Wednesday, August 10, 2016

Secret Science Club Post Lecture Recap: Return of a Nobel Winner

Last night, I headed down to the beautiful Bell House, in the Gowanus section of Brooklyn, for this month's Secret Science Club lecture. This month's lecture featured the triumphant return of physiology/medicine Nobel Prize winner and former director of the National Institutes of Health and the National Cancer Institute Dr Harold Varmus, currently with the Meyer Cancer Center at Weill Cornell Medical College, who delivered a lecture on the first anniversary of the Secret Science Club. For the record, this month marks the tenth anniversary of the Secret Science Club. This lecture was one in the continuing collaboration between the Secret Science Club and the Albert and Mary Lasker Foundation

Dr Varmus began his lecture by contrasting the current venue with the original venue of the Secret Science Club, the basement performance space of Park Slope's Union Hall, joking that the Secret Science Club really felt like a secret, something almost revolutionary given the contemporaneous occupant of the White House. He stressed the importance of keeping science in the public domain.

Dr Varmus then presented the basic facts about cancer. Cancer is not one disease, many cell types can give rise to unrestricted cell growth which invades other cells. There are many types of cancer- one wouldn't lump all infectious diseases together, so one shouldn't lump all cancers together. Cancers are illnesses of the genome. Some of the genetic risk factors are relatively minor, but other risk factors are closely related to the illness. Genetic changes occur in an individual's lifetime- DNA can be damaged by such factors as smoking or exposure to ultraviolet light. Small or large, changes to DNA can have dramatic results. Cancers are best described as 'too many cells doing bad things in the wrong places'. Different cancers can effect cells differently- some reduce cell function, while some increase function... all to the detriment of the organism.

Cancers become more frequent with age. The approach to fighting cancers must be multi-pronged. Researchers must observe and count cancers in populations. Screening must be performed- cancers must be diagnosed with specificity early on, and classified. Patients must me treated and comforted. Prevention must be attempted to reduce the incidence of cancer. Cancer must be studied in its various forms.

Dr Varmus displayed several graphs comparing the age-adjusted death rates for cancer and heart disease for individuals under the age of 85. He noted that the death rate for cancers peaked in the 1990s. He noted that the cancer death rates are decreasing, but not as dramatically as the death rate for heart disease. Different cancers have different mortality rates. Lung cancer mortality rates tend to be high, but are precipitously declining. Stomach and colorectal cancers are declining. Among women, there is a rapid decline of uterine cancers due to Pap smears, and the HPV vaccine could improve things further.

The traditional treatment for cancer involves surgery, chemotherapy, and radiotherapy. These therapies are extremely difficult for patients. An improvement in treatment would involve targeted therapies directed toward the genetic anomalies which produce the proteins which cause cancers. Two promising new therapeutic innovations are hormone therapy and immunotherapy. Of course, cancer prevention is preferable to treatment- tobacco use, viruses, obesity, and ultraviolet light exposure are all contributors to increased cancer risk. Vaccines against viruses such as HPV and hepatitis-B would reduce cancer risk. Screenings to recognize genetic predispositions to cancer are also promising.

Dr Varmus then proceeded to frame the discussion of the fight against cancer in historic terms, starting with Richard Nixon's signing of the National Cancer Act of 1971. This act was aspirational without a plan- we did not know how a normal cell becomes a cancer cell. There was a confidence, though, that money plus talent equals results. In the subsequent decades, new concepts, new methods, and new strategies emerged- genome research, DNA crystallography, computational methods. This fight culminated in President Obama's 2016 Precision Medicine Initiative. A base of information about diseases' genetic or molecular factors needs to be compiled. Taxonomy leads to better diagnoses, which lead to better treatments, which lead to better outcomes. Vice President Biden was tapped to lead the "moonshot" against cancer- a successful response to this challenge would be more effective, more efficient, and involve more collaboration.

Dr Varmus veered off to a short autobiography- his childhood was spent on Long Island. He studied literature in college though he did plan to attend medical school. After what he described as a 'prolonged adolescence', he became a scientist at the age of twenty-eight. He described the historical facts which influenced his life- hearing Eisenhower's push for scientific excellence, attending medical school while the Vietnam War raged, Nixon's signing of the National Cancer Act in 1971. He described his early days at the NIH as being a member of the 'yellow berets'. He displayed a picture of his 1968 cohort at the NIH and noted the gender imbalance of the organization. While at NIH, he started to study genetic expression in E. coli. He joked, "Few pleasures in life exceed a potent assay." In his case, he was measuring accurately how much RNA was made by a particular gene in E. coli. He noted that to answer complex problems, it was best to use simple models. Clear answers lead to more questions, both mundane and profound. He also noted that the 'gossip factor' was important to scientists- tell results to peers, even competitors, for the advancement of knowledge.

In cancer research, one must apply molecular models to complex organisms in order to determine when a normal cell becomes a violent miscreant which can kill the individual to which it belongs. The few genes in a virus which causes tumors in animals can change the behavior of an animal's cells permanently. How do these genes replicate? How do they cause cancers? How does one tiny retrovirus become thousands of particles? To answer these questions, Dr Varmus recounted the history of Peyton Rous and his researches into chicken tumors. Peyton Rouse, of the Rockefeller Institute (now Rockefeller University) described a transmissible chicken sarcoma in 1910. The sarcoma was caused by a virus which could change the behavior of cells in a petri dish- these 'rounded' cells looked different from the background cells in the dish.

Dr Warmus followed up on this area of inquiry with his collaborator and co-Nobel prize winner J. Michael Bishop. Displaying a sequence of photos of the pair, Dr Warmus joked, "The pictures show the changes in our own morphology over time." Dr Warmus and Dr Bishop's best known discovery was proto-oncogenes. In one instance, the tumor causing retroviral gene v-SRC is similar to, and derived from a cellular gene c-SRC. Genes code for enzymes, and genes with mutations cause cellular changes. Using a molecular probe, a nuclear-coded set of amino acids, it was determined that normal chickens have a set of genes which resemble viral genomes, a code for proteins similar to genes present in all metazoans, which suggests an important function. The discovery of c-SRC was important for being 'ahead of its time', there was no genetic sequencing at the time. The discovery also reversed existing thought- the normal gene was similar to the cancer gene. There were also evolutionary implications- evolution occurs through the same sort of changes which can result in cancers. Extensibility also comes into play, there are parallel cases of viral genes which are derived from cellular genes. Another factor is the functionality of the proto-oncogene, which encodes a novel enzyme, a tyrosine-protein kinase (the role of kinases in cancers was the subject of the June 2014 lecture by Dr Charles Sawywers). Understanding the role of proto-oncogenes in tumor foundation provides targets for therapies. In a particularly elegant symmetry, the discovery of the viral genes was the guide to the proto-oncogenes, and the viral genes are derived from cellular genes. The pattern of research into tumors typically goes as follows: human tumor cells are isolated, DNA from the tumor cells is purified and inserted into mouse cells, and the transformed cells become the focus of further experimentation.

Dr Warmus then brought up the topic of Chronic Myeloid Leukemia. CML typically has an early phase of five years, then a patient will undergo a blast crisis in the sixth year. CML patients typically have a 22/9 chimera, a transposition of genetic material between chromosome 9 and chromosome 22. This proto-oncogene was originally found in mouse tumors- a drug marketed as Gleevec blocks the oncogenic enzyme and kills the cancer cells, resulting in complete remission.

The situation is not always so simple- new studies reveal the complexity of cancer- for every type of cancer, there are ranges of mutational activity. In the case of lung cancers, which kill more than one million individuals annually, there are complex patterns of mutated genes, and heterogenous situations underlying the cancers. In a sizable percentage of lung cancers, it is hard to pin down genetic component, another sizable percentage can be attributed to mutations of the KRAS gene, and the remainder of cases can be attributed to various other driver genes. Even with these various underlying mutations, many drugs can be developed to cope with these cancers. The problem is that the lifespans of drugs are short, while cancers are not static- cancers evolve. In the case of renal cancer, heterogenous tumors can stymie targeted therapies and cancer 'phylogenies' are reminiscent of the evolutionary lineages of species. The evolution of various tumor subclones provides drug resistance to tumors, and increases the probability of metastasis.

Successful treatments must confront cancer's complexity- malignant cell behaviors should be targeted, not just a list of damaged genes and altered proteins. One promising avenue for treatment is harnessing the immune system to rein in or destroy cancer cells. For immunotherapy to 'come of age', targeted antibodies are necessary. Monoclonal antibodies can be developed to target specific antigens on tumor cells. The body's own T-cells can be engineered to target antigens on tumor cells with proteins known as chimeric antigen receptors.

Cancer prevention is of the utmost importance, involving risk assessment and early diagnosis, with liquid biopsies being a promising non-invasive early screening technique.

Dr Warmus ended his lecture with the observation that, in confronting cancer, one must grasp its complexity and seek simple solutions.

The lecture was followed by a Q&A session. The first question involved the origin of sarcomas- sarcomas arise from the mesenchyme, tissues such as fat and bone. Dr Warmus advised us not to mistake the causes of cancer with the mechanisms of cancer- cellular 'damage' may result from inherited genes or from the very process of mitosis. A lot of mutations arise through the process of cell division- the error prone nature of cell division is responsible for evolution as well as cancer. Some bastard in the audience, who had attended Dr Warmus' 2007 lecture, asked him about the changes that had occurred in the interim between the two lectures- which of them were the most significant? Dr Warmus noted that DNA sequencing had become much faster and cheaper in the intervening years. While the number of successes in cancer research have not profoundly changed the 'cancer landscape', a proliferation of small-scale successes has led to optimism about the long-haul. Immunotherapy, a new field, is very promising. Another questioner asked about liquid biopsies- mutations in newly formed tumors can be analyzed using blood samples. Regarding policies to improve cancer treatment, gene therapy reimbursement rates should be improved- genetic tests are not that expensive, and the costs pale in comparison to hospital stays and imaging. The cost of drugs is more difficult to control- different drugs have different success rates, should patients only pay for effective drugs? There is also a detrimental cost of not treating viral infections- novel solutions are required. Another individual asked if stress was a risk factor for cancer. Dr Warmus indicated that it was possible, but not on the level of tobacco use... he then quipped that cell division itself promotes cancer. Dr Warmus then brought up the Cancer Genome Atlas, a collaborative effort by scientists sharing data on the genetics of various cancers. The final question of the night involved antibody checkpoint inhibitors, specifically inhibitors of the PD-L1 protein. Dr Warmus cautioned that these therapies pose dangers- unchecked T-cells could attack normal cells, so this sort of therapy is not to be taken lightly. It's not a long-term therapy but the risk might be worth it on a short-term basis. The danger of using antibody checkpoint inhibitors is that the therapy perturbs a fundamental feature of the immune system.

Once again, the Secret Science Club, in conjunction with the Lasker Foundation and the Bell House staff, served up a fantastic lecture. Kudos to Dr Warmus, Margaret and Dorian, the staff of the beautiful Bell House, and the good people of the Lasker Foundation. Dr Warmus was around for the first anniversary of the SSC, so he was the perfect lecturer for the tenth anniversary.

Here's a video of Dr Warmus delivering a lecture to an audience at Paris' Institut Curie:

Pour yourself a libation, sit back, and soak in that ambience of the Secret Science Club. It's been ten years, ten great years of Learning While Intoxicated. Thanks again to Dorian and Margaret... happy tenth anniversary!


ifthethunderdontgetya™³²®© said...

Good jerb of attending these and posting about them yourself, B^4.

Big Bad Bald Bastard said...

Thank you, sir. My one blogging regret is that I didn't start in 2006 and recap all of the lectures.