Following the people and events that make up the research community at Duke

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Trust-Building, Re-Visited History, and Time Pertinent to Achieve Health Equity for Black Americans

Along with being a beautiful person and leading a productive life, Henrietta Lacks is the mother of modern medicine. Her scientific child was born without Henrietta’s consent through the clinical breakthroughs and medical miracles achieved with the help of her cervical cells – HeLa cells – stolen without her knowledge when she sought healthcare. Ironically, the same treatments developed from the cells of this Black woman are inaccessible for many Black Americans contemporarily. Though Ms. Lacks passed away from cervical cancer at the premature age of 31, her unique cells have become immortal. Her story lives on as a pertinent reminder of the importance of building trust between medicine and the Black community. In honor of her birthday, expert panelists met to both celebrate Ms. Lacks and discuss the path forward in trust-building, equity, and reckoning with our history to change the narrative of healthcare for Black Americans.

The panel honored Henrietta Lacks through discussion of the path forward for biomedical research and Black communities. The panel was hosted in August in remembrance of Ms. Lacks’ birthday on August 1st.

The panel, which took place on Tuesday, August 31, began as a conversation between Nadine Barrett (Ph.D.), Robert A. Winn (M.D.) and Vanessa B. Sheppard (Ph.D.). Among their many other titles and positions, Barrett is Director, Center for Equity in Research, Dukev CTSI and Associate Director of Equity, Community and Stakeholder Strategy, Duke Cancer Institute, Dr. Winn is the Director of the Virginia Commonwealth University (VCU) Massey Cancer Center, and Sheppard is the Associate Director of Community Outreach Engagement and Health Disparities at VCU Massey Cancer Center. The trio were joined by Reuben Warren (D.D.S., M.P.H., Dr. P.H., M.DIV.), Director of Tuskegee University’s Bioethics Center, along with a handful of other contributors including Veronica Robinson – Henrietta Lacks’ great-granddaughter and a registered nurse who represents the Lacks family on the NIH panel that reviews applications to conduct research using the HeLa genome.

A screenshot of panelists who took part in Tuesday’s conversation.

Winn began by referencing the U.S. 1932 public health service study that took place in Tuskegee, Alabama. The experiment exploited Black men in Tuskegee when an effective form of treatment for syphilis was discovered 15 years into the study but withheld from participants “to track the disease’s full progression.” In 1972, 40 years after the study began, it was the associated press, not the scientific community that finally led to the experiment’s demise and the issue of an apology from the U.S. President.

As Warren pointed out, the issue with the study was less about the treatment and more about the dishonesty, the falsifying information, and lies. “Stop calling them poor, stop calling them all sharecroppers,” Warren said of the Black men who participated in the study, “They were far more than that.” “[The study] was an issue of trust, not an issue of ignorance,” he continued. Unfortunately, when talking about this story, Winn said that Black Americans “don’t always talk about the power of us standing up and saying not again.

Bioethics violations have been a continuous part of the biomedical research enterprise in the U.S., and race and racism have been part of scientific inquiry, which continues to be of great concern, Warren said. Often, rather than putting preventative protections in place, bioethics regulations have come as a reaction to extreme violations of justice. Thus, Warren laid out a central theme of the panel that “You build trust by making yourself trustworthy and that takes time.” Rather than initiating transactional research with Black communities when the scientific and medical community needs something, Warren offered that they should start when they want to help with something.

Dr. Rueben Warren presenting examples of bioethics violations in the history of biomedical research, with most examples stemming from the United States

As Sheppard said, “[Black people] have earned a mistrust” for medical communities. This is largely hinged on Barrett’s argument that the American systems from health to education to criminal justice “are working as they were designed” – to ensure that the very inequalities that exist today came to be. Using the analogy of a marathon, Barrett said while white men in the U.S. started the race 450 years ago, Black men and women only began running this race hundreds of years later. “Those who start the race are going to…ensure that they thrive,” Barrett said. This has led to Black people dying disproportionately from often treatable diseases, Sheppard said, continuing to add that these sorts of disparities were front and center for the world to see during the COVID-19 pandemic.

In the creation of our structural inequalities, the system created “two bookends: Black and white.” But there has to be a narrative that keeps this story alive. “In order to create the change, we have got to do the work to change the narrative,” said Barrett.

Nadine Barrett (Ph.D.), Director of Health Equity and Disparities at Duke Cancer Institute

Robinson pointed to the importance of history, paralleling Warren’s comments that in focusing on health equities we are fully focusing on the future in a way that ignores the past and does not deal with “what really brought us into health disparities” in the first place. Robinson said that we “can no longer sweep [conversations on the historical injustices of medical racism] under the rug.” She continued to say that the reason why Tuesday’s conversation and the ongoing dialogue that is sure to follow is so powerful is because “we are no longer victims in our own legacies” by taking over conversations at the table rather than being the topics of discussion at the table.

Mistrust in the Black community for systems of medicine and healthcare are based on hundreds of years of action. Hesitancy – from Covid-19 vaccinations to participation in clinical trials for cancer research – amongst Black Americans “aren’t us saying no,” said Robinson, “We’re saying something happened.” Sharon Ribera Sanchez, Founder-Director of Saving Pennies 4 A Cure, is a cancer survivor and advocate for people of color to engage in clinical trials because of the difference they can make in medical developments that draw on more diverse and robust data.

But there is a bigger conversation than just having more Black folks take place in research and clinical trials, Winn said. “How are you going to look at my biology without looking at my history?” he asked, referencing the genetic implications of environmental conditions and stressors from socially constructed race that impact DNA.

An image of HeLa cells

The dialogue, which was opened and closed with a prayer, also spoke to the importance of establishing regular, ongoing, transparent relationships between the Black faith community and the medical community. This should happen, not just in times of crisis, because “mass hysteria is prime for miscommunication,” Ralph Hodge, pastor of the Second Baptist Church in South Richmond, Virginia, said.

“Today was a big way of us looking back at the past, looking at where we are at now, and moving forward to the solutions,” said Barrett. This comes by letting communities know that we care, said Winn, along with “doing things with our communities, not through them.”

A key factor in deconstructing this issue and achieving health equity is time. Time to reflect on the past in order to avoid reliving it; time to generate innovative solutions to the problems at hand; and time to invest in Black communities – to learn from them, support them, and earn their trust not because they can offer science something, but because science has something to offer them.

Post by Cydney Livingston

Invisible No More, the Cervix

How many people have seen their cervix? Obscured from view and stigmatized socially, the cervix is critical to women’s, transgender-men’s, and non-binary folks’ health — and potential reproductive health issues. A team formed through Duke’s Center for Global Women’s Health Technologies (GWHT) has created a device that not only holds immense medical potential but the potential to empower people with cervixes across the globe: It makes visible a previously invisible organ. 

Nimmi Ramanujam (Ph.D.), founder of GWHT and Professor of Engineering at Duke University, heads the team. Mercy Asiedu (Ph.D.), Gita Suneja (M.D.) Wesley Hogan (Ph.D.), and Andrea Kim have all been integral members of the interdisciplinary collaboration. Dr. Suneja is Associate Professor of Radiation Oncology at the University of Utah School of Medicine and a clinical researcher. Asiedu, former PhD student with Dr. Ramanujam and current postdoc at MIT, was integral to the development of Callascope.

The Callascope allows women and others who have cervixes, along with health professionals, to perform cervical exams without use of traditional examination tools that are larger, cannot be used for self-examinations, and often scary-looking.

When Wesley Hogan, director of Duke’s Center for Documentary Studies and research professor, heard about the idea “she was hooked.” Andrea Kim graduated from Duke University in 2018. Her senior thesis was a 12 minute documentary focused on the Callascope and its potential uses. Following graduation, over the last two years, she expanded the film to a 50-minute piece titled  “The (In)visible Organ” that was screened January 14, 2021. Kim moderated a panel with Ramanujam, Asiedu, Suneja and Hogan January 28th, 2021. 

Callascope: A handheld device that can be used to conduct cervical screenings. All that’s needed is a smart phone.

The Callascope addresses a dire global health need for better women’s reproductive health. Further, it empowers women as self-advocates of their own gynecological and reproductive health through reinvention of gynecological examination. Cervical cells have an “orderly progression,” says Suneja, we have a “great idea” of how cells become cancerous over time, “with multiple places to intervene.” Cervical examinations, however, are necessary for assessing cervical health and potential disease progression.

Originally from Ghana, Dr. Asiedu was interested in using her engineering skills to develop technology to “improve health outcomes,” particularly in countries like her own, which may lack adequate access to preventative healthcare and could benefit most from Callascope. Many women in underserved countries, as well as underserved areas of the United States, suffer disproportionately from cervical cancer — a preventable disease. 

Dr. Ramanujam, who served as a voluntary test-subject for Asiedu’s Callascope prototypes, says that it’s a really important tool “in actually changing [the cervix’s] narrative in a positive way” — it is an organ “that is indeed invisible.”

The hope is that with more awareness about and use of Callascope, cervical screenings, and vaginal health, cervixes may become more de-stigmatized and cultural norms surrounding them may shift to become more positive and open. Dr. Hogan stated that when Ramanujam pitched her the Callascope idea they were in a public restaurant. Hearing Ramanujam say words like “vagina” and “cervix” loud enough for others to hear made Hogan recognize her own embarrassment surrounding the topic and underscored the importance of the project. 

The project and the team serve as a wonderful example of intersectional work that bridges the sciences and humanities in effective, inspiring ways. One example was the Spring 2019 art exhibit, developed in conjunction with the team’s work, presented at the Nasher Museum which exposed the cervix through various mediums of art.

Multidisciplinary Bass Connections research teams contributed to this work and other interdisciplinary projects focused on the Callascope. Dr. Asiedu believes documentaries like Kim’s are “really powerful ways to communicate global health issues.” Kim who directed and produced “The (In)visble Organ” hopes to continue exploring how “we can create more cultures of inclusion …when it comes to reproductive health.” 

A piece of artwork from the (In)visible Organ art exhibit at Duke’s Nasher Museum in the spring of 2019.

Ramanujam emphasized the need to shift biomedical engineering focus to create technologies that center on “the stakeholders for whom [they] really [matter].” It is multi-dimensional thinkers like Ramanujam, Asiedu, Hogan, and Kim who are providing integrative and inventive ways to address health disparities of the 21st century — both the obvious and the invisible. 

Post by Cydney Livingston

Trust in Gynecology: The Impact of Race & Socioeconomic Status in Women’s Health

Nikki Mahendru’s mother didn’t go to the gynecologist for 45 years — and when she did, she regretted it. Ms. Mahendru felt “decades of anxieties and hesitancy reduced to five minutes of brisk interaction with her provider,” and left convinced that the “realm of women’s health was just not for her.” According to Nikki, a Duke University undergraduate, her mother’s “trust in the system was lost.” 

Mahendru joined Dr. Megan Huchko, the director of the Duke Center for Global Reproductive Health, and Dr. Chemtai Mungo, a Fogarty Global Health Fellow and OB-GYN doctor, on the Center for Global Women’s Health Technologies’ October 20 panel “Impact of Race and Socioeconomic Status in Women’s Health and Gynecology.” The panel was moderated by Ashley Deans and Alexandria Da Ponte.

Mahendru went on to detail an experience she had in the clinic with Carmen, a patient who spoke only Spanish and was also new to the gynecologist. The medical translator and Mahendru learned her story: she had been in pain for a year but had kept quiet due to money problems, had worked most of her life to send her kids to college, and was learning English via Rosetta Stone. With the details of Carmen’s story and an “equitable working relationship,” Mahendru and the translator could relay Carmen’s previous history to her provider. But Carmen’s provider knew only of her condition. 

Mahendru thinks gynecology done right has the potential to help women love their bodies and take care of their health, but gynecologists must earn the trust of their patients: “Acts of listening help bridge disparities.”

Dr. Huchko stated that throughout history, a male-dominated healthcare landscape saw the depiction of menses as ‘dirty,’ terms like ‘hysteria,’ and an overall lack of female control. The “father of gynecology” James Marion Sims exploited Black women in his development of the field, using unanesthetized slaves as subjects of experimentation. In general, Dr. Huchko sees a trend: “The lessening or decentering of women in women’s health corresponds to more discrimination.” In addition to the decentering of women, Dr. Huchko said that structural and individual factors “produce outcomes that prevent women from getting the care they need.” Like Mahendru, she identified trust as a central issue.

Dr. Megan Huchko, MD, MPH, is the director of the Duke Center for Global Reproductive Health

Dr. Huchko cited an experience in which she bore witness to the unattended consequences of racial bias in medicine. In Niger to repair women’s fistulas, which occur due to lack of postpartum care, Dr. Huchko felt she was attending to the downstream symptom of a much broader issue. She felt uncomfortable when the urogynecologist on her team ignorantly praised Sims without acknowledging his problematic history. Then, she saw this ignorance firsthand. 

Making a false assumption about the nature of the case, Dr. Huchko’s team chose to operate on a woman with a mass in her bladder. During the surgery, they realized the mass was a malignant tumor. With an unbiased eye and a complete exam and workup, this would have been clear. But because the team was looking at these women as “one-dimensional,” a woman with stage 4 cancer was subjected to a very invasive surgery that worsened her quality of life. 

Dr. Huchko experienced a similar lack of structural competency during her residency, where colleagues openly racially profiled people and overtly discussed disparities in pain tolerances among different ethnicities. Since then, “things have changed,” and she embraces this new culture of “being patient centered, exploring our own biases, and [having] zero tolerance for racial profiling.” She stresses the need for personal education and accountability alongside systemic change. Eventually, this will lead to women feeling “respected, seen, and heard.”

Coming to the US from Kenya, Dr. Mungo quickly came to appreciate the “sheer magnitude” of structural racism and its impact on health and healthcare. Dr. Mungo explained that “mutually reinforcing systems of disadvantage” for people of color, such as food deserts, are both the result and cause of healthcare disparities and result in enduring legacies of disadvantage.

Dr. Chemtai Mungo, MD, MPH, is a Fogarty Global Health Fellow and OB-GYN doctor

Dr. Mungo also observed that with healthcare in the US being so economically driven, the best care is often directed at those with racial and socioeconomic privilege. When she worked in a high resourced (read: white, wealthy) hospital, access to uterus-saving equipment such as interventional radiology meant that she only did one hysterectomy in four years. Doctors at the hospital also came in on weekends to get a person with cancer into the OR immediately.

Now, working at a “safety net hospital,” Dr. Mungo sees a stark difference. With non-existent interventional radiology and more part-time, “less invested” employees, Dr. Mungo has done three hysterectomies in three years — a 75% increase — and sees patients with time-sensitive conditions wait much longer before surgery. This “separate and unequal access to resources” is a cause for concern. 

Dr. Mungo also stressed the need to make practices “safe places” for patients of color by increasing minority representation. Dr. Mungo explained that while Black physicians make up only 5% of doctors and 3% of faculty, there is strong evidence that patients who are cared for by someone of their own race or ethnicity have better outcomes. “We live in a racist society,” Dr. Mungo stated, “so we need specific anti-racist policies.” 

Dr. Mungo also acknowledged that healthcare providers work within “templates” like 15 minute appointments, and posed the closing question, how can we make patients feel safe and heard within the constraints of modern medicine? 

Answering questions from the audience, Dr. Mungo and Huchko discussed medical algorithms that are based on race, like the VBAC calculator and GFR. 

Dr. Mungo indicted these algorithms as “an example of how institutionalized some [racial] biases are.” There is “no concrete evidence” on why these corrections for race — which typically act to reduce the probability of success for a procedure or favorability of an outcome — exist. Dr. Mungo would urge providers “not to stop at, ‘well, African Americans have an increased risk of diabetes.’ Ask why. Have them explain food deserts… and structural and environmental racism.”

Dr. Huchko stated that giving aspirin throughout pregnancy reduces preeclampsia, and is thus traditionally offered based on risk factors for preeclampsia, like low socioeconomic status and African American race. Sometimes, healthcare providers may not be able to address these risks without the acknowledgement of race as a risk factor. Dr. Huchko is right, African American women are at a higher risk for preeclampsia, and ignoring this correlation would probably do more harm than good. 

But per Dr. Mungo’s appeal, providers must interrogate these associations more deeply — and be ever anti-racist in their efforts — if they are to create the safe spaces and trusting relationships that Mahendru, Dr. Huchko, and Dr. Mungo each hope to see.

By Zella Hanson

Duke’s Fundamental Research Can Turn Viruses Into Marvels

The COVID-19 epidemic has impacted the Duke research enterprise in profound ways. Nearly all laboratory-based research has been temporarily halted, except for research directly connected to the fight against COVID-19. It will take much time to return to normal, and that process of renewal will be gradual and will be implemented carefully.

Trying to put this situation into a broader perspective, I thought of the 1939 essay by Abraham Flexner published in Harper’s magazine, entitled “The Usefulness of Useless Knowledge.” Flexner was the founding Director of the Institute for Advanced Study at Princeton, and in that essay, he ruminated on much of the type of knowledge acquired at research universities —  knowledge motivated by no objective other than the basic human desire to understand. As Flexner said, the pursuit of this type of knowledge sometimes leads to surprises that transform the way we see that which was previously taken for granted, or for which we had previously given up hope. Such knowledge is sometimes very useful, in highly unintended ways.

Gregory Gray, MD MPH
Gregory Gray, MD MPH

The 1918 influenza pandemic led to 500 million confirmed cases, and 50 million deaths. In the Century since, consider how far we have come in our understanding of epidemics, and how that knowledge has impacted our ability to respond. People like Greg Gray, a professor of medicine and member of the Duke Global Health Institute (DGHI), have been quietly studying viruses for many years, including how viruses at domestic animal farms and food markets can leap from animals to humans. Many believe the COVID-19 virus started from a bat and was transferred to a human. Dr. Gray has been a global leader in studying this mechanism of a potential viral pandemic, doing much of his work in Asia, and that experience makes him uniquely positioned to provide understanding of our current predicament.

From the health-policy perspective, Mark McClellan, Director of the Duke Margolis Center for Health Policy, has been a leading voice in understanding viruses and the best policy responses to an epidemic. As a former FDA director, he has experience bringing policy to life, and his voice carries weight in the halls of Washington. Drawing on faculty from across Duke and its extensive applied policy research capacity, the Margolis Center has been at the forefront in guiding policymakers in responding to COVID-19.

Through knowledge accrued by academic leaders like Drs. Gray and McClellan, one notes with awe the difference in how the world has responded to a viral threat today, relative to 100 years ago. While there has been significant turmoil in many people’s lives today, as well as significant hardship, the number of global deaths caused by COVID-19 has been reduced substantially relative to 1918.

One of the seemingly unusual aspects of COVID-19 is that a substantial fraction of the population infected by the virus has no symptoms. However, those asymptomatic individuals shed the virus and infect others. While most people have no or mild symptoms, other people have very adverse effects to COVID-19, some dying quickly.

This heterogeneous response to COVID-19 is a characteristic of viruses studied by Chris Woods, a professor medicine in infectious diseases. Dr. Woods, and his colleagues in the Schools of Medicine and Engineering, have investigated this phenomenon for years, long before the current crisis, focusing their studies on the genomic response of the human host to a virus. This knowledge of viruses has made Dr. Woods and his colleagues leading voices in understanding COVID-19, and guiding the clinical response.

A team led by Greg Sempowski, a professor of pathology in the Human Vaccine Institute is working to isolate protective antibodies from SARS-CoV-2-infected individuals to see if they may be used as drugs to prevent or treat COVID-19. They’re seeking antibodies that can neutralize or kill the virus, which are called neutralizing antibodies.

Barton Haynes,MD
Barton Haynes, MD

Many believe that only a vaccine for COVID-19 can truly return life to normal. Human Vaccine Institute Director Barton Haynes, and his colleagues are at the forefront of developing that vaccine to provide human resistance to COVID-19. Dr. Haynes has been focusing on vaccine research for numerous years, and now that work is at the forefront in the fight against COVID-19.

Engineering and materials science have also advanced significantly since 1918. Ken Gall, a professor of mechanical engineering and materials science has led Duke’s novel application of 3D printing to develop methods for creatively designing personal protective equipment (PPE). These PPE are being used in the Duke hospital, and throughout the world to protect healthcare providers in the fight against COVID-19.

Much of the work discussed above, in addition to being motivated by the desire to understand and adapt to viruses, is motivated from the perspective that viruses must be fought to extend human life.

In contrast, several years ago Jennifer Doudna and Emmanuelle Charpentier, academics at Berkeley and the Max Planck Institute, respectively, asked a seemingly useless question. They wanted to understand how bacteria defended themselves against a virus. What may have made this work seem even more useless is that the specific class of viruses (called phage) that infect bacteria do not cause human disease. Useless stuff! The kind of work that can only take place at a university. That basic research led to the discovery of clustered regularly interspaced short palindromic repeats (CRISPR), a bacterial defense system against viruses, as a tool for manipulating genome sequences. Unexpectedly, CRISPR manifested an almost unbelievable ability to edit the genome, with the potential to cure previously incurable genetic diseases.

Charles Gersbach, a professor of Biomedical Engineering, and his colleagues at Duke are at the forefront of CRISPR research for gene and cell therapy. In fact, he is working with Duke surgery professor and gene therapy expert Aravind Asokan to engineer another class of viruses, recently approved by the FDA for other gene therapies, to deliver CRISPR to diseased tissues. Far from a killer, the modified virus is essential to getting CRISPR to the right tissues to perform gene editing in a manner that was previously thought impossible. There is hope that CRISPR technology can lead to cures for sickle cell and other genetic blood disorders. It is also being used to fight cancer and muscular dystrophy, among many other diseases and it is being used at Duke by Dr. Gersbach in the fight against COVID-19. 

David Ashley, Ph.D.
David Ashley, Ph.D.

In another seemingly bizarre use of a virus, a modified form of the polio virus is being used at Duke to fight glioblastoma, a brain tumor. That work is being pursued within the Preston Robert Tisch Brain Tumor Center, for which David Ashley is the Director. The use of modified polio virus excites the innate human immune system to fight glioblastoma, and extends life in ways that were previously unimaginable. But there are still many basic-science questions that must be overcome. The remarkable extension of life with polio-based immunotherapy occurs for only 20% of glioblastoma patients. Why? Recall from the work of Dr. Woods discussed above, and from our own observation of COVID-19, not all people respond to viruses in the same way. Could this explain the mixed effectiveness of immunotherapy for glioblastoma? It is not known at this time, although Dr. Ashley feels it is likely to be a key factor. Much research is required, to better understand the diversity in the host response to viruses, and to further improve immunotherapy.

The COVID-19 pandemic is a challenge that is disrupting all aspects of life. Through fundamental research being done at Duke, our understanding of such a pandemic has advanced markedly, speeding and improving our capacity to respond. By innovative partnerships between Duke engineers and clinicians, novel methods are being developed to protect frontline medical professionals. Further, via innovative technologies like CRISPR and immunotherapy — that could only seem like science fiction in 1918 (and as recently as 2010!) — viruses are being used to save lives for previously intractable diseases.

Viruses can be killers, but they are also scientific marvels. This is the promise of fundamental research; this is the impact of Duke research.

“We shall not cease from exploration
And the end of all our exploring
Will be to arrive where we started
And know the place for the first time.”

T.S. Eliot, Four Quartets

Post by Lawrence Carin, Vice President for Research

The evolution of a tumor

The results of evolution are often awe-inspiring — from the long neck of the giraffe to the majestic colors of a peacock — but evolution does not always create structures of function and beauty.

In the case of cancer, the growth of a population of malignant cells from a single cell reflects a process of evolution too, but with much more harrowing results.

Johannes Reiter uses mathematical models to understand the evolution of cancer

Researchers like Johannes Reiter, PhD, of Stanford University’s Translational Cancer Evolution Laboratory, are examining the path of cancer from a single sell to many metastatic tumors. By using this perspective and simple mathematical models, Reiter interrogates the current practices in cancer treatment. He spoke at Duke’s mathematical biology seminar on Jan. 17.

 The evolutionary process of cancer begins with a single cell. At each division, a cell acquires a few mutations to its genetic code, most of which are inconsequential. However, if the mutations occur in certain genes called driver genes, the cell lineage can follow a different path of rapid growth. If these mutations can survive, cells continue to divide at a rate faster than normal, and the result is a tumor.

As cells divide, they acquire mutations that can drive abnormal growth and form tumors. Tumors and their metastases can consist of diverse cell populations, complicating treatment plans out patient outcomes. Image courtesy of Reiter Lab

With each additional division, the cell continues to acquire mutations. The result is that a single tumor can consist of a variety of unique cell populations; this diversity is called intratumoral heterogeneity (ITH). As tumors metastasize, or spread to other locations throughout the body, the possibility for diversity grows.

Intratumoral heterogeneity can exist within primary tumors, within metastases, or between metastases. Vogelstein et al., Science, 2013

Reiter describes three flavors of ITH. Intra-primary heterogeneity describes the diversity of cell types within the initial tumor. Intrametastatic heterogeneity describes the diversity of cell types within a single metastasis. Finally, inter-metastatic heterogeneity describes diversity between metastases from the same primary tumor.

For Reiter, inter-metastatic heterogeneity presents a particularly compelling problem. If treatment plans are made based on biopsy of the primary tumor but the metastases differ from each other and from the primary tumor, the efficacy of treatment will be greatly limited.

With this in mind, Reiter developed a mathematical model to predict whether a cell sample collected by biopsy of just the primary tumor would provide adequate information for treatment.

Using genetic sequence data from patients who had at least two untreated metastases and a primary tumor, Reiter found that metastases and primary tumors overwhelmingly share a single driver gene. Reiter said this confirmed that a biopsy of the primary tumor should be sufficient to plan targeted therapies, because the risk of missing driver genes that are functional in the metastases proved to be negligible.

 In his next endeavors as a new member of the Canary Center for Cancer Early Detection, Reiter plans to use his knack for mathematical modeling to tackle problems of identifying cancer while still in its most treatable stage.  

Post by undergraduate blogger Sarah Haurin

Post by Sarah Haurin

Overdiagnosis and the Future of Cancer Medicine

For many years, the standard strategy for fighting against cancer has been to find it early with screening when the person is still healthy, then hit it with a merciless treatment regimen to make it go away.

But not all tumors will become life-threatening cancers. Many, in fact, would have caused no issues for the rest of the patients’ lives had they not been found by screening. These cases belong to the category of overdiagnosis, one of the chief complaints against population-level screening programs.

Scientists are reconsidering the way to treat tumors because the traditional hit-it-hard approach has often caused the cancer to seemingly go away, only to have a few cells survive and the entire tumor roar back later with resistance to previously effective medicine.

Dr. Marc Ryser, the professor who gave this meaty talk

In his May 23 talk to Duke Population Health, “Cancer Overdiagnosis: A Discourse on Population Health, Biologic Mechanism and Statistics,” Marc Ryser, an assistant professor at Duke’s Departments of Population Health Sciences and Mathematics, walked us through how parallel developments across different disciplines have been reshaping our cancer battle plan. He said the effort to understand the true prevalence of overdiagnosis is a point of focus in this shift.

Past to Future: the changing cancer battle plan
Credit: Marc Ryser, edit: Brian Du

Ryser started with the longstanding biological theory behind how tumors develop. Under the theory of clonal sweeps, a relatively linear progression of successive key mutations sweeps through the tumor, giving it increasing versatility until it is clinically diagnosed by a doctor as cancer.

Clonal sweeps model, each shade is a new clone that introduces a mutation credit: Sievers et al. 2016

With this as the underpinning model, the battle plan of screen early, treat hard (point A) makes sense because it would be better to break the chain of progression early rather than later when the disease is more developed and much more aggressive. So employing screening extensively across the population for the various types of cancer is the sure choice, right?

But the data at the population level for many different categories of cancers doesn’t support this view (point B). Excluding the cases of cervical cancer and colorectal cancer, which have benefited greatly from screening interventions, the incidence of advanced cases of breast cancer and other cancers have stayed at similar levels or actually continued to increase during the years of screening interventions. This has raised the question of when screening is truly the best option.

Scientists are thinking now in terms of a “benefit-harm balance” when mass-screening public health interventions are carried out. Overdiagnosis would pile up on the harms side, because it introduces unnecessary procedures that are associated with adverse effects.

Thinking this way would be a major adjustment, and it has brought with it major confusion.

Paralleling this recent development on the population level, new biological understanding of how tumors develop has also introduced confusion. Scientists have discovered that tumors are more heterogeneous than the clonal sweeps model would make it appear. Within one tumor, there may be many different subpopulations of cancer cells, of varying characteristics and dangerousness, competing and coexisting.

Additional research has since suggested a more complex, evolutionary and ecological based model known as the Big Bang-mutual evolution model. Instead of the “stepwise progression from normal to increasingly malignant cells with the acquisition of successive driver mutations, some cancers appear to evolve more like a Big Bang, where the malignant ability is already concentrated in the founder cell,” Ryser said.

As the first cell starts to replicate, its descendants evolve in parallel into different subpopulations expressing different characteristics. While more research has been published in favor of this model, some scientists remain skeptical.

Ryser’s research contributes to this ongoing discussion. In comparing the patterns by which mutations are present or absent in cancerous and benign tumors, he obtained results favoring the Big Bang-mutual evolution model. Rather than seeing a neat region of mutation within the tumor, which would align with the clonal sweeps model, he saw mutations dispersed throughout the tumor, like the spreading of newborn stars in the wake of the Big Bang.

How to think about mutations within a tumor
credit: NASA

The more-complicated Big Bang-mutual evolution model justifies an increasingly nuanced approach to cancer treatment that has been developing in the past few years. Known as precision medicine (point C), its goal is to provide the best treatment available to a person based on their unique set of characteristics: genetics, lifestyle, and environment. As cancer medicine evolves with this new paradigm, when to screen will remain a key question, as will the benefit-harm balance.

There’s another problem, though: Overdiagnosis is incredibly hard to quantify. In fact, it’s by nature not possible to directly measure it. That’s where another area of Ryser’s research seeks to find the answers. He is working to accurately model overdiagnosis to estimate its extent and impact.

Going forward, his research goal is to try to understand how to bring together different scales to best understand overdiagnosis. Considering it in the context of the multiscale developments he mentioned in his talk may be the key to better understand it.

Post by Brian Du

Don’t Drink the Tap

Have you ever questioned the quality of the water you drink every day? Or worried that cooking with tap water might be dangerous? For most of us, the answer to these questions is probably no. However, students from a Bass Connections team at Duke say we may want to think otherwise.

Image result for image of water

From bottle refilling stations to the tap, drinking water is so habitual and commonplace that we often take it for granted. Only in moments of crisis do we start worrying about what’s in the water we drink daily. The reality is that safe drinking water isn’t accessible for a lot of people.

Image result for pink hog farm water
Pig waste discoloring lagoon water

Images like this hog farm motivated the Bass Connections project team DECIPHER to take a closer look at the quality of water in North Carolina. On April 16 they presented their concerning findings from three case studies looking at lead contamination, coal ash impoundments, and aging infrastructure at the Motorco Music Hall.

Motorco in Durham. The talk was inside, though.

Nadratun Chowdhury, a Ph.D. student in Civil and Environmental Engineering, investigated lead contamination in water. Lead is an abundant and corrosion-resistant material, making it appealing for use in things like paint, batteries, faucets and pipes. While we’ve successfully removed lead from paint and gasoline, a lot of old water pipes in use today are still fashioned from lead. That’s not good – lead is very toxic and can leach into the water.

Just how toxic is it? Anything over a blood-lead level concentration of fifty parts per billion – fifty drops of water in a giant Olympic swimming pool – is considered dangerous. According to Duke graduate student Aaron Reuben, this much lead in one’s blood is correlated with downward social mobility, serious health concerns, diminished capacity to regulate thoughts and emotions, and hyperactivity. Lower income and minority areas are more at risk due to the higher likelihood of owning contaminated older homes.

Rupanjali Karthik, a Master of Laws student, conducted research on the intersection of water and aging infrastructure in Orange County. Breaks in water pipes are common and can result in serious consequences, like the loss of 9 million gallons of drinkable water. Sometimes it takes 8 or 9 months just to find the location of a broken pipe. In 2018, the UNC-Chapel Hill water main break caused a huge shortage on campus and at the medical center.

Excess fluoridation is also an issue caused by aging infrastructure. In February 2017, a combination of human and machine error caused an excessive fluoride concentration coming out of an Orange County Water Treatment Plant. People were advised not to use their water even to shower. A UNC basketball game had to move locations, and stores were completely swept of bottled water.

Another issue is that arsenic, a known carcinogen, is often used as the fluoridation agent. We definitely don’t want that in our drinking water. Fluoridation isn’t even that necessary these days when we have toothpaste and mouthwash that supports our dental health.

Tommy Lin, an undergraduate studying Chemistry and Computer Science, topped off the group’s presentation with findings surrounding coal ash in Belmont, NC. Coal ash, the residue after coal is burned in power plants, can pollute rivers and seep into ground water, affecting domestic wells of neighboring communities. This creates a cocktail of highly concentrated heavy metals and carcinogens. Drinking it can cause damage to your nervous system, cancer, and birth defects, among other things. Not so great.

The group’s presentation.

Forty-five plastic water bottles. That’s how much water it takes Laura, a Belmont resident, to cook her middle-sized family Thanksgiving. She knows that number because it’s been her family’s tradition the past three years. The Allen Plant Steam Station is a big culprit of polluting water with coal ash. Tons of homes nearby the station, like Laura’s, are told not to use the tap water. You can find these homes excessively stockpiled with cases on cases of plastic water bottles.

These issues aren’t that apparent to people unless they have been directly impacted. Lead, aging infrastructure, and coal ash all pose real threats but are also very invisible problems. Kathleen Burns, a Ph.D. student in English, notes that only in moments of crisis will people start to care, but by then it may be too late.

So, what can people do? Not much, according to the Bass Connections team. They noted that providing clean water is very much a structural issue which will require some complex steps to be solved. So, for now, you may want to go buy a Brita.

Will Sheehan
Post by Will Sheehan

Opportunities at the Intersection of Technology and Healthcare

What’d you do this Halloween?

I attended a talk on the intersection of technology and healthcare by Dr. Erich Huang, who is an assistant professor of Biostatistics & Bioinformatics and Assistant Dean for Biomedical Informatics. He’s also the new co-director of Duke Forge, a health data science research group.

This was not a conventional Halloween activity by any means, but I felt lucky to be exposed to this impactful research surrounded by views of the Duke forest in fall in Penn Pavilion at IBM-Duke Day.

Erich Huang

Erich Huang, M.D., PhD. is the co-director of Duke Forge, our new health data effort.

Dr. Huang began his talk with a statistic: only six out of 53 landmark cancer biology research papers are reproducible. This fact was shocking (and maybe a little bit scary?), considering  that these papers serve as the foundation for saving cancer patients’ lives. Dr. Huang said that it’s time to raise standards for cancer research.

What is his proposed solution? Using data provenance, which is essentially a historical record of data and its origins, when dealing with important biomedical data.

He mentioned Duke Data Service (DukeDS), which is an information technology service that features data provenance for scientific workflows. With DukeDS, researchers are able to share data with approved team members across campus or across the world.

Next, Dr. Huang demonstrated the power of data science in healthcare by describing an example patient. Mr. Smith is 63 years old with a history of heart attacks and diabetes. He has been having trouble sleeping and his feet have been red and puffy. Mr. Smith meets the criteria for heart failure and appropriate interventions, such as a heart pump and blood thinners.

A problem that many patients at risk of heart failure face is forgetting to take their blood thinners. Using Pillsy, a company that makes smart pill bottles with automatic tracking, we could record Mr. Smith’s medication taking and record this information on the blockchain, or by storing blocks of information that are linked together so that each block points to an older version of that information. This type of technology might allow for the recalculation of dosage so that Mr. Smith could take the appropriate amount after a missed dose of a blood thinner.

These uses of data science, and specifically blockchain and data provenance, show great opportunity at the intersection of technology and healthcare. Having access to secure and traceable data can lead to research being more reproducible and therefore reliable.

At the end of his presentation, Dr. Huang suggested as much collaboration in research between IBM and Duke as possible, especially in his field. Seeing that the Research Triangle Park location of IBM is the largest IBM development site in the world and is conveniently located to one of the best research universities in the nation, his suggestion makes complete sense.

By Nina Cervantes        

Creative Solutions to Brain Tumor Treatment

Survival rates for brain tumors have not improved since the 1960s; NIH Image Gallery.

Invasive brain tumors are among the hardest cancers to treat, and thus have some of the worst prognoses.

Dean of the Pratt School of Engineering, Ravi Bellamkonda, poses for his portrait inside and outside CIEMAS.

Displaying the survival rates for various brain tumors to the Genomic and Precision Medicine Forum on Thursday, Oct. 26, Duke professor Ravi Bellamkonda noted, “These numbers have not changed in any appreciable way since the 1960s.”

Bellakonda is the dean of the Pratt School of Engineering and a professor of biomedical engineering, but he is first a researcher. His biomedical engineering lab is working toward solutions to this problem of brain tumor treatment.

Unlike many other organs, which can sacrifice some tissue and remain functional, the brain does not perform the same way after removing the tumor. So a tumor without clearly defined boundaries is unsafe to remove without great risk to other parts of the patient’s brain, and in turn the patient’s quality of life.

Bellakonda hypothesized that brain tumors have characteristics that could be manipulated to treat these cancers. One key observation of brain tumors’ behavior is the tendency to form along white matter tracts. Put simply, tumors often spread by taking advantage of the brain’s existing structural pathways.

Bellakonda set out to build a device that would provide brain tumors a different path to follow, with the hope of drawing the tumor out of the brain where the cells could be killed.

The results were promising. Tests on rats and dogs with brain tumors showed that the device successfully guided out and killed tumor cells. Closer examination revealed that the cells killed were not cells that had multiplied as the tumor grew into the conduit, but were actually cells from the primary tumor.

The Bellamkonda lab’s device successfully guided and killed brain tumors in rats.

In addition to acting as a treatment device, Bellakonda’s device could be co-opted for other uses. Monitoring the process of deep brain tumors proves a difficult task for neurooncologists, and by bringing cells from deep within the tumor to the surface, this device could make biopsies significantly easier.

Although the device presents promising results, Bellakonda challenged his lab to take what they have learned from the device to develop a less invasive technique.

Another researcher in the Bellakonda lab, Tarun Saxena, engaged in research to utilize the body’s natural protection mechanisms to contain brain tumors. Creating scar tissue around tumors can trick the brain into treating the tumor as a wound, leading to immunological responses that effectively contain and suppress the tumor’s growth.

Visiting researcher Johnathan Lyon proposed utilizing electrical fields to lead a tumor to move away from certain brain regions. Moving tumors away from structures like the pons, which is vital for regulation of vital functions like breathing, could make formerly untreatable tumors resectable. Lyon’s 3D cultures using this technique displayed promising results.

Another Bellakonda lab researcher, Nalini Mehta, has been researching utilizing a surprising mechanism to deliver drugs to treat tumors throughout the brain: salmonella. Salmonella genetically engineered to not invade cells but to easily pass through the extracellular matrix of the brain have proven to be effective at delivering treatment throughout the brain.

While all of these therapies are not quite ready to be used to treat the masses, Bellakonda and his colleagues’ work presents reasonable hope of progress in the way brain tumors are treated.

By Sarah Haurin

Designing Drugs Aimed at a Different Part of Life’s Code

Individual RNA molecules fluoresce inside a breast cancer cell.

Individual RNA molecules fluoresce inside a breast cancer cell. Credit: Sunjong Kwon, Oregon Health & Science University, via Flickr.

Most drugs work by tinkering with the behavior of proteins. Like meddlesome coworkers, these molecules are designed to latch onto their target proteins and keep them from doing what they need to do.

If a protein is responsible for speeding up a reaction, the drug helps slow the reaction down. If a protein serves as a gatekeeper to a cell, regulating what gets in and what stays out, a drug changes how many molecules it lets through.

But proteins aren’t the only doers and shakers in our bodies. Scientists are finding that strings of RNA — known primarily for their role in shuttling genetic information from nucleus-bound DNA to the cell’s protein-manufacturing machinery — can also play a major role in regulating disease.

A portrait of Amanda Hargrove

Amanda Hargrove is an assistant professor of chemistry at Duke University.

“There has been what some people are calling an RNA revolution,” said Amanda Hargrove, assistant professor of chemistry at Duke. “In some diseases, non-coding RNAs, or RNAs that don’t turn into protein, seem to be the best predictors of disease, and even to be driving the disease.”

Hargrove and her team at Duke are working to design new types of drugs that target RNA rather than proteins. RNA-targeted drug molecules have the potential help treat diseases like prostate cancer and HIV, but finding them is no easy task. Most drugs have been designed to interfere with proteins, and just don’t have the same effects on RNA.

Part of the problem is that proteins and RNA have many fundamental differences, Hargrove said. While proteins are made of strings of twenty amino acids that can twist into myriad different shapes, RNA is made of strings of only four bases — adenine, guanine, cytosine and uracil.

“People have been screening drugs for different kinds of RNA for quite a while, and historically have not had a lot of success,” Hargrove said. “This begged the question, since RNA has such chemically different properties than proteins, is there something different about the small molecules that we need in order to target RNA?”

To find out, graduate student Brittany Morgan and research associate Jordan Forte combed the scientific literature to identify 104 small molecules that are known interact with specific types of RNA. They then analyzed 20 different properties of these molecules, and compared their properties to those of collections of drug molecules known to interact with proteins.

The team found significant differences in shape, atomic composition, and charge between the RNA-active molecules and the protein-active molecules. They plan to use the results to compile a collection of molecules, called a library, that are chosen to better “speak the language” of the RNA-active molecules. They hope this collection of molecules will be more likely to interact with RNA in therapeutically beneficial ways.

“We found that there are differences between the RNA-targeted molecules and the protein-targeted drugs, and some of them are pretty striking,” Hargrove said. “What that means is that we could start to enrich our screening libraries with these types of molecules, and make these types of molecules, to have better luck at targeting RNA.”

Discovery of Key Physicochemical, Structural, and Spatial Properties of RNA-Targeted Bioactive Ligands.” Brittany S. Morgan, Jordan E. Forte, Rebecca N. Culver, Yuqi Zhang and Amanda Hargrove. Angewandte Chemie, Sept. 18, 2017. DOI: 10.1002/anie.201707641

Kara J. Manke, PhDPost by Kara Manke

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