in the left ventricle, one of the heart's chambers, that comes with fibrosis (scarring) and increased risk for heart attack and stroke. Why did people have different responses to the same doses of the same drug?

2.04  Unanswered questions drove her forward into the field of genetic epidemiology just as it was being founded. She said it was just good luck that she got into a field just as it was taking off.

3:00  She worked as a research nurse in general cardiovascular studies, but her office at the time was down the hall from the hospital's dialysis center. She got to know some of the veterans, and was struck by how many of the dialysis patients with severe kidney damage were African Americans. The experience brought home the human cost of the genetic contribution to disease.

4:15 Dr. Arnett said cardiology as a field is behind neurology and oncology, not only in genetic epidemiology, but also in pharmacogenomics, the study of the effect of each person's genetic variations on their response to drug treatments.

5:25  In her speech last year as began her term as AHA president, Dr. Arnett spoke about on the theme of  “transforming cardiovascular health through genes and environment.”  As a genetic epidemiologist she has a passionate interest in searching for genetic clues that may influence each person's disease risk. Some families with no traditional risk factors (not overweight; don't smoke) have struggled with tremendous disease burden and premature deaths. So learning how genes contribute to that is a must. That said, the thing that could save most lives from heart disease in America today would be a focus on environmental factors like the obesity epidemic. Our lifestyle is dominated by processed foods and sedentary inactivity, so Dr. Arnett believes we need to be "battling at both ends."

6:50  A focus of Dr. Arnett's tenure as AHA president has been hypertension or high blood pressure.  It affects more than a billion people in the world, and does tremendous damage. On the bright side, nations and  international institutions are starting to pay attention. The United Nations has held summits in recent years on diseases like hypertension that are caused by diet and lifestyle, where past efforts focused on infectious diseases. The World Health Organization has launched a campaign meant to reduce non-communicable diseases by 25 percent by 2025, with hypertension as a major focus.

7:25 In the U.S., the American Heart Association this year has partnered with the Million Hearts Initiative led by the Department of Health and Human Services, in an effort to prevent one million heart attacks in the next four years. The partnership will seek to achieve this goal through a combination of awareness campaigns, better access to care, new monitoring programs and initiatives that help people to take their medicine. Dr. Arnett said only a multi-pronged approach that include individuals, physicians, pharmacists, employers, companies and government agencies, combined with culture change, has a chance of making a difference.  New technologies may help the cause, including smart phone apps that monitor blood pressure and upload it directly to a patient's electronic medical record.

9:45 The field of genetics within cardiology continues its high-speed evolution, she said. It's moving toward analysis of each person's entire gene code, or genome, to look for small differences that contribute to that person's risk for heart disease. Past approaches that tried to find a  few genetic differences that placed large numbers of people at risk across populations are giving way to the study of individuals. Technologies have evolved to the point that whole genome sequencing of individuals is becoming affordable. It is being used around the country, said Dr. Arnett, to help diagnose diseases that seemingly have no cause. She and her colleagues are also using it to search for rare genetic variations that cause higher risk for left ventricular hypertrophy in some families.  

11:45 Dr. Arnett has focused on left ventricular hypertrophy in her work because it is one of the four basic causes of heart disease -- along with smoking, high blood pressure and high cholesterol -- first identified by the landmark Framingham Heart Study in 1967.  It is also the only one of the four that still has no known treatment for it (apart from lowering blood pressure).

12:38  The modern day life of the human body has changed drastically from the one in which it evolved, said Dr. Arnett.  We went from running constantly to hunt and eating mostly plants during the first 8,000 generations of human existence, to sitting on the couch eating a steady diet of fatty, heavily salted food for the last four generations.  Looking back even further, Dr. Arnett said, we evolved from saltwater fish, and with fine-tuned bodily mechanisms for regulating salt. The refrigeration and processing of food came about after World War II, drastically changing the way we eat. Heavily salted foods have changed the fluid balance in our bodies, which is regulated by the kidneys, to result in pandemic high blood  pressure. Our genes may be slowly evolving to better handle salt but it will take many generations. .

Human body as skin-growing factory?

It happens quickly, say surgeons. You step off a curb or light a backyard grill, and your life is changed forever by profound injury. Patients arrive at major trauma centers every day with burns covering most of their bodies, or with a combination of skin, bone and muscle lost to terrible circumstance. Trauma surgeons do what they can to put things back together but are limited by today's tools.

In recent decades, surgeons have partnered with bioengineers to try to create better technologies for the replacement of lost tissue. They still have a ways to go, but surgeons may one day take a product "out of a box" and use it to patch large gaps of missing tissue.

Along these lines, research efforts captured in a recent Wired Article seek to create truly artificial replacement skin out of self-healing polymers and flexible electronics. Another near-future approach will be to use a patient's own body as a high-speed skin-producing factory with the help of appliances, engineered proteins and biochemicals.

We asked Steven Thomas, M.D., a UAB specialist in reconstructive surgery for patients with complex wounds and severe burns, for his take on both approaches. As an assistant professor in the Department of Surgery within the UAB School of Medicine and a former army surgeon, Dr. Thomas has spent much of his career looking for a better way to repair damaged tissue, layer by layer.


Show notes for the podcast:

00:56 UAB has the biggest burn and trauma centers in Alabama and Mississippi, and Dr. Thomas' team deals regularly with patients that have lost large amounts of skin, muscle and bone.

2:21 Burns pose a particular challenge when it comes to repairing skin, especially when all layers of skin (dermis, epidermis, etc.) have been destroyed. This requires surgeons to borrow skin from the non-burned areas. They can then use bioengineering techniques to regrow skin, but currently technologies do so slowly. When burns cover the majority of the patient's body, it is a challenge to regrow enough skin fast enough to avoid scarring.

3:22  According to Dr. Thomas, there is no current treatment option that efficiently and quickly makes available large amounts of replacement skin. Those that are available cost hundreds of thousands of dollars, require multiple procedures and don't work for all patients.

3:45 One product on the market now called the cultured epidermal autograph is grown from a patient's own skin cells by the biotech company Genzyme. From 2 postage stamp-sized biopsies, the company says it can  grow enough skin to cover a patient’s entire body, but it may cost $600,000, said Dr. Thomas. What the field needs is inexpensive replacement skin that you could take off a shelf and apply.

5:10  Many current research efforts seek to create good artificial skin, but no one product has gelled yet. Today's attempts are not durable enough, he said, and need to be replaced by something that can be shipped and stored without losing its useful properties.

6:48 Some of the frontiers in artificial skin research include polymers that can knit themselves the way real skin does, but nothing to date does the job as well as the body itself  The problem is large gaps in skin, which scar instead of knit.

7:58 Dr. Thomas is convinced that the future of the field will be in using the patient's own body as a high-speed bioreactor to make replacement skin, but it needs help. A current UAB research project led by graduate student Paul Bonvallet in the lab of Susan Bellis, Ph.D. seeks to provide that help using the protein collagen taken from cows. Collagen is the ingredient that gives shape, strength and structure to the body's connective tissues like bone and tendon, as well as to skin.

8:15 The UAB project is having some success in laying a mat of collagen across large areas where a patient has lost all layers of skin. The mat serves as a framework or scaffold that enables the skin to re-knit in an orderly way over of the dermis. The experimental product contains no cells, but the body populates it as needed.

8:42 UAB is among the first in the country to combine dermis scaffold and skin grafts to get patients re-covered with skin after major injuries. Dr. Thomas mentioned one accident victim that was hit and dragged underneath a garbage truck, loosing much of his skin, along with some bone and muscle, from the waist down. Through a combination of therapies, the surgeons were able to re-grow the lost skin, and the man is up and walking today. Dr. Thomas believes that in most places that man would have lost his legs.

9:21 Underway already at UAB are efforts to combine scaffolds with different mixes of stem cells and enzymes that encourage growth. The combination of framework and tailored cells is getting closer and closer to mimicking native tissue, itself a mix of cells and scaffolds.

10:09 Depending on the type of collagen used, it can act as the highway with guide rails that shows skin cells the pattern they need to grow in to cover over a wound or burn. Some types of collagen are better at doing this without leaving a scar. Dr. Thomas' team has been able to get good-sized wounds to heal in a few weeks using collagen biotechnology that used to take months.

11:57 Returning to the effort to generate truly artificial skin mentioned in the Wired article, Dr, Thomas said that the military has invested in such technologies in hopes of better regenerating skin for wounded soldiers. Institutions like DARPA, the Defense Advanced Research Projects Agency, and AFIRM, the Armed Forces Institute of Regenerative Medicine, fund related research projects.

12:15 Dr. Thomas thinks that, while the body may be best at creating skin for burns and wounds, artificial skin made from polymers has the potential to dramatically improve the nature of artificial limbs. During his years at the Brooke Army Medical Center burn unit, Dr. Thomas saw lots of amputees come in, and worked with many soldiers trying to get used to prosthetic limbs. He said today's prosthetic arms have no proprioception, the sense of where the limb is in space and with respect to the rest of the body. They also have no sense of touch. Creating limbs with these capabilities would represent a huge leap for people with prosthetics, he said.

14:00 Dr. Thomas has worked with the Bellis lab experimenting with electrospinning, a process that uses electrical charge to draw a nano-scale thread of material from a liquid. It is particularly suited for the production of fibers out of large and complex molecules like collagen.  Electrospun collage can be woven into mats that promote cell growth and the penetration of cells into the engineered scaffold.  The other great thing about electrospun materials is that they are inexpensive.

15:59 To fill in a complex wound, Dr. Thomas would like to have a treatment that could regrow skin, muscle and bone in layers. Stem cells engineered in concert and in layers to achieve such complex healing is a future possibility, he said. It may be too much to ask one product to achieve all that, and may require a combination of stem cell-driven products used together with precise timing.

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).