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.

Advice for scientists from a Nobel Prize winner

The UAB School of Medicine recently played host to its leading regional forum, the Spring Immunology Symposium. Proof of the event's growing influence can be seen in  this year's keynote, Nobel Prize Laureate Rolf Zinkernagel, M.D., Ph.D., Professor in the Institute of Experimental Immunology at the University of Zurich. Dr. Zinkernagel won in his Nobel prize in 1996 for discoveries that helped to explain how the human immune system recognizes that one of its cells has been infected by a virus.

Included here is a brief video of Dr. Zinkernagel talking about his life's work, what young scientists should be thinking about and frontiers in immunology.



Dr. Rolf Zinkernagel, UAB Immunology Symposium, June 2013 from UAB School of Medicine on Vimeo.

Below is a summary of the video discussion in a Q&A format.

Q1. What should young people keep in mind who want to get into science and immunology?

• Success requires a scientist to be prepared for a ratio of 1 percent success to 99 percent failure and that a researcher perservere. 
• Young scientists should be prepared to work long hours because "the harder you work the luckier you get,"  
• It is important to find a research subject that you feel is extremely important and one where you burn to know the answer.  

Q2. What were the key decisions that led you to success in your field?

• Among Dr. Zinkernagel's important early decisions as a scientist was to first become a medical doctor. It enabled him to learn study a complex bodily system, the immune system, in its entirety as a foundation. 
• Dr. Zinkernagel started as a surgeon, but then got interested in immunology because of the immune rejections seen with transplanted organs. His focus remained on infectious disease from there on out, and not entirely by design.

Q3. What are your thoughts about how science differs around the word (e.g. in the U.S. versus Europe)?

• The United States, and the UK as well, treat research like a sport in some ways, with a spirit of "fierce, competitive openness" that gives new researchers an opportunity to show what they can do, and with relatively few restrictions. Of his native Switzerland, Dr. Zinkernagel said it has a good research environment, but its small size limits opportunities when compared to larger nations. 
• He also lauded the opportunistic outlook of the average American. That becomes important as researchers face seemingly unsolvable science problems, but just keep trying. 

Q4. What will the future of immunology look like?

• The next few years will see scientists gain a more and more detailed understanding of the processes and pathways involved in the immune system. He said that the field may go so deep that it identities a set of uniform processes because, at the root of everything, cells are cells despite their different functions.  
• That said, how cells and organs interact, the province of systems biology, still has a long way to go before researchers understand the sum of complex interactions that result in health or disease.
• In addition, immunology is a relatively "soft" science compared to physics, said Dr. Zinkernagel. There are yet many unknowns and presumptions that persist despite a lack of evidence to back them up, and many will turn out to be wrong. In that light, those involved in teaching the next generation of immunologists should take care to instill a combination of open-mindedness and critical thinking in their students.   

For a look back, here is another video created by Nobelprize.org after Dr. Zinkernagel won his award.

Food fungus worsens African AIDS epidemic

I keep coming across factors that, while not directly related to the nature of the human immunodeficiency virus (HIV), are nonetheless driving the African AIDS epidemic.

Take the recent news about a study from the School of Public Health, which found that a type of fungus coating much of the stored corn, rice and nuts in many African and Asian countries may be weakening immune systems and encouraging HIV infection.

Kept in sacks piled in warehouses, food stores in countries near the equator are often contaminated by Aspergillus flavus and A. parasiticus, fungi that produce a toxic substance called aflatoxin.

About 4.5 billion people worldwide are exposed to aflatoxin at unsafe levels, and chronic exposure has been linked to liver damage and related cancers.

Work by Pauline Jolly, Ph.D., professor in the Department of Epidemiology within the UAB School of Public Health, argues that aflatoxin exposure may be taking an even greater toll in areas where millions are infected with HIV. The research team divided 314 HIV-positive people from Kamasi, Ghana, into four groups based on their level of aflatoxin exposure.  The team found that those in the highest exposure group were 2.6 times more likely to have a high HIV viral load than those in the lowest exposure group. Higher viral load translates into higher rates of HIV transmission. For information, please see our news release and related coverage by the New York Times.

Along the lines of non-viral factors worsening the AIDS epidemic was another study published this past August, also from the School of Public Health. Janet Turan, Ph.D., associate professor in the Department of Health Care Organization and Policy, and her team found that the fear of being labeled HIV-positive was strong enough to keep mothers from Kenya from having their babies in health-care facilities. Communities there have come to see clinics and skilled care as mostly for HIV-positive women, and HIV often is linked to promiscuity in the eyes of a woman's family.

In Nyanza, Kenya, a region where one in five pregnant women is HIV-positive, skilled care during pregnancy and birth increases the likelihood that those infected will receive antiretroviral drugs that prevent the passing of HIV from mother to child.

It just seems like Africa can’t get a break.

More troubling yet, the search for solutions to the epidemic's many contributors is not accelerating in the age of research budget cuts. The grants that paid for Jolly's research into the aflatoxin and HIV have ended, leaving her unable to pay for a full data analysis of the consequences of combination exposure on sets of immune cells. She does not know where her next round of funding will come from.

“A fungal contribution to HIV transmission will only be proved once and for all by larger randomized studies for which there now is no funding," Jolly said. "The scientific and world-health communities need to decide soon whether or not this question is worth answering.”

Image post 5: eye nerves shed light on memory disorders

While most posts from The Mix feature a science story, we have also begun sharing images coming out of UAB research. Below is a brief description of what we are looking at and how related work may contribute to a better understanding of Alzheimer's disease.

Pictured here is a retinal ganglion (center), a kind of nerve cell near the eye’s retina that helps to process light into the images we perceive. It had been injected with a fluorescent dye, which made it glow green along with the cells connected to it electrically. In each of our eyes, 125 million photoreceptors capture light. They then trigger nerve messages in 1.5 million retinal ganglion cells, long extensions of which bundle together to form the optic nerve.

Captured by Christianne Strang, Ph.D., research instructor in the Department of Vision Sciences within the UAB School of Optometry, this image represents signaling mechanisms between the retina and surrounding nerve cells. Strang's lab seeks to understand how photoreceptors connect to surrounding nerve pathways, as well as the degree to which they signal using the neurotransmitter acetylcholine.

Within nerve pathways, each nerve cell sends an electric pulse down an extension of itself called an axon until it reaches a synapse, a gap between itself and the next cell in line. When it reaches an axon’s end, the pulse triggers the release of chemicals called neurotransmitters that float across the gap. Upon reaching the other side, they either cause the downstream nerve cell to “fire” and pass on the message, or stop the message. Certain neurological diseases, including Alzheimer’s, have been linked to a decrease in acetylcholine signals in nerve pathways related to vision and memory.

As for rest of the color scheme, the pictured eye tissue has also been treated with dyes that interact with choline acetyltransferase (blue), which helps to produce acetylcholine, and synaptophysin (red), which reveals the location of synapses. The work was done in the lab of Kent Keyser, Ph.D., professor in the School of Optometry.

Jolie news highlights changing nature of mastectomy

Breast cancer cells

The world pays extra attention to diseases when celebrities have them, so it dominated the news this week when actress Angelina Jolie revealed that she recently had a double mastectomy. Tests had revealed she has the BRCA1 genetic variation known to drastically increase breast cancer risk. A sad detail in her case was her mother's death from the disease, which points to the interplay between genetic tests and family history when assessing risk.

The media did a good job of explaining that each case is different, and that women should make decisions with respect to breast cancer surgery in partnership with their doctors and genetic counselors. Included in the coverage was a fine piece by The Associated Press that described how women who make the same decision as Ms. Jolie now benefit from new approaches and technologies.

The nature of mastectomies has changed in recent years to save more of the breast, reduce scarring and pain and, in some cases, to enable breast reconstruction during the same surgery that removes the cancer. About 220,000 women are diagnosed with breast cancer each year in the United States, and 40,000 die.

We asked Helen Krontiras, M.D., co-director of UAB Breast Health Center and scientist at the UAB Comprehensive Cancer Center, for her take on the news and emerging trends in breast cancer surgery, which is her specialty.

Making it easier

Women who had double mastectomies in years past likely faced the removal of their entire breasts, including nipples and good deal of skin. They then faced a series of surgeries required to rebuild the breast with skin taken from the belly, construct a nipple and tattoo a ring around it.

Today, most women chose to have some degree of reconstruction done during the same surgery as their mastectomy, said Dr. Krontiras. For reconstruction requiring implant, surgeons must still, in many cases, put in expanders to stretch the skin for a time before a second surgery to put the implant in. Some patients go straight to implant at the time of mastectomy. According to the AP article, about 25 to 30 percent of women nationally get immediate reconstruction.

Despite a growing focus on the cosmetic aspects of breast reconstruction, Dr. Krontiras emphasized that the first goal is obviously to remove all the cancer. Second to that, but still important, is the effort to preserve cosmetic outcome. In some patients, she starts with chemotherapy first to try to shrink the tumor to the point that patients become candidates for skin saving techniques. One factor making this possible is the increasing sophistication of chemotherapy against breast cancer based on the realization that breast cancer can be one of several cancers, with treatment now tailored for each patient's genetic make-up.

In addition, new approaches to mastectomy that save original nipples are gaining in popularity. Many studies now show that the rate of local breast cancer recurrence in patients that retain their nipple and areola are low and on par with older procedures that remove them, Dr. Krontiras said. Injections of body fat are used in some cases to fill in defects that may occur as a results of removing breast tissue.

Looking forward, women may one day benefit from an experimental out-patient technique called cryoablation. A liquid-nitrogen-cooled probe freezes bits of cancer to death, with the dead cancer tissue removed by normal bodily processes. The technique is currently being tested in clinical trials.

Talk it over

Jolie made the decision to have the double mastectomy because counseling revealed she had the BRCA1 gene, and because her mother had died of breast cancer. It has been reported that her health team told her she had an 87 percent chance of getting breast cancer.  Of course, such numbers are the opposite of universal, and vary greatly form patient to patient.

Dr. Krontiras recommends that women diagnosed with the BRCA 1 or 2 gene start with a discussion of options with their doctor and genetic counselor. Each patient’s risk for cancer will be managed by varying combinations of surveillance, chemoprevention and prophylactic surgery of breasts and/or the ovary. There is no once-size-fits-all approach.

She added that she hopes the widespread attention generated by Jolie’s announcement does not lead to a whole-sale increase in requests for mastectomy. Genetic predisposition for breast cancer affects less than 10 percent of all women diagnosed with breast cancer.

However, women who do carry such a gene can have an up to 85 percent lifetime risk for breast cancer. Therefore, asking questions about family history are important, and patients need to learn about risk on both their mother’s and father’s sides of the family.

While the BRCA genes are important predictors of breast cancer risk, they are likely to be the first of many as yet undiscovered genetic and familial factors that contribute to risk, Dr. Krontiras said. Even those with negative BRCA tests should be watched closely if family members have developed breast cancer.
     
Women and family members interested in genetic counseling with respect to breast cancer can visit the UAB Cancer Genetics Clinic site. There is a website offered by The National Society of Genetic Counselors that has information about family history, as well as another by the National Cancer Institute on preventive mastectomies.  More commentary is available in this UAB news story and in this article and video from Medpage Today.

Image post 3: dangerous clumps of fungus

While most posts from The Mix feature a science story, we have also begun sharing images coming out of UAB research. Below is a brief description of what we are looking at and how related work may help to diagnose and treat fungal infections.

Here is a scanning electron microscope image of the fungus called Aspergillus. It's in the process of germinating, or emerging from round spores (at the center) to begin growing. The fungus has sprouted long, branching filaments called hyphae.

Most people breathe in Aspergillus spores daily without incident, but those with lung diseases or weakened immune systems can contract Aspergillosis, symptoms of which range from allergic reactions to severe lung infections. The fungus is a major player in some forms of allergic asthma, as clumps of hard-to-remove hyphae build up in the lungs.

According to the CDC, fungal infections pose an increasing threat to public health because of the growing number of people with weakened immune systems, including AIDS, cancer and transplant patients. In addition, treatment-resistant fungal infections have emerged as a growing problem in hospitals. Global warming may be contributing to an increase in infections, as fungi thrive in warm, moist conditions. Please see the CDC fungal page for more.

Current treatments are largely incapable of reducing morbidity and mortality in Aspergillosis, said John Kearney, Ph.D., professor in the Department of Microbiology within the UAB School of Medicine. He and his team are developing a new kind of vaccine that could provide protection against invasive Aspergillosis. Bacteria elicit a stronger human immune response than fungi but contain some of the same proteins (e.g. chitin). Based on these common building blocks, it may be possible to develop a vaccine where bacterial protein vaccine ingredients are used to activate immune cells that also target a fungus and remove it from the body.

This image was made by Dr. Jeffrey Sides from the Kearney laboratory at UAB using an instrument made available by the UAB School of Engineering.

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.

Mind-blower: epigenetics makes memories

Do you remember your five-year-old birthday party? How about your wedding? Emerging science argues that you can do so because those experiences turned off genes at the time in a certain set of nerve cells in your brain. Stranger still, nerve cells may have this capability because they have re-purposed epigenetic mechanisms that other human cells use to "remember who they are."

To back up for a moment, epigenetic mechanisms are chemical changes that turn genes on and off without changing the genes encoded in DNA that we inherit from our parents. Research in recent years has established that they lend an extra layer of regulatory finesse to human genetics and make our complexity possible.

Epigenetics first made a splash in developmental biology. Researchers realized that while we have the same set of genes in every one of our cells, we develop 250 different cell types by the time we are born. Epigenetic mechanisms switch off a different set of genes (and leave a certain set on) in each cell type to result in the 250 types.

Stem cells that become bone or blood or liver cells as we develop "remember" their specialized nature, and they pass that memory on to their descendants as they divide and multiply in the constant turnover under way in most human organs.

This genetic memory is known to be accomplished by epigenetic mechanisms like methylation, the chemical attachment of a methyl group (one carbon and three hydrogens) to certain spots on the DNA chain. The process can turn surrounding genes off (prevent gene expression), while demethylation can turn them back on in an ongoing back and forth.

It really gets fascinating when you consider that the nerve cells making up the brain, unlike nearly every other human cell type, never divide and multiply, and so they never pass on genetic memory. One theory on this is that nerve cells have put their genetic memory mechanisms to another purpose: remembering.

Most of this is theoretical of course, and it is the subject of intense study in the lab of David Sweatt, Ph.D., chair of the UAB Department of Neurobiology and director of the Evelyn F. McKnight Brain Institute here. He sat down with The Mix to discuss his presentation at a recent UAB Epigenetics Symposium about how nerve cells may have evolved to store memories.




Show notes for the podcast:

1:47 Sweatt's lab explores the role of epigenetics in the adult human brain. That has required a re-definition of epigenetics, a science once thought pertinent only to cells that divide and multiply, and that pass on epigenetic marks to their descendants. Nerve cells in the brain do not divide, multiply or turn over as a population, and yet, epigenetics mechanisms are at work. The field now recognizes that such mechanisms contribute to learning and memory.

4:14 The genetics and epigenetics of inheritance has finally answered one of the most long-standing questions in human history: how are traits passed down from parents to children? Epigenetics in neurobiology is also answering another longstanding, philosophical question: What makes us who we are? It turns out that epigenetic mechanisms "sit at the interface" of nature (genes) and nurture (environmental factors make epigenetic mechanisms that turn genes on and off).

5:58 Epigenetics have provided for scientists a fundamental answer for how a single transient experience can make a permanent change in the biochemistry of the brain. It is no small thing that we are now beginning to understand this once-mysterious process.

8:10 Methylation is the mechanism that silences perhaps half or three-quarters of the genes in the human genome to make a nerve cell a nerve cell. Those changes are life-long, and so that set of silenced genes is the same in that family of cells for a lifetime.

12:02 A foundational discovery made in other labs in recent years is that epigenetic changes to nerve cells are necessary for humans to remember things for the long term. Once the field knew that, they could begin to try to understand the mechanisms.

12:35 If anyone who is listening to this podcast today remembers it tomorrow,  it will be because of changes in the genes being expressed in the nerve cells of their brains as they listen. There is a continuous, dynamic interplay between our experiences and the parts of our genes recording memories. Epigenetic mechanisms are powerful regulators of gene transcription and translation, and appear to have been applied by evolution to the problem of storing memories.

13:22 If evolving nerve cells could talk, they might have said, "OK, I have to control which genes are turned on and off in certain nerve cells to store memories, what is the toolbox I have at hand to accomplish this?" It's the same toolbox of epigenetic mechanisms it uses to control gene expression in general.

13:35 Methylation has been been mentioned as part of the toolbox. Then there is histone acetylation. DNA does not just float around in the nuclei of human cells, but is instead wrapped around protein "spools" called histones that help to organize, protect and regulate them as part of a larger package called chromatin. Part of DNA regulation is spatial, and works by controlling when certain parts of DNA chains are able to unravel from their spools. The unraveling makes a stretch of code accessible to the protein-making machinery. Attachment of an acetyl group (a methyl group plus an oxygen) to a histone tends to make genes on that spool more accessible. In addition, there is phosphorylation and ubiquitination, processes that now appear to regulate both chromatin in general and behavioral memory formation.

14:51 With environmental factors (sunlight, smoking and pollution) known to make epigenetic changes, many labs are trying to determine whether such changes have roles in many diseases. Humans have a protective compartment surrounding their brains that screens out many toxins called the blood-brain barrier.

16:23 Sweatt's presentation at the UAB epigenetics symposium discussed how he is working to determine the exact biochemical mechanisms by which methylation is changing the firing patterns of nerve cells to endow networks of nerves with the ability to store memories. What are the exact and ongoing patterns of active methylation and demethylation as the brain reacts to sensory experiences?

18:00 To study the process of memory formation, Sweatt's lab examines certain classes of basic memories that we share, presumably, with study animals like mice. For instance, to survive, our animal ancestors would have had to be able to remember which places were dangerous and which offered food or security (spatial recognition of surroundings).

19:02 Humans appear to have "place cells" in our hippocampus, the part of the brain that tells you where you are and where you have been. When you walk into a new room, or even a new place in a room, a particular set of hippocampal neurons fires in certain patterns in such a way that allows the brain to record a 3D map of that place. Different cells fire when you are in different places. One experiment under way in Sweatt's lab is seeking to test whether certain DNA methylation patterns enable those cells to record that sense of place.

21:27 All this research is ultimately aimed at understanding the normal brain so as to come up with new treatments for those with disorders that affect memory (dementia, Alzheimer's, etc.) and learning. Sweatt's lab and many others are seek to build the framework for the development of new molecular targets for new kinds of drugs.

The previous three podcasts in this epigenetic series were Epigenetics has impact on health beyond DNA, Epigenetics, aging and cancer and Obesity, exercise and epigenetics: no excuses.

Dr. Sweatt’s research is largely funded by the McKnight Brain Research Foundation.

Top Seven Obesity Myths

We “just know” that having sex burns enough calories to make a difference, breastfeeding protects a baby against future obesity and gym classes keep kids thin.

It turns out these are among many popular obesity myths; widespread beliefs held dearly despite evidence to the contrary. That is the conclusion of an article just published in the New England Journal of Medicine. Such inaccurate beliefs, the authors argue, are leading to inaccurate public health recommendations, wasted resources and a less healthy America.

David Allison, Ph.D., associate dean for science in the UAB School of Public Health, led a research team that analyzed articles published in the scientific and popular press to separate myths from evidence-supported facts.

The authors also defined six “presumptions” – beliefs held to be true even though more studies are needed. For instance, some have presented as fact the idea that regularly eating versus skipping breakfast contributes to weight loss, but the few studies that have been done have found no effect.

The team identified research-proven facts as well. Weight-loss programs for overweight children that involve parents and the child’s home, for instance, achieve better results than programs that take place in schools. Also, many studies show that while genetic factors play a large role in obesity, “heritability is not destiny.” Big enough changes to lifestyle and environment can bring about as much weight loss as the most effective weight-loss drugs. This is the kind of information that should be shaping public policy, Allison said. The most valuable message is an old, unpopular one: eat less in general and use up more energy than you take in.

For more on the top myths, presumptions and facts, please see the UAB press release and the NEJM article it covers.

Dr. Allison added that the field should conduct more randomized, controlled clinical trials to answer key obesity questions as it advises the public. This type of study rules out chance effects and counters researcher bias. Public health advocates, says Allison, need to be clear with the public about what has and has not been proven. Mixing seemingly good ideas in with proven ideas does not serve the public good.

Allison said the widespread acceptance of obesity myths and presumptions raises the larger question of why we so often believe things that are not so. The authors identified several factors that seem to contribute to this. One is the “mere exposure effect,” where repeating an idea often enough makes people more likely to believe it. Another factor is that people may like certain ideas so much that they hesitate to let them go despite evidence to the contrary. Then there is the phenomenon of “confirmation bias,” where we tend to systematically seek out only the sources of information that confirm our opinions.

Given this whirlwind of effects, it is a wonder we know anything at all.

Epigenetics has impact on health beyond DNA

As a science writer, I struggle to translate complex ideas like genetics into straightforward language.  Having covered genes many times over the years, I have come to depend on a few handy stock sentences that I recycle in story after story:

• 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. 
• Human genetic material includes about 3 billion bases, the “letters” that make up the DNA code containing genetic instructions.

Then about seven years ago, research surfaced that required the crafting of a new group of stand-by sentences. It turned out that, while genes were important, they represented just one part of a more complex human genomic system. Genes, the specific batches of code directly for the construction of proteins, were found to comprise just two percent of human DNA. Then humans were found to have one-fifth as many genes as wheat. What made us so complex then if not our genes alone?

The explanation was that we put the same genes to many uses with the help of complex regulatory mechanisms that govern when, where and to what degree our genetic material is accessed and activated. Some of these functions are performed by myriad non-gene DNA snippets called regulatory elements.

Still other recently discovered mechanisms contribute further to our genetic regulatory finesse, and without changing the instructions encoded in the DNA we get from our parents. Such changes represent the province of the emerging field of epigenetics and the focus of a recent UAB Epigenetics Symposium. The Mix – the UAB research blog – interviewed some of the presenters and is featuring the talks in a series.

Our guest for this podcast is Bruce Korf, M.D., Ph.D., chair of the UAB Department of Genetics, one of the organizers of the symposium.

Show notes from the Podcast:

:40 Epigenetics is defined as changes in human gene expression caused, not by changes in the order of base pair "letters" making up the DNA code (such changes are called mutations), but instead by chemical actions that affect the ability of the instructions encoded in a given stretch of DNA to be read and followed.

1:15  Researchers have long known that changes that turn genes on or off play a critical role in fetal development and in the response of humans to their environment, but not what controls those changes. It's now becoming clear that epigenetic mechanisms can permanently silence a gene, for instance, in a particular cell type.

2:01  Cells divide and multiply as the human fetus develops.  Epigenetic changes do not just turn off a gene at a particular point in time, they turn it off in that cell and in all its descendants. That makes such changes useful a gene needs to be turned off permanently to, not only enable a stem cell to become a brain cell, but also to make it the proper sire of a line of many brain cells. The same genes that got a cell to the right stage in development may need to shut down for it remain the right cell type.

2:18 Methylation, the chemical attachment at a certain point on the DNA chain of a methyl group (one carbon atom bonded to three hydrogen atoms), is a principle type of epigenetic regulatory change.

2:25 Methylation is the attachment of a methyl group to cytosine, one of the four bases that encode genetic instructions with the DNA chain. When the methylation occurs at a cytosine that falls next to a guanine, another of the four bases, the methylation will make it possible for other proteins to bind to the DNA chain such that the surrounding gene is silenced.

2:47 The methylation interferes with a process by which DNA forms a complex with proteins called histones to form chromatin, which in turn makes stretches of DNA available to the gene expression machinery upon receipt of the right signals.

4:11 While we inherit our DNA code from our parents, epigenetic changes are not passed on. When a sperm or egg cell is produced, all the epigenetic marks are wiped clean.  Thus, epigenetic fine-tuning of gene expression begins a anew with each person. Combine this with the fact that sunlight, cigarette smoke and the foods we eat make epigenetic changes, and we all become authors of our own gene code.

4:56  "Superfoods" like broccoli have linked to methylation status, and experiments months in mice have shown that diet can change the methylation status of specific genes (say those involved in cancer risk).    

5:19 An interesting area of research in epigenetics is looking at lifelong risk of certain diseases (like Type 2 diabetes) based on events and influences that occur while that person is still in the womb.

6:18 Dr. Korf said the UAB epigenetics symposium is being held now because recent meetings on the UAB School of Medicine strategic plan revealed that many researchers were working in this area independently, and would benefit from collaborations.

7:35 Among the examples of key epigenetics research efforts underway at UAB, David Sweatt is looking at at the potential role of epigenetic changes in learning and memory, TrygveTollefsboll at fundamental aspects of epigenetic biology and Molly Bray at the impact of epigenetic changes on lifelong obesity risk.

8:00 The field is in its infancy in terms of determining epigenetic changes and what drives them tissue by tissue in conjunction with environmental factors. What is truly exciting now is the emergence of extremely powerful tools, the bioinformatics and high-speed genetic analysis technologies, that are driving the field forward.  There will probably prove to be as many epigenomes as there are tissue types in the body.

9:14 Some of the most exciting near future advances are coming in the epigenetics of cancer.  Mounting evidence suggests that some of the changes that turn genes off contribute to the development of cancers.
Tracking epigenetic changes may have predictive value in looking will benefit from a therapy and who is at risk for a cancer.

9:33 It has now been shown that some drugs interact with epigenetic changes, which raises the possibility of using drugs to turn back on genes silenced by abnormal, epigenetic mechanisms as part of disease.