The tough thing about getting people excited and interested in genetics is that most people don’t know what a genome is. I’m dead serious. I come across these non-genome-knowers all of the time. I recently had a conversation with someone I just met: obviously intelligent, well-read and presumably a genome-knower. This person had heard the term “genome” before, but he just couldn’t define it. He had a vague inclination that a genome has something to do with DNA. But he did not specifically know that a genome is a copy of his genetic material and is present in each of his trillions of cells. Wow!

This is why I applaud Baba Brinkman. Brinkman is a ridiculously unique genome-knower and displays the best kind of artistic hybrid vigor: a well-honed intellect combined with a very rare rap-star, rhyming phenotype. He is best known for his hip-hop theatre show “The Rap Guide to Evolution.” Brinkman says that his goal in producing his new off-Broadway show, “Ingenious Nature,” now playing at Soho Playhouse, is to “popularize the findings of science by personalizing and dramatizing them through comedy, music, and character-driven theatre.”

In this show, Brinkman explores the evolutionary psychology of modern dating, by taking the audience through genetic data that is relevant to the subject of dating, but also just relevant period. He starts the show with the beat “I have a gene,” that is set to the inspiring sound of Martin Luther King’s “I have a dream.” It just seems to make sense to start a show about the science of dating with the discovery of the genetic factor that dictates sex: the SRY gene. Raps Brinkman, “Think of all the different kinds of guys, / From gangster to interior designers to firemen / They all have SRYs inside them.”

If you are looking for an evening that merges genetics and entertainment, you have until January 6, 2013 to go see this show. And afterward, talk to Brinkman and tell him what you thought. He invites your peer review.

Rational pharmacological treatment of autism spectrum disorders can only occur when the genes and the molecular pathways disrupted in this disease are well-understood. Today, three papers in Nature by Matthew State and colleagues, Evan Eichler and colleagues and Mark Daly and colleagues report the largest exome sequencing efforts in autism to date, involving nearly 600 trios and 935 further cases with the disease. Altogether, the papers provide strong evidence for three new autism genes (CHD8, KATNAL2 and SCN2A) and support the idea that autism is an extremely heterogeneous disease, meaning that many genes can confer high-risk for the disease. Previously, scientists estimated that the number of high-risk autism genes was ~200. However, the new data suggests that there are likely ~1000 high-risk autism genes, which can and should be identified with further sequencing.  

Last week, the CDC announced new data that shows that autism spectrum disorders currently affect 1 in 88 children in the United States.  While this complex set of debilitating developmental diseases are thought to have a significant genetic component, the genetic causes are mostly unknown. Currently, treatment for the disorder relies on intensive behavioral therapy.

However, there are efforts to develop drugs for autism, particularly syndromic disorders in which the genetic etiology is well-defined. A clinical trial for IGF-1 in 22q13 Deletion Syndrome (Phelan-McDermid Syndrome), which is caused by deficiency at SHANK3 just recently started at Mt. Sinai School of Medicine. (In 2006, this journal published the first report of SHANK3 mutations in autism. This journal subsequently published the first mutations in SHANK2 in autism in 2010.) In addition, Seaside Therapeutics has four different clinical trials for STX209 (arbaclofen) in Fragile X syndrome as well as in children with autism spectrum disorders.

However, the best hope for developing new drugs for autism will be realized when the genetic basis of the disease is better understood. To that end, efforts such as the Autism Sequencing Consortium  and the Simons Simplex Collection are planning to sequence the exomes and/or genomes of thousands of individuals with autism within the next few years.

Last year, this journal published the first autism exome trios, mostly from the Simons Simplex Collection.  In that study, Evan Eichler and colleagues specifically chose to sequence the exomes of 20 families with sporadic autism (i.e. no other familial history), reasoning that these families would be more likely to harbor de novo mutations of large effect. That study identified possibly causative de novo mutations in 4 out of the 20 families in the genes FOXP1, GRIN2B, SCN1A and LAMC3. The study showed that trio-based exome sequencing might be an effective approach for identifying new autism genes.

Today, three papers deliver on that approach and report the largest set of autism exomes published to date.

Matthew State and colleagues sequenced whole exomes of 238 families in the Simons Simplex Collection (SSC). These pedigrees consist of 2 unaffected parents, an affected individual and in 200 families, an unaffected sibling. Within these 200 quartets, the authors identified significantly more non-synonymous de novo mutations in autistic individuals compared to their unaffected siblings (125 vs. 87 respectively). The authors hypothesized that observing de novo mutations in the same gene in multiple, unrelated individuals would be a statistically robust approach to identifying high-risk autism genes. Using simulations and modeling, the authors determined that two or more nonsense and/or splice site de novo mutations would be highly unlikely to occur by chance. Only a single gene in the entire cohort met these criteria; two autistic individuals were found to carry nonsense mutations in SCN2A. The authors then performed an analysis with the sequencing data generated by Evan Eichler and colleagues. In these 414 individuals with autism, the authors found two other genes that met this strict set of criteria (KATNAL2 and CHD8).

Evan Eichler and colleagues sequenced the exomes of 189 trios and 50 unaffected siblings. This study finds that the majority of de novo mutations are of paternal origin (4:1 bias) and that this is positively correlated with paternal age. Altogether, the study validated ~120 severely disruptive de novo mutations, 39% of which occur on a highly interconnected b-catenin/chromatin remodeling protein network. The authors also identified recurrent disruptive mutations in NTNG1 and CHD8. The authors note that this data is consistent with a multi-genic model of autism “where both de novo and extremely rare inherited mutations contribute” to the overall genetic component of the disease in any one affected individual.

Mark Daly and colleagues sequenced the exomes of 175 ASD trios and found that about half of the ASD cases harbored a de novo missense or nonsense variant. Consistent with the other two papers, genetic modeling suggests that most of these de novo events are not related to ASD. The authors note that the de novo events that do confer a high-risk for autism (i.e. those that are nonsense or occur at splice-sites in two or more unrelated individuals) likely occur in several hundred (most of which are, as yet, unidentified) genes and are incompletely penetrant. In combination with data from the two other papers, the authors conclude that the de novo nonsense, splice and frameshift mutations that occur in SCN2A, KATNAL2 and CHD8 are unlikely to occur by chance, and are therefore strong evidence that they are bona fide autism genes. Daly and colleagues further evaluated these three genes in 935 autism exomes and 870 controls. They found 3 additional loss-of-function mutations in CHD8 and KATNAL2 as well as a splice site de novo mutation in SCN2A. The authors conclude that despite the significant challenges to conclusively identifying genes that confer high-risk for autism, analysis of larger datasets and deeper integration with inherited variants should pave the way to a more complete genetic understanding of this debilitating set of neurological diseases.

Finally, the involvement of CHD8, an ATP-dependent chromatin remodeling factor is intriguing. In the current issue of this journal, there are several papers that report mutations in the SWI/SNF complex and ARID1B in Coffin-Siris syndrome and mutations in SMARCA2 in Nicolaides-Baraitser syndrome. These three papers identify germline mutations in chromatin remodeling factors in syndromes that include intellectual disability (some with marked language impairment) and epilepsy. The molecular links between chromatin remodeling and these phenotypes, which overlap features of autism spectrum disorders, remain to be established.

Like most scientists out there, I’ve dreamt about having lab equipment in my kitchen. Wouldn’t it be so efficient to make pancake batter in a 500 mL conical, slap a piece of ParaFilm on top, invert a few times and pour directly into a frying pan? Or better yet, what if I could use a hot plate and a magnetic stirrer every time I made risotto? In her recently released movie, Losing Control, Harvard Biophysics PhD-turned-filmmaker Valerie Weiss brings a story embedded in science to the silver screen, complete with a scene in a home kitchen-turned-lab.

The story revolves around a female Harvard PhD candidate who is on a mission to collect empirical proof that her boyfriend is ‘the one’. Given her background, Weiss infuses the film with scenes that will be familiar to those who work at the bench. Cases in point: the cold room filled with freezer boxes labeled with time tape and filled with eppendorf tubes marked by a Sharpie, the lab meeting where no one understands what the speaker actually works on, social hour in the hallway with food on carts (although beers in dry ice buckets would have added an even more realistic touch) and late nights in the lab that begin with the comment, “Oh no, I forgot to set up my experiment before I left!”

Apparently, this is the first film ever allowed shot on Harvard campus, which grounds the film with a suitably academic backdrop. Although there are other elements of the plot and the characters that are not quite as realistic, if you’re a scientist or a former one, the familiarity of this movie feels good. Weiss says she made this film to draw attention to female scientists, and to realistically convey one on screen as smart, but vulnerable.  While I don’t know how many young women will be drawn to science as a result of this movie, many young scientists would do well to look to Weiss herself as a source of inspiration.

“Peter, we changed its DNA!” —Mira Sorvino as entomologist Dr. Susan Tyler in Mimic

Most practicing scientists cringe when they watch Hollywood versions of science; the above line from Mimic is a memorable example that I find particularly cringe-worthy. Risks of sweeping generalizations aside, I think most bench scientists would agree that science is just not accurately represented in popular culture. How many unrealistic scenes of the molecular forensic lab in CSI does a practicing scientist need to watch to draw this conclusion anyway?

At “Celluloid Science: Humanizing Life in the Lab," an event held at the New York Academy of Science last night, regular science contributor to the New York Times Carl Zimmer led a thoughtful panel discussion on the challenges and efforts of those who tell stories of science through film.

Valerie Weiss, a filmmaker and former biophysicist, kicked off the panel with commentary and clips from her upcoming feature film, Losing Control. The independent comedy produced by her company, PhD Productions, is set for release on Valentine’s Day 2012 and is centered on a female scientist seeking experimental proof that her boyfriend is “the one.” The film is loosely based on Weiss’s experience in graduate school at Harvard University. Having been a female bench scientist for most of my adult life, the trailer seems largely accurate and endlessly amusing. For better or for worse, I can’t say I have (or know anyone who has) personal experience with the ubiquitous laboratory safety shower, but I look forward to watching the scene in its entirety, as I can’t imagine any scene involving unfortunate snafus with laboratory safety showers as not funny.

David Heeger, Professor of Psychology and Neuroscience at NYU, gave a short talk on his research on neurocinematics, which is essentially the science of human reaction to film. Heeger’s experimental approach uses functional MRI (fMRI) to monitor human brain activity while watching film. Heeger presented intriguing results that show that for well-produced films, the resulting brain activity patterns of research subjects are very similar. In contrast, when subjects are shown segments of reality (in this case, clips from a camera set up in Washington Square Park, which some might argue are actually the very opposite of reality), there is a very weak correlation between individuals’ brain activities. The research seems to suggest that film quality might not be subjective, although brain activity does not correlate with film preferences between individuals.

The panel then shifted to a well-known evolutionary biologist from the University of Wisconsin at Madison, Sean Carroll, who is also the Vice President for Education at the Howard Hughes Medical Institute. Carroll spoke on his belief in the power of the story, and HHMI’s mission to reach a broad audience with well-crafted and accurate scientific stories through film. To this end, HHMI has set aside $60 million over 5 years for its in-house film production unit. Carroll screened a short 10 minute film entitled, “The Making of the Fittest: Natural Selection and Adaptation” that is intended for the classroom. The film tells the story of the evolution of light and dark rock pocket mice in the lava flows of the Southwest desert. With wide open landscapes as the backdrop, the film accurately illustrates a specific example of Darwin’s process of natural selection. Carroll summarized the message of the film elegantly, “Mutation is random, but natural selection is not.”

Next-generation sequencing technologies are enabling unbiased searches for new cancer genes at an unprecedented scale. In 2011, a flurry of cancer exome and whole-genome papers have been published in high-impact journals, with more in the pipeline. The first genes to be targeted for personalized treatment will be ones harboring recurrent mutations at a high frequency and those with already known inhibitors/modulators. The delivery of personalized therapies in cancer will no longer be bottlenecked by a lack of targets; the development of effective therapies will require new insights into how cancers become resistant to drugs and hopefully, therapeutic interventions that bypass acquired resistance.

Melanomas are tumors of melanocytes, the pigment-producing cells in skin, and occasionally in the iris of the eye (uveal melanoma). Every year, melanoma is diagnosed in approximately 160,000 new cases and leads to death in 48,000 people worldwide. Exposure to UV radiation is a major risk factor for melanoma, and the incidence of melanoma is rising. Patients with stage IV disease have a poor prognosis, with a median survival of 8-18 months post-diagnosis. Currently, dacarbazine is the only chemotherapeutic drug approved by the FDA for metastatic melanoma and has a median overall survival of 5.6-7.8 months after treatment begins.

Phase III clinical trial results for PLX4032 show remarkable clinical activity in melanomas with BRAF mutations.

In 2002, mutations in the protein kinase BRAF were identified in 66% of malignant melanoma tumors analyzed; subsequent studies estimate that 40-60% of melanomas have mutations in BRAF. Nearly 90% of mutations in BRAF lead to a valine to glutamate change (p.Val600Glu). In order to develop small molecule inhibitors of p.Val600Glu, Gideon Bollag of Plexxikon, Inc. in Berkeley, CA and colleagues screened a library of 20,000 compounds using a structure-guided approach. In 2008, the scientists reported that the compound PLX4720 specifically inhibits BRAF p.Val600Glu with potent anti-melanoma effects in in vitro and in vivo models.

Recently, the long-awaited results of phase III clinical trials of the BRAF kinase inhibitor (PLX4032, an analogue of PLX4720) were published ), showing increased overall survival in patients on PLX4032 compared to the chemotherapeutic agent dacarbazine. In the study, 675 patients with metastatic melanoma carrying the p.Val600Glu mutation were randomly assigned to treatment with PLX4032 or dacarbazine. After six months, overall survival in the PLX4032 group was 84%, but only 64% in the group receiving dacarbazine. Of all patients treated with PLX4032, 48% had a confirmed response, although the authors report that most patients showed tumor shrinkage. Despite the obvious benefit of PLX4032 treatment, the effectiveness of the treatment is short-lived, as many responsive tumors become resistant to treatment within 8-12 months. Determining the mechanisms responsible for acquired resistance to PLX4032 is a top priority for further investigation, and some insights have already been made. Surprisingly, in three recent studies

resistance has not been found to be caused by second-site mutations in BRAF, but activation of alternative compensatory pathways.

The promise of personalized treatment in cancer is another step closer with the identification of mutations in ERBB4 in ~20% of melanoma tumors by Yardena Samuels and colleagues.

In a study published in this journal, Yardena Samuels of the National Human Genome Research Institute and colleagues sequenced 86 members of the protein tyrosine kinase gene family in 29 metastatic melanomas. They identified 19 genes with 30 somatic mutations and sequenced these 19 genes in a larger number of melanomas. The most highly mutated gene in this screen was ERBB4, with mutations in 19% of melanomas. Crystal structure analysis showed that positioning of mutations found in ERBB4 were reminiscent of mutations found in the ERBB family members EGFR and ERBB2 in lung cancer, glioblastoma and gastric cancer.

Lapatinib is a dual receptor tyrosine kinase inhibitor that targets EGFR and HER2; this drug was approved by the FDA in 2010 for treatment of HER2-overexpressing metastatic breast cancer. Functional analysis of a subset of the ERBB4 mutations led Samuels and colleagues to hypothesize that mutant ERBB4 might be inhibited by the pan-ERBB inhibitor lapatinib. The scientists found that this small molecule can reduce melanoma cell proliferation in vitro. Armed with this pre-clinical validation data, a multi-center phase II clinical trial at the National Institutes of Health Clinic Center (Principal Investigator Dr. Udo Rudloff) and Memorial Sloan-Kettering Cancer Center (Principal Investigator Dr. Mark Dickson) is currently underway. The trial is testing lapatinib for stage IV melanomas harboring ERBB4 mutations (Clinical Trials.gov Identifier NCT01264081 and Protocol 10-222, respectively).

In the first exome analysis of melanoma also published in this journal and available free for download, Samuels and colleagues identified 68 genes with somatic mutations. They found that GRIN2A is mutated in 25% (34 mutations in 135 samples) of melanomas analyzed. GRIN2A is a glutamate (NMDA) receptor subunit that also is mutated in neurodevelopmental phenotypes and reported in this journal last year. The germline mutations in neurodevelopmental disorders do not overlap with the somatic mutations in melanoma, but mutations in both diseases lead to early stop codons that presumably are null alleles. In melanoma, the spectrum of mutations in GRIN2A cluster to two regions of the protein. The authors also observed three recurrent alterations in residues that are evolutionarily conserved.

The glutamate signaling pathway is likely to be functionally significant in melanoma, since another highly mutated gene was PLCB4, a phosopholipase isozyme known to signal through metabotropic glutamate receptors. Adding another connection between phospholipase activity and melanocytic-derived tumors, Boris Bastian and colleagues recently reported recurrent somatic mutations in the G-proteins GNA11 and GNAQ in uveal melanoma. Somatic mutations in GNAQ were also found in blue naevi; mutations in GNAQ were limited to codon 209 and lead to overactivation of the MAP kinase pathway. Both GNA11 and GNAQ are G-proteins (alpha subunits) that stimulate phospholipase C-beta.

In another link between melanoma and glutamate signaling, Samuels and colleagues note that GRM3, a metabotropic glutamate receptor activated by glutamate, is mutated in 16% of melanoma tumors (unpublished data). A role for glutamate signaling has been seen in neuronal tumors, with an excess of glutamate associated with more aggressive growth of tumor cells. There are published reports of glutamate inhibitors suppressing tumor growth; further investigation of the possible therapeutic benefit of modulating glutamate signaling in GRIN2A, PLCB4 and GRM3 melanomas seems like a natural next step.

Finally, Samuels and colleagues identified a recurrent mutation in TRRAP in 4% (6/167) of melanomas (p.Ser722Phe). The likelihood of this occurrence is ~ 5 X 10-20, suggesting this mutation is functionally significant. TRRAP is part of a protein complex that has histone acetyltransferase activity and is an essential cofactor for the oncogenic transcription factors c-Myc and E1A/E2F. Functional experiments show that the p.Ser722Phe mutation is transforming and that mutant TRRAP is required for survival of melanoma cells; insights into how mutant TRRAP contributes to carcinogenesis is an important area for future research. The identification of TRRAP mutations adds melanoma to the long list of cancers harboring mutations in proteins with histone modifying activity.

I pose an age-old question: what is it that makes us human? I think it depends who you ask. Ask a cognitive neuroscientist and they may say it’s our theory of mind, which is a fancy way of saying humans have empathy. Ask an evolutionary biologist and they will likely point out all the morphological traits that distinguish us from other primates, such as the large size of our cranial vaults or our opposable thumbs. Ask a psychologist and they may cite our conscience or our ability to use symbolism. But no matter who you ask, most would likely agree that our capacity for sharing resources and the social rules that regulate sharing are specific to human culture.

In a new study published in Nature, https://www.nature.com/nature/journal/vaop/ncurrent/full/nature10278.html

Michael Tomasello and colleagues report a series of experiments in 2-3-year-old children and chimpanzees and conclude that 3-year-old children are more likely to equitably divide resources gained by collaborative activities compared to a non-collaborative situation. They further conclude that collaborative activity does not seem to influence sharing in chimpanzees.

It is known that 3- to 4-year-old children typically divide resources unequally and are more likely to maintain possession of any resources for themselves than share with others. However, as children approach five to seven years of age, they start to share resources more equitably. Tomasello and colleagues hypothesized that children might share a resource more equitably at an earlier age if they had to work collaboratively to attain it, compared to when resources are provided by adults (as resources usually are when children are 3-4 years old).

In this study, pairs of age-matched children were put in a room by themselves (after a demonstration phase) and exposed to a collaboration, no-work, or parallel-work condition. In the collaboration scenario, the children faced a rope attached to an enclosed apparatus. Pulling on the rope together would bring toys in the enclosed apparatus toward them, and the ‘lucky’ child would gain three toys, while the ‘unlucky’ child would gain one toy. In the no-work condition, the children entered the room with the toys already positioned in the end-state. The ‘lucky’ child shared the extra toy with the ‘unlucky’ child more often in the collaboration condition compared to the no-work condition. To control for the possibility that sharing was influenced by the fact that the collaboration condition required work, the authors also ran a parallel-work condition. Here, each child had to pull on their own rope to attain the toys. The authors still observed that the ‘lucky’ child shared toys with the ‘unlucky’ child more often in the collaboration condition compared to either the no-work or parallel-work conditions.

Next, the authors hypothesized that collaboration would not influence resource sharing in chimpanzees. They placed pairs of chimpanzees on opposing sides of an apparatus that required simultaneous pulling of a rope to move grapes to a see-saw that was accessible to both chimpanzees. The ‘lucky’ chimp attained 2 grapes and a chance to take the other grape, while the ‘unlucky’ animal received 1 grape and also had a chance to take the other grape. In the first study, the ‘unlucky’ chimp tipped the see-saw and took the other grape for itself in 63% of trials. The ‘lucky’ chimp never actively tipped the seesaw toward the unlucky animal. Next, the authors tried to encourage the ‘lucky’ chimp to share by disabling the seesaw to the ‘unlucky’ chimp. They noted that the ‘lucky’ chimp tipped the food to itself in 98% of cases, and found no difference in sharing in collaborative vs. control conditions.

This study demonstrates that humans as young as 2- to 3-years-old are able to recognize rewards attained through collaborative efforts and demonstrate a sense of “distributive justice.” Since chimpanzees do not require collaboration for acquisition of resources in the wild, the authors suggest that chimpanzees have not, as a species, developed this sense. This study provides evidence that a sense of “distributive justice” distinguishes humans from other primates and reinforces the notion that collaborative efforts played an important role in human evolution. And so I end with another question. Are humans inherently kind or selfish? I don’t think we know the answer to that question, but this study implies that for humans, evolution has favored the kind.