Tag Archives: cancer

Does a new treatment for leukemia herald a new era in drug discovery?

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Brent R. Stockwell, Ph.D. is an Associate Professor of Biological Sciences and of Chemistry at Columbia University, an Early Career Scientist of the Howard Hughes Medical Institute and author of The Quest for the Cure: The Science and Stories Behind the Next Generation of Medicines, which was called “critical reading” by Robert Bazell, chief science correspondent at NBC News and “an absolute page-turner” that manages to “distill a complex, changing field into a beautifully written, well-crafted story” by Siddhartha Mukherjee, winner of the 2011 Pulitzer Prize for General Nonfiction.

Dr. Stockwell’s research involves the discovery of small molecules that can be used to understand and treat cancer and neurodegeneration. He has received numerous awards, including a Burroughs Wellcome Fund Career Award at the Scientific Interface, and a Beckman Young Investigator Award. He has published 59 scientific papers, is an inventor on 10 issued US patents, has given 60 invited presentations around the world, and has received 33 research grants for over $10 million. He co-founded the biopharmaceutical companies CombinatoRx (now Zalicus) and Solaris Therapeutics. You can follow him on Twitter at @bstockwell.

A few years back, a 75-year-old woman whom we will call Dorothy went to see her doctor and received a disturbing diagnosis: Dorothy had developed chronic lymphocytic leukemia (CLL), a type of cancer of the white blood cells. Hearing the words diagnosis and cancer together in the same sentence in your doctor’s office will likely induce a sense of fear and panic, before any mitigating factors seep into your consciousness. This fear alone may jeopardize your well-being, as has been remarked upon in a recent Soapbox Science blogpost by David Ropeik.

Dorothy was at the beginning of her disease course. Each patient’s cancer can be assigned a specific stage in its evolution from a single ill-behaved cell to a massive metastatic invader1. Dorothy was fortunate, if such a word is appropriate in this context, to have stage 0 CLL, which indicates merely an unusually large number of lymphocytes (white blood cells), but no other, more dangerous, manifestations of disease. Since cancers are better treated at early stages, this appeared to be good news, in a relative sense. Unlike more aggressive and rapidly fatal cancers such as pancreatic cancer, the clinical course of CLL is uncertain. One patient may live with the disease for decades without treatment, whereas others will rapidly develop a more advanced disease and need aggressive drug therapy, which may or may not be effective2. So, although Dorothy faced an uncertain future, all indications were that she should be optimistic.

Two years passed as Dorothy watched her leukemia, and in this time, it evolved to stage 1 CLL, manifesting as enlarged lymph nodes. Nine moths later, Dorothy’s health problems began to mount. She endured deep-vein thrombosis, a clotting of her veins, which caused a blockage in one of her arteries in her lungs. Three months later, in April of 2010, Dorothy came down with a weeklong fever and cough, and developed swelling of her legs and a general weariness, for which she was admitted to Montreal General Hospital3. Within days, Dorothy’s liver failed, and her mental health declined, as she faded from consciousness into a delirious state. Finally, 48 days after she was admitted to the hospital, and three years from her initial diagnosis, Dorothy succumbed to her disease.

With our burgeoning knowledge of cancer genetics and mechanisms, why is there no drug that could have slowed or reversed the course of Dorothy’s leukemia—is there any hope for the CLL patients of the future? An emerging trend in cancer therapeutics is the need for precise matching of drugs to disease subtypes—could one make a drug that is designed to address the unique networks and proteins found in CLL tumor cells? Such a tailor-made drug for CLL would likely have fewer side effects than the systemic, blunt chemotherapy this is commonly used to treat most cancers today. Moreover, such a customized drug would likely be more effective, by disabling the specific molecular defects found in CLL. This customization of drugs to diseases is an emerging challenge in cancer drug discovery, and indeed in all of medicine—how do we turn our increasingly sophisticated understanding of disease mechanisms into better therapies for patients?

Increasingly in this post-genomic era, our molecular understanding of disease leads us to a protein that appears to be an ideal candidate for attack with a drug. However, more often than not, these therapeutically and biologically attractive proteins are considered undruggable, resistant to modulation with small molecule drugs (most drug molecules are considered small compared to proteins, which are quite large on the scale of atoms).

Orally available drugs typically function by penetrating inside cells and tissues and directly attaching themselves to crucial proteins that regulate or cause disease. However, proteins vary tremendously in their susceptibility to drug-based attacks. A few proteins have large cavities or pockets that are perfectly suited to tightly enveloping small molecule drugs, whereas most proteins have relatively smooth and featureless surfaces, akin to the side of a sheer cliff, with no footholds for drug molecules. Indeed, all known drugs affect just 2% of human proteins, and most of the remaining proteins are considered challenging or impossible to target with small molecule drugs. Unfortunately, most disease-regulating and disease-causing proteins lie within this more challenging category of potential drug targets, suggesting it may not be possible to address the diseases controlled by these proteins.

The Bcl-2 family of proteins has been thought to represent such a class of challenging drug targets, because they function by interacting with other proteins, as most challenging proteins do. That is, their molecular function is to engage in a tight-fitting interaction across a large region of their surface with other proteins—a surface area much larger than a traditional drug molecule can cover. A grand challenge for chemists and biochemists is to create methods for disrupting these large protein-protein interactions. If it were possible to disrupt any protein-protein interaction of interest, potently and specifically, a wealth of new medicines would be within reach; these would likely be far more effective than out current drugs, and they could be targeted to each disease subtype to reduce systemic side effects, such as hair loss and nausea, that are so common with older, blunter drugs.

One approach that is emerging as effective for attacking protein-protein interactions with small molecules is fragment-based drug design. In this approach, pioneered by Stephen Fesik4, instead of throwing thousands of randomly chosen drug candidates at a target protein to find one that sticks, researchers break drug candidates down into smaller functional units, and test these fragments, as they are known, for their ability to interact with a specific protein. Fesik and his colleagues used this approach to design a molecule, piece by piece, that can specifically and potently interact with the Bcl-2 family of proteins that prevent apoptosis, a specific form of cell death that many tumor cells become resistant to5.

This approach appears to have born fruit: in December of 2011, it was reported in the Journal of Clinical Oncology that patients with CLL were particularly susceptible to treatment with the Fesik drug that targets the Bcl-2 family of proteins6. Bcl-2 family proteins play a pivotal and specific role in allowing CLL tumor cells to survive, as though their default state is death. In these specific tumor cells, Bcl-2 proteins serve as a critical switch that turns off their death program; blocking the Bcl-2 proteins with a small molecule drug can re-activate this death program.

 

Figure 1. Structure of the Bcl-2 protein (red, white and blue surface) bound to a portion of the Bax protein (grey balls and sticks). When these proteins are bound together as shown, CLL tumor cells can survive and grow.   

 

This Bcl-2 targeted drug represents new hope for CLL patients, such as Dorothy. However, the implications are even broader: an otherwise challenging set of proteins (Bcl-2 family proteins) has succumbed to a small molecule drug attack. There are more than 20,000 protein-coding human genes, and only 2% of these have been targeted with small molecule drugs. Perhaps we are seeing the beginning of the assault on the remaining proteins, untouched by drugs until now. If fragment-based screening and other emerging methods for tackling these difficult proteins are successful, we may see a renaissance in the coming decade in the fields of drug discovery and medicine.

Figure 2. Model of a small molecule inhibitor (ABT263, from Abbott Laboratories, grey balls and sticks) bound to Bcl-2 (white, red and blue surface), displacing the Bax protein. By disrupting the Bcl2-Bax protein-protein interaction, this small molecule drug candidate can initiate cell death in CLL tumor cells. Images generated by Miki Hayano and Gisun Park.

References

1. NCI. Stages of Chronic Lymphocytic Leukemia. National Cancer Institute;  [cited 1/18/2005]; Available from: https://www.cancer.gov/cancertopics/pdq/treatment/CLL/Patient/page2.

2. Gribben JG, O’Brien S. Update on therapy of chronic lymphocytic leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(5):544-50.

3. Esfahani K, Gold P, Wakil S, Michel RP, Solymoss S. Acute liver failure because of chronic lymphocytic leukemia: case report and review of the literature. Curr Oncol. 2011;18(1):39-42. PMCID: 3031356.

4. Shuker SB, Hajduk PJ, Meadows RP, Fesik SW. Discovering high-affinity ligands for proteins: SAR by NMR. Science. 1996;274(5292):1531-4.

5. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O’Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435(7042):677-81.

6. Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, Carney DA, He SZ, Huang DC, Xiong H, Cui Y, Busman TA, McKeegan EM, Krivoshik AP, Enschede SH, Humerickhouse R. Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011.

The War on Cancer…Phobia

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untitled.bmpDavid Ropeik is an international consultant in risk perception and risk communication, and an Instructor in the Environmental Management Program at the Harvard University Extension School. He is the author of How Risky Is It, Really? Why Our Fears Don’t Always Match the Facts and principal co-author of RISK A Practical Guide for Deciding What’s Really Safe and What’s Really Dangerous in the World Around You. He writes the blog Risk; Reason and Reality at Big Think.com and also writes for Huffington Post,  Psychology Today,  and Scientific American.

He founded the program “Improving Media Coverage of Risk,” was an award-winning journalist in Boston for 22 years and a Knight Science Journalism Fellow at MIT.

If you were to be diagnosed with cancer, how do you think you would feel? It would depend on the type of cancer of course, but there’s a good chance that no matter the details, the word ‘cancer’ would make the diagnosis much more frightening. Frightening enough, in fact, to do you as much harm, or more, than the disease itself.  There is no question that in many cases, we are Cancer Phobic, more afraid of the disease than the medical evidence says we need to be, and that fear alone can be bad for our health. As much as we need to understand cancer itself, we need to recognize and understand this risk, the risk of Cancer Phobia, in order to avoid all of what this awful disease can do to us.

In a recent report to the U.S. National Institutes of Health (NIH), a panel of leading experts on prostate cancer, the second most common cancer in men (after skin), said;

“Although most prostate cancers are slow growing and unlikely to spread, most men receive immediate treatment with surgery or radiation. These therapeutic strategies are associated with short- and long-term complications including impotence and urinary incontinence.”

“Approximately 10 percent of men who are eligible for observational strategies (keep an eye on it but no immediate need for surgery or radiation) choose this approach.”

“Early results demonstrate disease-free and survival rates that compare favorably (between observation and) curative therapy.”

“Because of the very favorable prognosis of low-risk prostate cancer, strong consideration should be given to removing the anxiety-provoking term ‘cancer’ for this condition.”

Let me sum that up. Many prostate cancers grow so slowly they don’t need to be treated right away…the unnecessary treatment causes significant harm…and one of the reasons nine men out of ten men diagnosed with slow-growing prostate cancer accept, indeed choose these unnecessary harms, is because “cancer” sounds scary.

Consider more evidence for Cancer Phobia. In “Overdiagnosis in Cancer”  doctors at Dartmouth classified “25% of mammographically detected breast cancers, 50% of chest x-ray and/or sputum-detected lung cancers, and 60% of prostate-specific antigen–detected prostate cancers”, as ‘overdiagnosed’, which they defined as “1. The cancer never progresses (or, in fact, regresses) or 2. The cancer progresses slowly enough that the patient dies of other causes before the cancer becomes symptomatic.” The doctors described the negative health effects such patients suffer from a range of treatments that often involve radical surgery and noted; “Although such patients cannot benefit from unnecessary treatment, they can be harmed.”

Add to those harms the damage from stress caused by the diagnosis of cancer, or even the fear of getting it. Chronic stress raises blood pressure and contributes to heart disease. Even more directly as regards cancer, chronic stress weakens the immune system, the very system our bodies need to help prevent, fight, or recover from, the disease itself. and beyond these harms to individual patients, consider the cost of Cancer Phobia at the societal level.

The basic biological mechanics of what causes both cancer and heart disease are still inadequately understood and need fundamental research. But the U.S. National Institutes of Health spend about four times as much on cancer research as on heart disease research, despite the fact that heart disease kills about 10% more people (60,000 each year, 25 per day), than cancer. We are spending far more on the second leading cause of death than we are trying to figure out what is much more likely to kill us.

Despite all the progress we’ve made on cancer, a recent Harris poll found that cancer is the most feared disease in the U.S., 41% to Alzheimer’s 31%. (Only 8% of American are most afraid of the leading cause of death in the U.S., heart disease). In August 2011, Cancer Research UK found 35% of Britons feared cancer most, followed by Alzheimer’s at 25%.And this fear is hardly new. 40 years ago the U.S. National Cancer Act of 1971, which declared “War on Cancer” said “…cancer is the disease which is the major health concern of Americans today.”

Cancer Phobia goes even further back. The term itself was coined in an article by Dr. George Crile, Jr., in Life Magazine, in 1955, “Fear of Cancer and unnecessary operations”. His insights describe conditions  today as accurately as they did then; “Those responsible for telling the public about cancer have chosen the weapon of fear, believing that only through fear can the public be educated. Newspapers and magazines have magnified and spread this fear, knowing that the public is always interested in the melodramatic and the frightening. This has fostered a disease, fear of cancer, a contagious disease that spreads from mouth to ear. It is possible that today, in terms of the total number of people affected, fear of cancer is causing more suffering than cancer itself. This fear leads both doctors and patients to do unreasonable and therefore dangerous things.”

Unfortunately, Dr. Crile Jr. overlooked the key truth about our fear of cancer; Cancer Phobia is hardly just the product of zealous health and environmental advocates magnified by media alarmism. It comes from the innate way we perceive all risks, a process that relies not only the statistical and medical facts, but on how those facts feel. Risk perception is a blend of conscious reasoning and subconscious instinct, and neuroscience suggests that between the two, instincts and emotions have the upper hand. While we’ve been busy studying cancer, we have also learned a lot about the specific psychological characteristics of cancer that make it particularly frightening.

The more pain and suffering a risk involves, like cancer, the scarier it is.

The less control over a risk we feel we have, the scarier it is. Despite great medical progress, cancer is still something that too often can’t be controlled. It is still widely assumed that a diagnosis of cancer is a death sentence.

The more a risk feels imposed on us, rather than the result of something we did by choice, the scarier it is. Many people continue to believe that a majority of cancers are ‘done to us’ by outside forces, despite the medical evidence that environmental cancers (beyond those caused by our lifestyle choices of diet and exercise) make up perhaps 10-15% of all cases.

The greater our ‘mental availability’ about a risk – how readily the risk comes to mind – the scarier it is. Cancer is constantly in the news. And the very mention of the word ‘cancer’ is instantly overwhelmingly negative, a psychological effect called Stigmatization that makes it difficult for us to think about things objectively.

“Cancer” is no longer the automatic death sentence it was once feared to be. From 1990 to 2010 the overall death rate from cancer in the U.S.has dropped 22% in men and 14% in women.  (Incidence in the U.S.has stayed about the same.) In the U.K., the male mortality rate has dropped 26% and the female rate has declined 16% since 1980, (even while the incidence rate in the UK have increased 22%).

We have learned an immense amount about cancer, allowing us to treat, or even prevent, some types that used to be fatal. But we have also learned a great deal about the psychology of risk perception and why our fears often don’t match the evidence. We are failing to use that knowledge to protect ourselves from the significant, tangible health risks of our innately subjective risk perception system. The proposal of the NIH panel to replace the “C” word with something else that is medically honest but emotionally less frightening, is a tiny first step in the right direction, to open a new front in the War on Cancer, the battle against Cancer Phobia.

Bioinformatics what is it and how it can bring prehistory to life?

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Ivan Karabaliev joined Eagle Genomics located at the Babraham Research Centre in Cambridge, UK, a bit more than a year ago and has been discovering the essence of bioinformatics. Coming from a business marketing background, Ivan likes to explain the complex world of bioinformatics to new audiences and the general public.

Explained in just one sentence, bioinformatics is the science of managing, analysing, storing and merging biological data (DNA sequences, proteins, etc.) using advanced computing techniques. Put another way, it is the application of computer science and information technologies to solve biological questions. Simple questions include asking what a specific region of given DNA is responsible for, or how closely related one organism is to another by comparing their genomes.

The genome is the entirety of an organism’s hereditary information; the genetic make-up of all living organisms. It contains the instructions needed for a living organism to grow and function. When we know the sequence of a gene, the role it has in an organism and the diseases caused by malfunctioning copies of the gene, this information can be used to improve life for the organism. This is where bioinformatics comes along, to better interpret and understand genetic messages.

The genomes of organisms, some of which can be several billion DNA base pairs long, can be stored in biological databases. The data stored may include gene function, structure, localization (both cellular and chromosomal), physiological or clinical effects of genetic mutations, as well as similarities of biological sequences and structures.

In 1990 the Human Genome Project was formally given a green light, encouraged by the need to understand and help cure human diseases – the genomic revolution started to take its first steps. The project was led by Dr. Francis Collins, head of the International Human Genome Institute. The whole human genome, which is 3 billion base pairs long, was sequenced in 2000. The news was proclaimed by Bill Clinton:

Humankind is on the verge of gaining immense, new power to heal. It will revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases!

You can watch a YouTube video of the announcement here. During the announcement a very important fact was neglected: the sequence was not truly complete, but a mere first draft. About 10 percent of the human genome had not been read.

It wasn’t until 2003 that the human genome’s sequencing was officially completed. Since then, along with the constant improvement of bioinformatics, genetic investigations have enabled the development of new tests, drug targets and have given fresh insights into the basis of human disease. However, these pioneering investigations have also revealed just how complicated human biology is and how much remains to be understood.

The human genome project is a great example of the application of bioinformatics. The project stores huge amounts of genetic data in a database that analyses and maintains human genome sequences. The database is able to write complex, biologically-aware algorithms to analyse the massive amount of information and to compare it to other related data. This enables the efficient sequencing and identification of all three billion chemical units in the human genetic instruction set, helping to find the genetic roots of diseases. But, this is just one example of how bioinformatics can be used. Below is an overview of some of the other interesting applications of bioinformatics:

• The Microbial Genome Project where scientists are determining the DNA sequence of C. crescentus, one of the microorganisms used for sewage treatment. Genomes of highly resistant bacteria are sequenced and analyzed to aid the waste treatment industry. Some bacteria can reduce levels of uranium in water. Other bacteria species like the Geobacter are capable of breaking down petroleum compounds so polluted waters can be treated.

• Climate change can also be aided thanks to bioinformatics. How? Well the Department of Energy in USA launched a program to decrease atmospheric carbon dioxide levels. One method of doing so is to study the genomes of microbes that use carbon dioxide as their sole carbon source.

• In the food industry, researchers anticipate that understanding the physiology and genetic make-up of Lactococcus lactis bacteria used in the dairy industry (buttermilk, yogurt, cheese, also used to prepare pickled vegetables, beer, wine and breads) will prove invaluable for food manufacturers as well as the pharmaceutical industry. Similar advances are expected in forensic science where bioinformatics tools are used to compare crime-scene samples to existing databases to see if they are present there or if they are related to other microbes.

• Another and potentially controversial application of bioinformatics is in defence. Scientists have built the virus poliomyelitis using entirely artificial means. They did this using genomic data available on the Internet and materials from a mail-order chemical supply. The research was financed by the US Department of Defence as part of a biowarfare response program to prove to the world the reality of bioweapons. The researchers also hope their work will discourage officials from ever relaxing programs of immunization.

• In agriculture, sequencing of the genomes of plants and animals has enormous benefits for the field. Bioinformatics tools are used to search for potentially useful genes within these genomes and to elucidate their functions. The gathered genetic knowledge could then be used to produce stronger, more drought-, disease- and insect-resistant crops, or to improve the quality of livestock making them healthier, more disease-resistant and more productive.

Future uses of bioinformatics

• Medicine will become more personalised with the development of the field of pharmacogenomics, which is the study of how an individual’s genetic make-up affects the body’s response to drugs. At present, many drugs fail to make it to the market because a small percentage of patients show adverse affects to a drug often due to sequence variants in their DNA.

• Enhancement of gene therapies. Gene therapy is the approach used to treat , cure or even prevent disease by changing the expression of a person’s gene. Currently this field is in its infancy. There are currently many ongoing clinical trials for different types of cancer and other diseases.

• And finally my favourite example for potential use of bioinformatics is in sequencing dinosaur DNA. Remember Spielberg’s movie Jurassic Park based on the book by Michael Crichton? Scientist Mark Boguski read the book and decided to do a simple experiment to replicate the movie’s premise of dinosaur DNA having been preserved inside an amber-encased mosquito. He found out that the genetic sequence quoted in the book and movie had nothing to do with dinosaurs, so he wrote a journal article about his findings. Crichton came across this manuscript and approached Boguski to provide him with a real DNA sequence for his second book: The Lost World. (Read the full story here.) This is the actual paper where Boguski wrote his findings:

Conclusion

Bioinformatics isn’t going to replace lab experiments any time soon. For now it is best used to help “focus” and complement scientific research. In most cases, bioinformatics helps to eliminate false positives, saving time and money pursuing false leads. However, with the ever-increasing volumes of data, bioinformatics has become an important part of all genomic research projects and the future is bright. As developments in genomic and molecular research technologies improve, in line with developments in information technology, bioinformatics is becoming a major player in the understanding of biological processes and disease.

Engineering improvements in surgical technologies

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Dr Pete Culmer is a Senior Translational Research Fellow in the School of Mechanical Engineering, University of Leeds (UK). He has a background in medical engineering, with a PhD and subsequent post-doc work developing technology for rehabilitation assessments and interventions. He was awarded his current position, funded by the Biomedical Health Research Centre (BHRC), in 2010 and works with a growing team of researchers including engineers, surgeons and psychologists, conducting research in Surgical Technologies._

I’m at a large white console that wouldn’t be out of place in a games arcade, staring into a 3D display and carefully manoeuvring two hand-held controllers. Across the room, the other half of the surgical robot looms over the operating table, its arms mirroring my movements. It gives me a helping hand, ironing out the slight shake in my hands and scaling things so the small instruments it holds move more delicately than I could ever manage on my own. I’m trying to tie off a knot, yet despite all this technological help I mess up, miss the loop of thread and instead plunge the needle into the soft mass beneath. Oops…

It sounds like science fiction, but this robot system, the da Vinci, is widely used for minimally invasive surgery in healthcare systems around the world. This one is in the heart of Leeds General Infirmary where I’m sitting with colleagues, currently laughing at my lack of surgical prowess. Luckily this is just a practice using silicon models rather than people and I’m an engineer, not a surgeon.

It might seem unusual for an engineer, but this is part of my job in the Surgical Technologies research group at the University of Leeds. The group, led by Anne Neville (Prof. of Engineering and next up at the da Vinci’s controls) and David Jayne (Prof. of Surgery, watching on amused), focuses on developing new technology to improve modern surgery, with a particular emphasis on laparoscopy (minimally invasive surgery (MIS) on organs such as the bowel within the abdomen). For engineers it’s a challenging and fascinating task, but with systems like the da Vinci already in use, is new technology still necessary and beneficial? Understanding this question takes clinical expertise and experience and this is why our group comprises both surgeons and engineers working closely together. The answer, by the way, is a definite ‘yes’; laparoscopic surgery is sometimes described as being like trying to tie your shoelaces using a pair of long chopsticks….we need to give surgeons all the help we can to improve this situation.

As a researcher I’m fortunate in having a 5 year fellowship position which has been incredibly valuable in helping me establish a career in academia. It provides me with the opportunities, resources and crucially the time to develop my own research. My interests focus on developing ‘smart’ surgical tools that integrate sensors, data analysis and feedback systems to improve the surgeon’s operating experience. But there’s way too much work for one person alone so a key part of my job involves developing our research group by working with colleagues to obtain funding for new PhD students and post-docs. This gives us more hands on deck but also a wider set of skills to better tackle the multidisciplinary work, from robotics specialists to trainee surgeons with clinical expertise.

One interesting area we’re looking at is how human tissue can be damaged by surgical tools – and how we can help prevent it. In laparoscopy, organs and tissues are manipulated by grasping them with plier-like tools. However, the tools are on long levers (the chopsticks) which pass through the abdominal wall and their mechanisms are affected by friction – factors which make it extremely difficult for the surgeon to ‘feel’ and regulate the forces that they apply to the tissue. This can result in tissue damage through excessive force, like getting a bruise but with potentially far more serious consequences for the patient. So we need to understand how the damage is caused; how much force is too much and how long a ‘grasp’ is too long? Our approach highlights the multidisciplinary nature of this work; using computer controlled lab equipment we grasp tissue specimens with precisely controlled forces. Then we relate this to clinical measures of tissue damage through histological analysis – looking at small sections of the tissue under a microscope and assessing how structures and cells have been deformed or destroyed. Using this information we’re working to develop improved tools that minimise tissue damage. The solutions have come from a range of different engineering fields; tribology: new bio-inspired materials with surfaces that reversibly adhere to tissue (think bio-velcro), mechanics: computational models of how tissues react to forces; robotics: tools that can actively and automatically regulate the forces they apply to prevent damage.

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The other side of my work here involves teaching, something I’ve gradually moved into and really enjoy. We have an emphasis on linking our research with teaching here at Leeds. I think (hope!) this keeps things interesting and relevant for the students, it definitely does for me. I teach a 1st year computing course and the material could be quite abstract so it’s important to ground it with real-world examples – from controlling equipment at CERN to autonomously recording high scores on Guitar Hero, both important in their own way! One part I particularly enjoy is running projects for 3rd and 4th year students; it gives them a bite-sized taste of research and the opportunity to apply the engineering skills they’ve learnt without the normal constraints of lab-classes etc. This year I ran a project with my colleague Rob Hewson. Hatched over a strong coffee or two, we thought it might have been a touch ambitious…the idea was to investigate how palpation could be applied to laparoscopic surgery. It’s commonly used by clinicians (e.g. in breast examinations) to detect and assess lumps, which could potentially be cancerous, by feeling the tissue and its mechanical properties (tumours are typically much stiffer than healthy tissue). However, in laparoscopic surgery the surgeon cannot directly touch the tissue so an alternative approach is needed. The student team surpassed all our expectations, developing a proof-of-concept system that uses a computer model to simulate liver tissue (including a tumour) and then allows you to feel, and virtually palpate the tissue using a ‘haptic’ interface. They worked hard to achieve a lot in a short space of time and it was great to see this recognised when they were runners up in the Global NI student design competition, receiving some attention in the press which they took in their stride! We’ve now submitted the work for publication – certainly a tough act for this year’s students to follow!

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It’s the end of a long week; over the last few days we’ve run a conference on Oncological Engineering which has had some fascinating talks, I’ve started teaching our new intake of first year students and there’s been lots going on in our research projects. It’s a mix that constantly keeps me on my toes and reflects the challenge of working in modern day academia with its often competing demands. I’m not looking for sympathy though, it’s stimulating, rewarding and involves working with a great bunch of people, I wouldn’t have it any other way -already looking forward to next week!

Making science make sense

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This week’s guest blogger is Laura Blackburn who works as a Scientific Communications Officer at the Cancer Research UK Cambridge Research Institute (CRI). After a PhD in Zoology, she dabbled in science writing, first as an intern at Science, then as the News and Views Editor at the Journal of Experimental Biology. She joined the CRI in 2007 where she writes and edits articles on their research in print and online, organises scientific meetings and acts as a coordinator for internal and external communications.

It’s just after lunch on a Wednesday and my brain is tired. A background in Zoology (specifically insect physiology and behaviour) is no match for the intricacies of the regulation of gene transcription. The Institute’s lunchtime talks, from our PhD students and postdocs, stretch my brain and provide a fantastic opportunity to absorb as much information as I can while eating lunch. I’m hoping, in my case at least, that chewing while listening increases my chances of absorbing a lot of what is being said. As a former working scientist I am lucky that I can still indulge my love of learning science, without the hours of necessary lab-time.

The research at the Cambridge Research Institute (CRI), one of the five Institutes core-funded by Cancer Research UK, covers a broad spread from basic science to clinical research. Our 22 research groups focus on basic cell biology such as regulation of gene transcription, epigenetics and senescence, through to computational biology and statistics, cancer stem cells, imaging and experimental therapeutics. One of the CRI’s goals is translational research, also known as ‘bench to bedside’ research that aims to take the discoveries made in the lab through to practical application in the clinic as quickly as possible. You can see Cambridge’s Addenbrooke’s Hospital out of the Institute’s windows, so it’s exciting to think that treatments developed in our laboratories could end up being used in a building less than five minutes walk away.

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Picture of the CRI. Credit: Charles Thomson/Cancer Research UK

My role in all of this is to help make our research accessible to the outside world, from other scientists, through to our supporters, which includes donors, fundraising groups and volunteers. Every November my team begins work on the scientific report, the annual review of the Institute’s achievements. I write some sections of the report and edit the rest, generating a bundle of Word documents that my colleague turns into a coherent printed publication. While this report is an important annual record of our progress, it’s not that user-friendly for non-scientists so we also produce a layman-friendly booklet for our visitors. We’re lucky to have so many dedicated and enthusiastic supporters and it’s important that we make our work accessible to them. We hope that by providing this information, giving them lab tours and talks from scientists, demystifies what we do and makes our research more accessible and less intimidating.

We’re currently working on the third edition of our booklet so I have been refreshing my knowledge on what our researchers do. In order to effectively write and edit articles for non-specialists, it really helps me to get the concepts clear in my mind, hence my seminar-induced brain ache.

One area that I have been learning about this week is DNA quadruplexes, four-stranded stable structures that commonly occur in guanine-rich reaches of DNA and are studied by Shankar Balasubramanian’s research group. The interesting thing about guanine(G)-quadruplexes is that they are common in the promoter region of many genes, including some oncogenes. Therefore one of their implicated roles is in the regulation of gene expression. A proposed novel anti-cancer strategy involves developing therapeutics that stabilise G-quadruplexes in the promoters of oncogenes, repressing transcription and therefore preventing the production of the protein. One of the group’s research goals is to map where G-quadruplexes form in the genome using a variety of chemical probes that stabilise these structures in the cell. The next step is to isolate the genomic DNA attached to these probes and use next-generation sequencing technology to find the location of the G-quadruplexes in the genome. Knowing the location of these G-quadruplex ‘hot spots’ can give researchers a clearer idea of how their formation could be used to develop novel approaches to treating cancer.

Another field that I have been reading up on is molecular diagnostics, studied by Nitzan Rosenfeld’s group. This makes use of the fact that the DNA sequence of the cells in a tumour differ from the sequence in normal cells. The techniques that the group are developing involve studying tumour-specific DNA molecules that are circulating in the blood, meaning that studying them only involves taking a blood sample, rather than a much more invasive tumour biopsy. The blood sample can therefore contain a lot of valuable information about the cancer, such as how it is progressing, whether it might relapse, or how it is responding to therapy. It is not entirely clear how these small sections of DNA end up in a patient’s blood, but it is probably due to tumour cell death. The blood also contains a higher amount of normal DNA than tumour-specific DNA, so picking out and accurately measuring the tumour-specific DNA is not easy. This work is still in its early stages so the lab are also studying how the collection and processing of blood samples affects the amount and quality of circulating tumour DNA that they can find. They are developing methods for analysing the circulating DNA sequences, so that this approach can be adapted for simple use in the clinic. In parallel, they are exploring how blood DNA levels change during the course of patients’ treatment. The major challenge of this project is to design diagnostic tests that are informative and give results that are easy to interpret and could give clinicians the information they need to optimise a patient’s treatment.

With an overhaul of the CRI’s website coming up in the next fortnight, I’m looking forward to getting to grips with the latest advances in everyone’s work and updating the site. The next few years are going to be an exciting time for the CRI and although I can’t claim to be a cancer expert by any stretch of the imagination, I can be sure that most weeks I will learn something new.