Equations against cancer: Using math to predict a tumor's path

Hassan Fathallah-Shaykh, M.D., Ph.D., believes that math can transform medicine, and he has the numbers to prove it.

In the clinic, this UAB neurologist specializes in treating brain tumors. In his lab at the Comprehensive Cancer Center, Fathallah-Shaykh, who is also a professor of mathematics at UAB, wields equations as well as petri dishes. His mathematical models of cancer behavior are offering new insights on tumor growth. Eventually, they could be used to personalize treatment based on the unique characteristics of each patient’s cancer cells and anatomy.

Fathallah-Shaykh is one of a growing number of researchers worldwide exploring the field of mathematical biology, which “uses mathematical tools to generate models of biological problems,” he said. Building mathematical models based on the current understanding of a disease, for example, allows researchers to “test whether the assumptions are accurate,” Fathallah-Shaykh said.

Hassan Fathallah-Shaykh

Models can also be used “to test a treatment strategy, understand why it fails or works, and optimize therapy,” he added. The results of these tests can also generate new insights and hypotheses that can be investigated in the laboratory. “None of these goals can be achieved by traditional methods,” Fathallah-Shaykh said.

Model Behavior

Working with colleagues at the University of Bordeaux, and UAB graduate student Elizabeth Scribner, Fathallah-Shaykh has created an elegant model of the aggressive brain cancer glioblastoma multiforme (GBM). It produces simulations on the scale of clinical MRI scans, so that its predictions can be tested directly against patient data. In a paper published on Dec. 15 in PLOS ONE, the researchers demonstrated that their model can reproduce the typical GBM growth patterns seen on patient scans. They also revealed its value as a research tool.

The model predicted a previously unknown pattern of tumor growth in patients with recurrent GBM treated with the anti-angiogenesis drug bevacizumab. This growth, powered by a cycle of proliferation and brain invasion, is characterized by an expanding area of invasive cells and dead cells known as necrosis, the researchers say. A subsequent search of 70 patient MRI scans by the researchers turned up the same pattern in 11 cases.

“We hope to tailor radiation therapy, chemotherapy and other treatments based on a personalized model of a patient’s tumor.”

That pattern explains the disappointing results of recent Phase III clinical trials of anti-angiogenesis therapies against GBM, the researchers say. Anti-angiogenesis drugs attempt to kill tumors by preventing them from growing new blood vessels. But the model demonstrated how GBM cells can flee from the oxygen-depleted treatment area — and quickly begin expanding again as soon as therapy stops or the tumor becomes resistant to the drugs. (For more on the model and these findings, see “SimTumor,” below.)

“We’ve shown that we can predict new insights on cancer behavior,” Fathallah-Shaykh said. The results have already spurred Fathallah-Shaykh to pursue new therapies in his lab to limit tumor mobility. Ultimately, the researchers hope to use their model to personalize therapy to the unique characteristics of a patient’s tumor. They could do that by analyzing the existing growth pattern of a tumor and building that into the model’s parameters. Then they could simulate its future behavior on a virtual MRI slice that reproduces the unique anatomy of the patient’s brain. “We hope to tailor radiation therapy, chemotherapy and other treatments based on a personalized model of a patient’s tumor,” said Fathallah-Shaykh.

Advancing Mathematical Biology Research Hassan Fathallah-Shaykh, M.D., Ph.D., is a perfect ambassador for the highly interdisciplinary field of mathematical biology. In addition to his faculty positions in the departments of Neurology, Mathematics and Cell, Developmental and Integrative Biology, he holds an appointment in the School of Engineering. That breadth of expertise has enabled him to establish collaborations with researchers at UAB and at several international universities, and he is working to interest more colleagues in mathematical biology. This spring, Fathallah-Shaykh helped organize a symposium on the topic as part of the College of Arts and Sciences’ Interdisciplinary Innovation Forum series. The meeting attracted some of the mathematical biology’s most famous names. Meanwhile, he is helping to attract new talent to the discipline by teaching undergraduate and graduate courses on Mathematical Biology in the math department. “It is quite clear that the next great advances in medicine cannot happen without math,” Fathallah-Shaykh said. “These are exciting times.”

From Flies to Colon Cancer

Since he joined the UAB faculty in 2008, Fathallah-Shaykh has been developing ever more advanced models to predict the behavior of biological networks. He began by building a model of the molecular clock in a fruit fly’s brain. Despite the fly’s tiny size, it’s a challenging puzzle. The clock is a tangled web of positive and negative feedback loops, with five different genes producing proteins that inhibit and activate one another (as well as themselves, in some cases) in a regular cycle.

First, Fathallah-Shaykh and his collaborators “showed we can replicate everything the clock is known to do,” he said. Then they proved it was a useful research tool, answering a perplexing question about the fruit-fly gene Clockwork Orange that had stumped biologists for years.

The researchers next adapted their model to track the developing neural networks in fruit-fly embryos. To do this, they utilized the Kalman filter, a mathematical technique to analyze and predict changes that helps track planes in flight. Now, “we’re using the model to study molecular networks in colon cancer,” Fathallah-Shaykh said.

Coping with an Information Explosion

Fathallah-Shaykh has always been fascinated with math. “It’s like a symphony; it’s beautiful,” he said. “But it’s also very applicable.” He cemented the connection between medicine and math as a neurologist at Rush University Medical Center in Chicago when he enrolled in a doctoral program in mathematics at the nearby University of Illinois–Chicago. “I would go to class in between patients,” he said.

Math is essential to making progress against the toughest questions in medicine, Fathallah-Shaykh contends. To illustrate the problems that researchers face, he points to a chart of all the known molecular pathways involved in Alzheimer’s disease. It’s a mass of interlocking loops and tangles that fills an entire page. Researchers specialize in tiny sections of this wiring diagram, but understanding how it all works together is another problem entirely. Even worse, these networks are intertwined in such a way that multiple paths can lead to the same destination. That may help explain why treatments that work beautifully in isolated cell lines in a lab so often fail when they encounter the complex networks of the body.

There’s another wrinkle. “Cells migrate, they communicate, they interact with one another over time,” said Fathallah-Shaykh. The waves of mutations, which are a hallmark of cancer, make the problem particularly complex, he noted. “Whole pathways are deleted and new connections start turning up.” It’s a perfect example of a nonlinear dynamic system, like the weather or the stock market, in which slight changes in one parameter can lead to wildly diverging outcomes.

The good news, said Fathallah-Shaykh, is that “mathematics has very rich tools” to model just these types of systems, as he has demonstrated with his cancer simulations. But this work has another exciting element for Fathallah-Shaykh as a mathematician: It opens new horizons in math theory. “Equations have already been developed from biological problems,” he said, “and there is very strong evidence that they will produce spectacular advances in mathematics.”

SimTumor

At the heart of Hassan Fathallah-Shaykh’s new mathematical model of glioblastoma multiforme (GBM) are 10 partial differential equations. Here’s how it works — and what it has revealed about GBM behavior.

Formula 10

Equations track each of four different cell types, with unique rules of behavior.

Proliferative GBM cells (P), which make up the bulk of the tumor, divide but don’t move.

Invasive GBM cells (I), found on the fringes of the tumor, move but don’t divide.

Healthy brain cells (B) neither divide nor move, although they are displaced by the growing tumor.

Cells in the center of the tumor, cut off from nourishing blood vessels, are starved of oxygen (hypoxia) and die, becoming necrotic cells (N).

The remaining six equations track angiogenesis (new blood vessel formation), oxygen levels, and rates of necrosis and cell division.

Built for Speed

Fathallah-Shaykh’s first GBM model, published in August 2014 in the Bulletin of Mathematical Biology, consisted of many more equations. It required a supercomputer, and several days, to run. The model published in PLOS ONE can run in 50 seconds on a typical desktop computer.

And They’re Off!

The simulation begins with a tiny clump of tumor cells surrounded by healthy brain. As the program continues over several virtual weeks, this mass expands in the characteristic manner seen on patient MRIs, with a dark region of necrotic cells in the center, surrounded by a large group of proliferative cells and an outer rim of invasive cells.

Grow or Go

The model’s main assumption is that proliferative cells can turn into invasive cells in hypoxic conditions. This is in keeping with the “grow or go” hypothesis of GBM behavior, which says that low oxygen levels spur GBM cells to flee the dying core of the tumor. When these new invasive cells reach healthy, oxygenated areas of brain, they switch back into proliferative mode and start growing again.

How GBM Escapes Anti-Angiogenesis Therapy

As tumors grow, cells at the core lose contact with nourishing blood vessels and die.

To get around this problem, tumors release VEGF (vascular endothelial growth factor), which induces the body to create new blood vessels (a process known as angiogenesis). In fact, the well-known Folkman Hypothesis states that tumors must be able to induce blood vessel growth in order to keep growing.

Clinicians had high hopes that anti-angiogenesis medications such as bevacizumab (Avastin), could keep tumor growth in check. But two high-profile Phase III clinical trials, which released results in early 2014, found that bevacizumab therapy did not prolong overall survival in patients with recurrent GBM, although it did extend progression-free survival and patient quality of life.

Fathallah-Shaykh’s model, programmed to simulate the effects of anti-angiogenesis therapy, reveals an explanation for this “unusual clinical finding.” When bevacizumab therapy causes oxygen levels to drop, proliferative cells turn into invasive cells and flee the scene. When they reach an area with sufficient oxygen, they convert back into proliferative cells and begin a new cycle of growth. This sets up the tumor for rapid “rebound” growth as soon as it becomes resistant to bevacizumab or therapy is discontinued. That explains why patients treated with bevacizumab in the recent trials didn’t experience any increase in overall survival rates over those who were not treated.

Toward New Treatment Approaches

The model underlines the importance of better understanding the molecular mechanisms of brain cell invasion, particularly the active transport of invasive cells toward healthy brain regions, says Fathallah-Shaykh.

There are currently no available biomarkers to identify the quantity of invasive cells in a patient’s tumor. But finding such a biomarker, and drugs that can target these cells to prevent tumor migration, is a current research focus in Fathallah-Shaykh’s lab. “If we’re going to kill these tumors,” he said, “we have to target the cells that are invading.”

Unique gene machine opens new pathways to personalized medicine

In the UAB Nanostring Laboratory, researchers such as Eddy Yang are taking advantage of the nCounter Analysis System's novel digital profiling technology to examine specific signaling pathways in cancer and other diseases. That work could lead to new insights to improve diagnosis and treatment decisions.

Cancer is a devious enemy. In lab tests, researchers have identified plenty of exciting genetic targets — weak links that should allow them to destroy tumors by halting production of a crucial enzyme, for example, or blocking a signal the cell needs to keep growing. All too often, however, these promising findings fizzle out in further testing.

That is because cancer cells can take advantage of multiple, redundant signaling pathways to avoid areas that come under attack. “Tumor cells will just figure out a way to bypass them,” said Eddy Yang, M.D., Ph.D., an associate scientist in the UAB Comprehensive Cancer Center and associate professor in the UAB Department of Radiation Oncology.

Mapping out the complex pathways involved in cancer and other diseases is a crucial step in finding better treatments — and identifying the best treatments for individual patients. If you know all the routes a tumor can use to evade attack, you can find therapies — or combinations of therapies — to block them all. Indeed, tracing cancer-related signaling pathways, and finding ways to use these insights to improve diagnosis and treatment decisions, is a major focus of research at the Cancer Center, Yang says. But spotting these pathways amid the information overload of a genomewide screening test can be extremely complex and time-consuming.

nCounter: In Focus 48-800 genes can be studied simultaneously Applications include gene expression analysis, microRNA and lncRNA analysis, copy number variation analysis, ChIP-String analysis and leukemia fusion gene analysis The system's novel digital technology is based on direct multiplexed quantification of nucleic acids; it provides highly reproducible data over 5 logs of dynamic range Preconstructed panels include: PanCancer Pathways Panel, Human Kinase Panel, Human Immunology Panel, microRNA Panels, Cancer Copy Number Variation Assay See the UAB Nanostring Laboratory site for more information and a schedule of fees and services

Targeting Crucial Pathways

Now, UAB researchers and clinicians have a new tool to investigate signaling pathways — and to translate their discoveries into clinic-ready diagnostic tests. The unique nCounter Analysis System, produced by Nanostring Laboratories, “is a platform to measure the expression of genes in a targeted manner,” Yang said. “Instead of looking at the whole genome, you can investigate anywhere from 48-800 genes at a time.” Researchers can zero in on certain pathways that they are studying, Yang explains, or they can use preset panels of previously identified cancer networks.

Yang directs the new UAB Nanostring Laboratory, which is open to investigators across campus. He is using the nCounter to pursue his own research in experimental treatments for breast, prostate, and head and neck cancers. “I’m very interested in understanding the pathways that make a tumor tick,” Yang said. “I want to know which ones make it resistant to therapy and which ones could actually make it more sensitive to treatment.” With the nCounter, Yang said, “we can look from a 10,000-foot perspective rather than from sea level. It’s an exciting technology.”

Another advantage of the nCounter is that, unlike other technologies, which may require whole molecules of high-quality RNA or amplification for analysis, the nCounter can gather information from small pieces of RNA. That means researchers can use it to look at pathways in tissue that is up to several decades old, retroactively verifying new patterns they have found instead of having to collect new samples for analysis. The nCounter can also perform a range of other tests, Yang says, including analysis of microRNAs, gene fusions and gene amplifications.

From Concept to Clinic

The nCounter is more than a research tool. It can run new diagnostic tests such as the ProSigna Assay, which gives clinicians an estimate of a patient’s likelihood of tumor recurrence based on which pathways are active in that patient. It is an excellent example of personalized medicine in action, Yang says. He envisions UAB researchers using the nCounter to develop novel tests to inform treatment decisions in cancer and other diseases. UAB is one of the first institutions nationwide with the ability to do both laboratory and clinical testing using the nCounter.

“We hope to use the pattern of the pathway of genes to help guide therapy,” Yang said. “That’s the personalized medicine approach.”

Yang and collaborator Andres Forero, M.D., senior scientist at the UAB Cancer Center, will use the nCounter as part of a clinical trial testing a new treatment approach against triple-negative breast cancer. The trial, which recently began enrolling patients, is testing two different drugs — a PARP inhibitor and an EGFR inhibitor — to block two different pathways used by these tumors.

“By blocking PARP, you block the ability of the tumors to repair DNA damage,” which should eventually result in cell death, Yang explains. But the tumors can take advantage of an alternate backup pathway to repair that damage, meaning PARP inhibitors alone are often ineffective. “By blocking EGFR, we will block that backup pathway,” Yang said. [To learn more about this study, call (205) 934-0309; visit the Clinical Trials section of the Comprehensive Cancer Center's website to see all current studies.]

Using the nCounter, the researchers will compare the pathways altered in patients who respond to the therapy with those in patients who aren’t helped by the combination. In the future, that could let them identify the most appropriate patients for this treatment with a simple test. “We hope to use the pattern of the pathway of genes to help guide therapy,” Yang said. “That’s the personalized medicine approach.”

Superfoods and breast cancer: Study takes a closer look at broccoli and green tea

Could a combination of broccoli sprouts and green tea offer protection against breast cancer — and transform hard-to-treat breast tumors into a type that responds to medication?

A series of studies in the lab of UAB biologist Trygve Tollefsbol, Ph.D., D.O., have generated encouraging findings. Tollefsbol, who is also a senior scientist in the UAB Comprehensive Cancer Center, has shown that mice given sprouts in their chow and green tea polyphenols in their water are protected against tumor development. Intriguingly, he has also shown in animal studies that the combination can change estrogen receptor-negative (ER-) tumors, which have few treatment options, into estrogen receptor-positive (ER+) tumors, which can be treated with the anti-estrogen drug tamoxifen.

Now, Tollefsbol has received a $1.5-million, five-year grant from the National Institutes of Health to pinpoint the molecular mechanisms behind these effects. "We already have a lot of preliminary data showing that this combination works," Tollefsbol says. "The grant will allow us to extend that research and explore the effects genome-wide."

The immortality enzyme? Telomerase fights aging, fuels cancer

In a lab in the heart of Campbell Hall, UAB biologist Trygve Tollefsbol, Ph.D., D.O., stores the secret to immortality—but you may not want it.

Trygve Tollefsbol is a renowned expert on telomerase, an enzyme that
plays crucial roles in determining our lifespans and fueling cancer growth.

Telomerase, the enzyme in question, is a quirky character. Even though it is dormant most of the time, it appears to play a key role in all three of Tollefsbol’s main research interests: aging, cancer, and epigenetics.

Telomerase’s job is to lengthen telomeres, little caps at the end of our chromosomes that keep the chromosomes from becoming unstable during cell division. (They’re kind of like the plastic cylinders on the ends of shoelaces, Tollefsbol says.) But a little bit gets shaved off with each cycle of division. Eventually, there is very little protective telomere left, and cells age and stop dividing.

Hit man: A suspect emerges in the chaos of aggressive brain cancer

New research from UAB oncologist Markus Bredel identifies the splicing enzyme PTBP1 as a key factor
in the spread of glioblastoma multiforme.  

Glioblastoma multiforme is one of the deadliest human cancers. "The tumor can double in size within a few weeks," says Markus Bredel, M.D., Ph.D., a professor in the UAB Department of Radiation Oncology and senior scientist in the neuro-oncology program at the UAB Comprehensive Cancer Center. "Usually, by the time we see a patient, they often have apple-size lesions."

That explosive growth "comes with a substantial amount of genetic chaos," Bredel says. "If you look at the whole genome in a brain tumor, out of the 30,000 genes, you very often have changes in up to 50 percent; they're up or down, lost, amplified, mutated."

A Change for the Worse

Markus Bredel

But in that chaos, patterns emerge with surprising regularity, Bredel says. "When Gene A is up, Gene B is very often down." In two papers published in JAMA in 2009, Bredel's research team argued that "there needs to be a reason why glioblastomas co-select for certain genetic events. The tumor cells must benefit."

In those papers, Bredel's lab identified dozens of gene-gene links that were candidates for additional scrutiny. They focused on one particular pair: The oncogene EGFR, or epidermal growth factor receptor, which is crucial for normal cell growth and wound healing, and the tumor-suppressor ANXA7 or annexin A7. EGFR is of interest in many cancers, because it is often hijacked to fuel the aggressive growth of tumor cells.

"We found that ANXA7 is probably a regulator of EGFR," Bredel says. "So it's to the benefit of the tumor cell to knock down this regulator." But it wasn't clear at the time how this was happening. "ANXA7 resides on a different chromosome from EGFR, so it's a completely independent event, but somehow the tumor cells were disabling it," says Bredel.

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.

Image post 9: infection blocks trash removal to cause ulcers, cancer

What's that ... a meteor blazing past a molten planet?  No, it's a self-destructing cell just shed from a gastric gland made up of the tightly packed blue cells running across the bottom.

Gastric glands that secrete digestive juices into the stomach, like all epithelial cells (skin, lining of blood vessels, etc.), constantly shed old cells from their outer layers and replace them with new ones. The turnover keeps tissues viable throughout adult life. When the shed cells sense they have outlived their usefulness, they initiate self-destruct mechanisms.

With some cells always in the process of self-destructing, other nearby cells are charged with swallowing up the dying cells and disposing of them. That explains the red cloud surrounding the yellow dot at the center of the image. An antigen-presenting cell (dyed red) has engulfed a self-destructing cell (yellow) to remove it.

The system works pretty well until a person's stomach gets infected with the bacteria Helicobacter pylori.

The infection causes cells to release TNF-alpha, a signaling chemical that triggers the waves of cell activation and chemical release meant to kill invading bacteria or viruses (inflammation). While the process protects us against infectious disease, it also plays a role in many disease processes when it goes too far.

A recent study by a team of UAB researchers found that, along with triggering inflammation, TNF-alpha also blocks the engulfment and removal of dying cells. Cellular debris builds up to drive further inflammation in a vicious cycle.

Why does this matter?  Inflammation caused by Helicobactor pylori is behind the development of nearly all ulcers. Furthermore, the same chronic inflammation damages DNA, creating risk for hard-to-treat gastric cancer.

The image was created by Diane Bimczok, DVM, Ph.D., an instructor in UAB's Division of Gastroenterology and Hepatology, using routine fluorescence microscopy and digital imaging. Phillip Smith, M.D., was senior author of the related study. 

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.

Goal: keep your transplanted organ permanently

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

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

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

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

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


Show notes for the podcast:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Epigenetics, aging and cancer

We used to talk about how "the blueprint" for the human body was encoded in genes. These long chains of DNA held the instructions for the building of proteins, which made up the body's structures and carried its messages. End of story, right?  Actually, it's just the beginning.

Recent research has shown that genes, while crucially important, represent just one aspect of the human genetic system. The human body achieves its unique level of complexity by putting the same genes to many uses. In this light, mechanisms that "decide" when and where genes are turned on and off become central to human health and disease.

Interestingly, one set of these regulatory mechanisms, epigenetic changes, contribute to our genetic regulatory finesse without changing the instructions encoded in the DNA we inherit from our parents. Epigenetic mechanisms are chemical reactions that turn genes on and off during our lifespan, and largely thanks to our interactions with the world around us. Evidence is mounting that environmental factors like the foods we choose to eat constantly change the performance of our genetic material, and in ways that drive the aging process and cancer risk.

Such changes were the focus of a recent UAB Epigenetics Symposium, and The Mix – the UAB research blog – sat down with some of the presenters. Today's guest is Trygve Tollefsbol, Ph.D., professor of in the UAB Department of Biology, and an expert on the relationships between epigenetics, cancer and aging.

 

Show notes for the podcast: 

:53 Epigenetics is defined as changes in human gene expression caused not by changes in the order of base pairs, the DNA "letters" making up our genes. Epigenetic changes are instead the result of chemical reactions that determine whether or not the instructions encoded in a given stretch of DNA are read and followed..

2:20 If a person is born with a cancer-causing mutation, a permanent change in the order their DNA code within a gene, current medicine cannot often or easily reverse it. Physicians try to treat the cancer, but cannot easily address the underlying genetic problem.

2:39 One of the most exciting things about epigenetic changes, Tollefsbol said, is that they are easily reversible. Researchers hope they will soon be able to manipulate epigenetic mechanisms to reverse disease processes. This becomes especially relevant when you consider that perhaps "half of cancer cases" are caused by epigenetic changes instead of mutations in the DNA code, Tollefsbol said.

3:54 Two important epigenetic mechanisms that regulate when genes are turned on or off are DNA methylation and histone acetylation. Methylation is the chemical attachment at a certain point on the DNA chain of a methyl group (one carbon atom bonded to three hydrogen atoms). This attachment can make it possible for other proteins to bind to the DNA chain such that the surrounding gene is silenced.

5:40 In addition, DNA does not just float around lose in the nuclei of human cells. Long chains of DNA are wrapped around protein "spools" that help to organize, protect and regulate them. 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. The spools are proteins called histones, and the attachment of an acetyl group (a methyl group plus an oxygen) to a histone tends to make genes on that spool more accessible.

6:50  Enzymes, protein catalysts in the body, which encourage epigenetic changes include DNA methylase and histone acetyltransferase. They serve as editors of the proteins that are controlling gene expression. Researchers in the future may be able to manipulate such enzymes with drugs that reverse epigenetic processes contributing to many diseases.

8:26 Epigenetics is a central interest in Tollefbol's lab, especially with respect to cancer and aging.  His team is interested in countering the epigenetic changes that contribute to the aging process, many of which appear to be influenced by diet. Both the quality and the quantity of the food we eat affects our gene expression. Evidence is mounting that caloric restriction, the hard choice to consume fewer calories, contributes to longer life and protects against cancer through epigenetic processes.

10:47  Whether or not a person gets cancer as they age in part comes down to a battle between genetic mechanisms that encourage cell growth (and that get broken to create abnormal growth) and others that suppress tumors by countering growth. It's a gas pedal versus the brakes. Evidence is emerging that epigenetic changes brought about by environmental factors (diet, sunlight exposure, air quality) can shift the balance from health toward disease as we age.

12:10  In the car analogy, oncogenes are the gas pedal for abnormal growth, while tumor suppressor genes are the brakes. Oncogenes encourage cell division. Each cell divides to become two, the number of cells goes up and growth occurs. Tumor suppressors block cell division. Taking the car analogy further, one then has to consider how much gas is in the tank. DNA within a human cell, packaged in chromosomes, can be copied into a new generation of cells only so many times. Each time a cell divides, the tail end of the chromosome called the telomere gets a little shorter until it is gone. Like the amount of gas in a tank, this serves as a physical limit on cell division, limiting the lifespan of a line of cells and its ability to drive tissue growth. Limited telomere length also serves as another protection against tumors as cancer cells seek to become immortal.

12:27 The older we get, the more likely we are to acquire problems with telomerase, the enzyme that sets telomere length in the womb, and then shuts down in most normal adult cells. Cancer cells are "addicted" to telomerase, which extends the length of their telomeres indefinitely. This fills the gas tank and makes the cells "immortal" as they divide and multiply indefinitely. Evidence suggest that many of the mechanisms that contribute to abnormal telomerase activity are epigenetic chemical modifications, said Tollefsbol.

14:02 While telomeres get shorter and shorter as a measure of aging, you can't just give telomerase to a person and think they will live for seven hundred years.The same process that causes aging via the suppression of telomerase after we leave the womb protects us from cancer.

15:29 Drug designers have seized on the realization that cancer cells depend on telomerase to become immortal and that normal cells don't use it. Selective telomerase inhibitors have been developed and some are in clinical trails. While the arrival of effective drugs in this class would be a boon, Tollefsbol's lab has determined that many compounds in common foods epigenetically prevent the activation of telomerase.  Broccoli, Brussels sprouts, cabbage, green tea and avocados are examples of foods containing compound that epigenetically turn of the gene that encodes telomerase.

17:37  The main thrust of Tollefsbol's presentation at the recent UAB Epigenetics Symposium was the concept of the "Epigenetics Diet," a term coined by his team. Specifically, Tollefsbol and colleagues are looking closely at the action of the chemical called solforaphane found in broccoli, cabbage and Kale that has beneficial epigenetic effects, including the turning down of the gene that expresses telomerase. While long-term studies need to be done, it may that eating more of these foods from childhood on protects a person against cancer later in life.

19:17 Tollefsbol also presented the results of a study that showed feeding isolated human cells less sugar (caloric restriction) not only enabled the cells to live longer but also to killed precancerous cells in their midst via epigenetic mechanisms. The finding may have implications for ongoing public health and policy debates surrounding the proposed causes of the U.S. obesity epidemic and potential remedies.

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.

Evolving in a sea of microbes

2012 was the year of the microbiome, the set of bacteria, viruses and fungi living in our noses, mouths and guts. It made national news in June when the Human Microbiome Project first reported on what the bug mix looks like on and in a typical, healthy American.

New understanding of our microbial communities is laying the foundation for advances in the treatment of infectious, autoimmune and inflammatory diseases, including the process by which inflammation contributes to cancer.

For these reasons the UAB Comprehensive Cancer Center chose "cancer and the microbiome" as the theme for its recent research retreat, and The Mix interviewed retreat presenters for a podcast series.

Today's guest is George Weinstock, Ph.D., professor of Genetics at the Washington University School of Medicine.  We talked about his leadership role in genomics revolution, including his contribution to the design of both the Human Genome Project and the Human Microbiome Project.

Show notes for the podcast

1:12 Our world has been dominated by microorganisms for three billion years. All life then involved in this sea of microbes, and humans are no exception.

1:45  Having evolved in a world awash with microbes, the human body is colonized by specific sets of them that provide us with hundreds of times more functions than our own genes can't deliver. Human cells, for instance, have borrowed signalling pathways from microbes that help us digest our food, protect us from being infection, etc.

2:39 Insects have microbiomes too, they they are much simpler than ours. One related theory is that our immune system is more sophisticated because it had to learn to safely handle the many bugs we "invited" to help us digest our food. Taking the idea a step further, some experts think the immune system’s ability to repel unwelcome invaders might represent a lucky, evolutionary after-effect of its more ancient role — managing a stable of helpful bacteria.

3:58 At the heart of Weinstock's decades-long career is DNA sequencing, the technology that enables researchers to determine the order of DNA coding units as a step toward understanding the function of each DNA snippet. The same methods were used to do this for 25 years, but then in 2006 new methods matured that made possible to vastly accelerate the pace of sequencing.  Weinstock's lab can now do in a day what it once took years to do.  For instance, his team can determine the sequence of several human genomes in a day, each requiring the analysis of 3 billion units of code.

6:06 The new high-speed technologies have made possible massive undertakings in genomics, including the 1,000 Genomes Project, The ENCODE project and the Human Microbiome Project.

7:06 Weinstock is among the pioneers that helped to launch the Humane Genome Project, which ran from 1998 to 2003 and offered the first estimate of the 20,000 or so genes present in the human blueprint. Before that project, he was among the very first to sequence a genome from any creature, in his case the bacteria responsible for causing syphilis.

9:36 Weinstock also helped to organize the Human Microbiome Project, which this summer published a series of reports in Nature and several Public Library of Science journals that revised the understanding of how microbes drive either health or disease. Researchers from 80 institutions spent five years collecting and sequencing samples from 242 healthy volunteers.

11:07 Bugs don't colonize humans one by one, but instead as part of large, complex communities.  They interact so thoroughly with each other and our cells that they must be analyzed together. Newly available technologies made it possible to analyze the genes of thousands of organisms at once, and the National Institutes of Health decided to invest heavily. The goal is to quickly advance the understanding this huge aspect of human health driven by our microbes. The NIH funded several genome centers to sequence bacterial genomes, with Weinstock's lab among them.

11:34 Beyond just looking at bacteria, the project funded a number of clinical researchers to study how each person's microbiome affects everything from acne to urinary tract infections to the risk for inflammatory disease in premature babies to cancer.

12:28  While the NIH did not think the project would instantly cure diseases (the genomics are too complex), they did hope to understand how you study the microbiome and what resources would be required. 

Gut bugs' relationship with estrogen-related cancer

The human microbiome made news earlier this year when the Human Microbiome Project reported its first results on the typical set of microbes living on and in the average, healthy American. It's still in the news because researchers keep finding new ways in which our bacteria, viruses and fungi interact with our bodies to drive disease risk.

Along those lines, the subject of today's podcast is the emerging evidence that each woman's particular set of gut bacteria may influence how she processes the hormone estrogen. One theory holds that some bug species produce enzymes that increase a woman's lifetime estrogen exposure, and potentially, her risk for estrogen-related cancers.  

Talking on that theme in today's podcast is Claudia Plottel, M.D., clinical associate professor of Medicine in the New York University School of Medicine. She is an expert on the "estrobolome,"  the complete set of bacterial genes that code for enzymes capable of metabolizing estrogens within the human intestine. Her interview is the latest in a series recorded recently at a "cancer and the microbiome" research retreat held by the UAB Comprehensive Cancer Center. 




Shownotes for the podcast

1:00 Trillions of microbes, an immense community, live inside the human body and on its surfaces, interacting with the body to either help or harm it.

1:55 As a medical doctor who treats patients, Plottel has a unique perspective on microbiome research, and on how it may factor into patient care. Interacting with patients gives her a context to ask questions about the microbiome, while her research into the microbiome has made her more aware that any therapy is treating both the human body and its bacteria.

2:30 Beyond probiotics, there are few clinical treatments available that address a person's microbiome on the way to treating their disease, but several are on the horizon. For instance, approaches are under development that promise to restore a healthy population of microbes in a person, or even transplant them from a healthy person.

3:20 A major focus of Plottel's research is the interaction between each woman's gut microbiome and the hormone estrogen. It has been long known that estrogen, a vital hormone for human health, is processed in the liver, and that some of it enters the gut, where it interacts with each person's unique microbial community.

3:42 Also well established is that some of the estrogen entering the gut is recirculated through the body, while the rest of it is excreted. Evidence suggests that each person's mix of gut bugs determines how much estrogen is recirculated, making the microbiome a key regulator of each person's circulating estrogen levels over time.

4:27 Researchers know from studying large groups of women that the occurrence of certain cancers is estrogen-related, and that the incidence of these cancer types varies greatly across the globe. Microbial populations vary along with estrogen-related cancer rates, and projects under way in Plottel's lab seek to determine whether or not the two are linked.

5:22 One enzyme produced by certain bacteria, beta glucuronidase, is present in the guts of about 44 percent of women with healthy estrogen metabolism, so the thought is it plays a major role.

6:08 It has been established that antibiotic treatments change the make-up of the gut microbiome, and that it takes time for the community of helpful bacteria to recover after treatment. Some theorize that antibiotics throw off bacterial regulation of estrogen, and Plottel's team is currently running experiments to see if this is the case.

7:03 Plottel hypothesizes that women who happen to have gut bacteria with stronger or weaker enzyme function may have have higher or lower levels of re-circulated estrogens over their lifetimes, which in turn represents higher or lower risk for certain types of cancers. If this proves to be the case, researchers may be able to use prebiotics and probiotics to reduce risk.

9:00 Estrogen and cholesterol are chemical relatives, and some theorize that obesity, higher blood cholesterol, changes in gut bug profiles and higher risk for estrogen-based cancers are all related. In studies in mice, Plottel observed that antibiotic treatment that changes estrogen metabolism causes the mice to gain weight. Studies in women have also shown that obesity is a risk factor for estrogen-related cancers such as those occurring in the lining of the uterus (endometrial cancer) and in post-menopausal breast cancer. Plottel and others are working now to untangle these many threads.

10:10 The field of microbiome research is exploding in part thanks to the availability of new computational tools that can deal with its complexity, says Plottel. Most of the bacteria making up the estrobolome cannot be grown in culture for study by standard methods, so researchers must rely on genomic technologies and methods that have only become available in recent years.

10:58 Researchers need to look at cancer differently in the context of the microbiome, says Plottel. They should be looking more closely at the organ in which cancers occur, and seeking to determine if the microbial community specific to that organ is playing a role in cancer development.