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DNA Day 2009

April 25, 2009 by Dan Koboldt

Yesterday I participated in the genome center’s DNA Day Ambassadors program, where employees visit area schools to spread the wonders of DNA to students. My school was Our Lady of Lourdes, a catholic school whose 8th grade class I previously visited to talk about my work in genomics.

We brought them a real DNA experiment, some genome center pencils, and hopefully, some excitement about DNA and science in general. Thanks to the Tech D boys Kevin and Devin, I could show off a couple of very cool looking Illumina flowcells and pass them around. My best prop for the visit, however, was a guy named Vince Magrini.

Vince Engages the Class

I somehow managed to recruit the genome center rising star and group leader of our Technology Development to join me on the visit to Lourdes. He was a natural, engaging with the class right away. It also proved fortunate because he’d developed the protocols for the strawberry DNA extraction experiment that we brought for them to do.

Intro to DNA

Before the experiment, the class tolderated my 15 or so slides on DNA, the history of the double helix, and Watson & Crick. Not that they cared, but with some searching I was able to find a can of the original “Photo 51” that Rosalind Franklin took by X-ray diffaction of the crystalline structure of DNA. I also found an early hand-drawn sketch by Francis Crick, his first drawing of the famous double helix structure. We talked about some of the things that are inherited, too, like eye color and hair color. DNA Day has its responsibilities, after all.

Smashing Strawberries

Filtering the Solution

Then Vince took other, and within minutes, the entire room smelled of strawberries. There were around forty kids divided into eight or nine groups, and all of them were eager to participate in the fruit smashing. Vince guided them through cell lysis (soap), precipitation (salt), and then separation (ethanol). There were varying levels of scientific rigor, among the groups, and thus various levels of success. To be perfectly honest, we weren’t as precise as we could have been when adding salt and ethanol to their mixtures. But most of the groups at least precipitated some DNA, and all seemed to have a good time. They all enjoyed putting on the gloves and getting to work – and thanks to the foresight of the outreach department, we had diapers down to absorb most of the mess. Pam Nangle from the genome center came along, and it was she who took all of these great pictures.

We wrapped up with some discussions about genetics while Vince prepared an even more impressive demonstration – a flash gel of their strawberry DNA isolations (as well as some human DNA controls and a ladder) that he ran and put under a blacklight. They came up in groups to see the gel and get a 5-minute lesson from Vince. Then suddenly the hour and fifteen minutes was over, and we were packing up to head home.

Vince's Flash Gel

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Genetic Testing in Cancer

March 4, 2009 by Dan Koboldt

Genome Technology’s Daily Scan picked up a very interesting article from the Boston Globe on personal genetic screening of cancer patients, which is to begin within the year at Massachusetts General Hospital. Their plan is to screen tumors of 5000-6000 cancer patients for 110 mutations in 13 key cancer genes. This is an important step for personalized medicine, and also, something that we should have been doing a long time ago.

Why All Tumors Should Be Genotyped

Despite the reluctance of some clinicians to rely on genetic information for personalized treatment, and the reluctance of most insurance companies to pay for it, the body of evidence supporting personalized genetics-driven cancer treatment is substantial. The Boston Globe article cited one anecdote about a woman diagnosed with lung cancer who wasn’t responding to surgery and chemotherapy. A genetic test revealed that the tumors were positive for EML4-ALK, a transforming fusion gene identified in 2007. Luckily, a pharmaceutical company was testing a drug that targets the fusion protein.

Another anecdote supporting personalized cancer treatment was told at AGBT 2009 by Marco Marra. They’d had an 80 year old male patient with papillary adenocarcinoma, a tumor of unknown origin that was found on his tongue. He underwent surgery, but after 4 months there were lots of lung metastases (he showed a PET-CT). The tumors had EGFR amplifications but didn’t respond to erlotinib, an EGFR inhibitor. Light transcriptome sequencing revealed some clear genomic alterations in the PTEN/RET pathway (PTEN was lost, RET was activated, but not mutated). Long story short, they treated the man with the renal cell carcinoma drug sunitinib, a tyrosine kinase inhibitor that targets RET, and the patient’s response in just a few months was near miraculous.

So Mass Gen is screening 13 genes in every tumor. I’d hoped to learn which genes/mutations were being screened, and the equipment that will be applied, but unfortunately the Boston Globe article was sparse on the details. (Please, post a comment if you have any). I could make some educated guesses: EGFR, KRAS, RET, TP53. Yet 13 genes seems like a rather paltry number, considering the number of new cancer genes being identified by large cancer sequencing projects.

Who Pays for Genetic Testing?

Of course, I admit that genetic testing can be expensive, and the fact that insurance companies are already balking makes this a serious concern. From the article:

"...representatives of the state's three major health plans said they pay
for gene testing only when it has proven medical benefits, meaning
insurers may balk at paying for some of the new testing."

As expensive as some of these cancer drugs are, one would think that insurance companies would be all for testing patients a priori to pick the best one. With the rapid advance of DNA technologies, it won’t be long before genetic testing is a lot cheaper than chemotherapy, and maybe then the insurance companies will come around.

Systematically Correlating Mutations with Drug Response

In the meantime, it looks like we have to go out and prove the medical benefits – that means screening large numbers of patients, and cross-referencing their mutational profiles with how they respond to treatments. I wonder, can we test something like this in vitro – culture cells from various tumors, characterize their mutations in a number of genes, and then throw various cancer drugs at them. Compare the mutations to the drug response, especially for known drug-target pairs, and you could rapidly build a cancer pharmacogenetics database.

High Interest in Fusion Genes / Fusion Proteins

It’s curious to me that the woman with lung cancer had a recently-identified gene fusion, and the drug company (ta-da!) already had a drug in trials that targets it. Fusion genes seem to be a hot topic – especially those that involve protein kinases, like the well-known BRC-ABL fusion in leukemia. It seems like we should be finding lots of these, and if they make good drug targets, so much the better.

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Class Visit to Our Lady of Lourdes

November 20, 2008 by Dan Koboldt

Yesterday I visited Our Lady of Lourdes to talk to Rich Falkler’s 8th grade science class about my work at the WashU genome center. It’s a Catholic school in Clayton, a relatively well-to-do area juxtaposed between St. Louis City and west county. Weeks ago, I asked the teacher about what knowledge base the students would have in genetics, and was impressed to learn that their curriculum included not only Mendel and Punnett squares, but also polygenic traits, sex-linked genes, and genetic engineering. In fact, the first two chapters of their Prentice Hall textbook cover heredity and modern genetics.

The Challenge: Trying Not to Bore 8th Graders

Although I was interested in science as a kid, I don’t remember feeling excited in my middle school science classes. I suppose that’s an age when college is a far-off unknown and there are bigger fish to fry. Certainly the curriculum of my 9th grade biology class was not as comprehensive as what these students had, but then again, that was almost fifteen years ago. I said as much to Patty, the school parent (and relative) who invited me to the class. She reminded me, in half-jest, “you went to public school.” Ouch.

I didn’t expect to wow them, but hoped I’d do enough, at least, to avoid deterring twenty bright young minds from a future career in science. So earlier in the week I consulted with the closest thing we have to kids around here: the Technology Development group. They offered some advice about how to keep kids entertained:

Put statistics in terms that they understand (i.e., translate megabases to Harry Potter books)
Talk about money (i.e., how many new corvettes could you buy for the price of a 454 machine)

My friends in TechD also hooked me up with some cool lab items to pass around: 454 picotiter plates, Solexa flowcells, Agilent DNA-sizing plates, and other items. The kids really enjoyed these and fortunately none were dropped or pocketed while being passed around (perish the thought!). I also brought a flash drive with some high-res images of 3730 sequencers, 454/Solexa machines, sequence traces, etc. The class had a Mac computer with a “smart board” (small projection screen) that made these very useful.

High Marks for Curiosity

The teacher told me in advance that his students were very inquisitive, so I opened the floor for questions. The two adults in the room (Rich and Patty) offered up a few to get things going: what’s the difference in sophistication between what we do and FBI DNA forensics labs (a lot), how does our funding picture look with the new administration (not bad), and what exactly do I do (good question)? The students offered some excellent questions as well. They wanted to know why so many recessive alleles (like O blood type) persist in populations. One had seen a show about a girl with hirsutism (hair all over her body), and asked if the cause was genetic. Another just wanted to hear about the freakiest genetically-mutated organisms I’d seen in my time.

That Reminds Me Of A Story…

So as it turned out, I ended up just telling stories – about fruit flies that couldn’t fly, or the day one of our sequencers caught on fire (a slight dramatization). The best story I told them was about mice on McDonalds – an experiment in which researchers at Case Western fed two strains of mice the equivalent of a Big Mac and large Coke every day. One strain, as you’d expect, got the obesity/diabetes/heart disease package as a result. The other strain? Just fine. No weight gain, no health problems.

“Some people are like that too,” I said. “They can eat whatever they want, all the time, and never gain a pound.”

“Katie!” one of them said loudly, accusing a girl in the front row.

Looking Forward to Next Year

I talked for about 45 minutes, and fielded questions for perhaps half an hour. Earlier this week I’d worried that I wouldn’t be able to fill the time, but thanks to inquisitive students, it was easy to do so. I worried, too, about presenting topics (like evolution) that might not be as welcome in a Catholic school classroom. It was a relief to realize that this was not a problem. In fact, in response to a question I posed about human versus chimpanzee genomes, a student mentioned that “supposedly we are descended from them.” Science and religion did not seem incompatible at all.

I left the class with a couple of posters about the human genome and DNA analysis techniques. Rich Falkler mentioned the possibility of another visit next year. I’m certainly willing, and also told him about DNA day, when our genome center’s Outreach department sends an army of “DNA Ambassadors” to area classrooms. Next year I’ll probably be one of them.

MassGenomics

Medical genomics in the post-genome era