Kinase Inhibitors as Therapeutics: A Review

The review “Kinase Inhibitors: the road ahead” was recently published in Nature Reviews Drug Discovery. In it, authors Fleur Ferguson and Nathanael Gray provide an up-to-date look at the “biological processes and disease areas that kinase-targeting small molecules are being developed against”. They note the related challenges and the strategies and technologies being used to efficiently generate highly-optimized kinase inhibitors.

This review describes the state of the art for kinase inhibitor therapeutics. To understand why kinase inhibitors are so important in the development of cancer (and other) therapeutics research, let’s start with the role of kinases in cellular physiology.

The road ahead for kinase inhibitor studies.

Why Kinases? Continue reading

The Age of the Genome: Commercial DNA Sequencing, Familial Searching and What We Are Learning

Crowd of people at the street, city center

All of these people are 99% the same at the genomic level. The individuals of the human species are far more alike than different.

There are 3 billion (3,000,000,000) bases in my genome—in each of the cells of my body. Likewise, Johanna, the writer who sits next to me at work also has 3 billion bases in her genome. Furthermore, our genomes are 99% the same. Still, that’s a lot of places where my genome can differ from hers, certainly enough to distinguish her DNA from mine if we were both suspected of stealing cookies from the cookie jar. The power of discrimination is what makes genetic identity using DNA markers such a powerful crime solving tool.

The completion of the human genome project in 2003 ushered in a tremendously fast-paced era of genomics research and technology. Just like computers shrank from expensive, building-filling mainframes to powerful hand-held devices we now call mobile phones, genome sequencing has progressed from floor-to-ceiling capillary electrophoresis units filling an entire building to bench top sequencers sitting in a corner of a lab. The $99 genome is a reality, and it’s in the hands of every consumer willing to spit into a tube.

Commercial DNA sequencing services are promising everything from revealing your true ancestry to determining your likelihood to develop dementia or various cancers. Is this progress and promise or is it something more sinister?

As it turns out, that isn’t an easy question to answer. What is probably true is that whole genome sequencing technologies are being put into the hands of the consumer faster than society understands the ethical implications of making all of this genomic information so readily available. Continue reading

Beer Is Complicated: Proteome Analysis via Mass Spectrometry

still life with a keg of beer and draft beer by the glass.The art of brewing alcoholic beverages has existed for thousands of years. The process of beer brewing begins with barley grains, which are malted to allow partial germination, triggering expression of key enzymes. The germinated grains are then dried and milled. Next, starch, proteins, and other molecules are solubilized during mashing. During mashing, solubilized enzymes degrade starch to fermentable sugars, and digest proteins to produce peptides and free amino acids. Fermentable sugars and free amino acids are required for efficient yeast growth during fermentation.

After the mash, the wort is removed, and hops are added for bitterness and aroma, and the wort is boiled. After boiling, the wort is inoculated with yeast, and fermentation proceeds to produce bright beer. Typically this bright beer is then filtered, carbonated, packaged, and sold. Many proteins originating from the barley grain and the yeast are present in beer, and these have been reported to affect the quality of the final product. However, some of the biochemical details of this process remain unclear. To better understand what happens during the various steps of the brewing process,  Schultz et al. used mass spectrometry proteomics to perform a global untargeted analysis of the proteins present across time during beer production and described this work in a recent paper (1). Samples analyzed included sweet wort produced by a high temperature infusion mash, hopped wort, and bright beer. Continue reading

Genomic Breakthroughs One Letter at a Time

In honor of Human Genome Month, I delved into our Cartoon Lab archives to retrieve this example of the excitement that occurred while sequencing the Human Genome Project.

For more entertaining science cartoons, visit our Cartoon Lab.

The Pan-Cancer Atlas: “The End of the Beginning”

Yesterday, a series of 27 papers representing the most comprehensive genomic analysis of human cancers to date was published in Cell Press journals.

The collection constitutes the final outputs from the Cancer Genome Atlas (TCGA) project, a collaboration between the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) involving analysis of over 11,000 tumors representing 33 different cancers. The many research teams involved analyzed tumor DNA, mRNA, miRNA and chromatin, comparing them to matched normal cellular genomes to perform a complete molecular characterization of cancer-specific changes. The results have been presented with much hope that open access to this type of comprehensive analysis will build on recent advances in understanding tumor biology and spur further progress in developing new approaches to treatment. (See this news item for more detail).

The Pan-Cancer Atlas results are collected on a cell.com portal, where they are presented in three collections grouped by topic: Cell of Origin, Oncogenic Processes and Signaling Pathways. Each collection is accompanied by a “Flagship” paper introducing the topic and summarizing the findings. It seems fitting that these findings have been published in #HumanGenomeMonth. This comprehensive analysis of the genomic and metagenomic profiles of tumors illustrates one powerful application of the type of genomic analysis pioneered by the original Human Genome Project, and shows just how much has been made possible since the initial publication of the human genome fifteen years ago. Continue reading

Back for More: Thoughts from 3 Regular Attendees on the International Forum on Consciousness

The International Forum on Consciousness offers a lively two days of information sharing and discussion regarding important—and often challenging—topics. Over the years, we have been guided through a range of topics, including creativity, near death, entheogens, intelligence in nature, business evolution and the effects of sensory inputs.  This year, we’re tackling Means and Metrics for Detecting and Measuring Consciousness.  You can find out more here: https://www.btci.org/events-symposia-2018/international-forum-on-consciousness/ .

As we work on the final details for this year and registrations flow in, I took a moment to pause and reflect on the fact that several of the registrants have joined us for many, if not all, of our past events. It’s gratifying to see that they are taking time out of their normal routines to make their way to the Promega campus again this spring.  So, I asked a few of them to share their thoughts for this post and this is what they had to say: Continue reading

Letter from Uganda: A Promega International Internship Scholarship Recipient Shares her Experiences

Sydney Roberts, left, at work at a rural community outreach health clinic outside of Kabale, Uganda where she helped conduct basic health screenings. Here she is measuring a woman’s MUAC (midupper arm circumference).

Sydney Roberts, left, at work at a rural community outreach health clinic outside of Kabale, Uganda where she helped conduct basic health screenings. Here she is measuring a woman’s MUAC (midupper arm circumference).

We were inspired by a letter we recently received from one of the recipients of the Promega International Scientific Internship Scholarship. The scholarship supports undergraduate students at the University of Wisconsin – Madison. who are undertaking an international internship aimed at using science to improve the quality of life in the world. Students from all scientific fields are eligible but preference is given to those whose internships use molecular biology techniques. Students must be based in a country other than their own for at least six weeks and cannot be in a country where the recipient has already spent significant time.

Sydney Roberts, a junior at UW Madison majoring in Community and Nonprofit Leadership with a certificate in Global Health, was awarded the Spring 2018 Promega scholarship. As a result, she’s spending her spring a long way from her hometown of Cedarburg, WI. Sydney is currently working in Kabale, Uganda, a town in the southwestern part of the country near the border of Rwanda, as an intern with the Kigezi Healthcare Foundation (KIHEFO).

KIHEFO operates a primary care clinic, HIV/AIDS clinic, Nutrition and Rehabilitation center, and works with rural community groups. Sydney is supporting local staff members as they treat clients, provide counseling sessions for families affected by disease, and work on global health initiatives that support prevention of these diseases and health complications. She has only been in Uganda for a few weeks, but she says her experiences have already been life-changing. Continue reading

How to Reduce Cell Culture Variability

Scenario 1: Jake needs a flask of MCF-7 cells for an assay, so he sends an email to the graduate student listserv asking for cells. Melissa replies that she has an extra flask of cells that she could share. Jake happily accepts the cells and begins his experiment.

Scenario 2: Michael passaged his cells yesterday and, according to the protocol, was supposed to plate cells today for treatment. However, his previous experiments were delayed, so he decides to plate them tomorrow instead. The cells look healthy, so it should be ok.

What is wrong with the above scenarios? These actions may seem harmless, but they could be the cause of variability, leading to irreproducible results. Continue reading

The Intersection of Poetry and Science

March 21, 2018 is World Poetry Day, we’re getting into the spirit with some scientific poetry. Science and poetry overlap more than many diehards in either camp would like to admit. History is filled with poets who dabbled in science, as well as scientists who dabbled in poetry. In honor of World Poetry Day, I’ve pulled out some of my favorites. Continue reading

Counting Crows: Evidence for Hard-Wired, Inborn Ability to Detect Numerical Sets

“The Great Book of Nature is written in mathematical language” –Galileo Galilei (1)

carrion crow (corvus corone) headshot portrait against a blue background

Carrion Crow (Corvus corone)

If mathematics is the language of the universe, might we find the ability to do math hard-wired in species?

Research in primates has demonstrated that even without training, humans and monkeys possess numerosity, the ability to assess the number of items in a set (2,3).

A paper in Current Biology from Wagener and colleagues provides evidence that crows are born with a subset of neurons that are “hard wired” to perceive the number of items in a set (4). This work provides yet more evidence supporting a hypothesis of an innate “number sense” that is provided by a specific group of “preprogrammed” neurons.

In this study, Wagener’s group measured the responses of single neurons in two “numerically naïve” crows to color dot arrays. They measured neurons in the endbrain region known as the niopallium caudolaterale (NCL), which is thought to be the avian analog of the primate prefrontal cortex. They found that 12% of the neurons in NCL specifically responded to numbers and that specific neurons responded to specific numbers of items with greater or lesser activity.

This is the first such study to investigate the idea of an innate “sense of number” in untrained vertebrates that are not primates, and as such it suggests that a hard-wired, innate “sense of number” is not a special feature of the complex cerebral cortex of the primate brain but is an adaptive property that evolved independently in the differently structured and evolved end brains of birds.

Many questions remain. Are there similarities in the actual neurons involved? What does learning do on a physiological level to these neurons: Increase their number, increase connections to them?  What other vertebrates have similar innate mechanisms for assessing numbers of items? What about other members of the animal kingdom that need to have a sense of number for social or foraging behavior? How is it accomplished?

And finally, one last burning question, if birds are dinosaurs, does that mean that dinosaurs perished because they didn’t do their math homework? Asking for an eleven-year-old I know.

  1. Tyson, Peter. (2001) Describing Nature with math. NOVA  http://www.pbs.org/wgbh/nova/physics/describing-nature-math.html 
  2. Izard, V. et al. (2009) Newborn infants perceive abstract numbers PNAS USA 106, 10382–85.
  3. Viswanahtan, P. and Neider, A. (2013) Neuronal correlates of a visual “sense of number” in primate parietal and prefrontal cortices. PNAS USA 110, 1118–95.
  4. Wagnener, L. et al. (2018) Neurons in the endbrain of numerically naïve crows spontaneously encode visual numerosity Cur. Biol. 28, 1–5.