MassGenomics

Yesterday was one of those gorgeous spring days in Missouri – warm and windy, with everything coming into bloom.  I drove over to the WashU non-medical campus to hear the annual Viktor Hamburger memorial lecture, given this year by Dr. Sydney Brenner.  The auditorium was filled to the brim, with attendees finally sitting on the steps and standing in the back of the room.  It was unsurprising not only because he’s a Nobel laureate, but also revered among the nematode research community which in St. Louis is quite large.

It turns out that Dr. Brenner, who was born in South Africa, has a charming accent and a bit of a rambling style, which he’s certainly allowed.  He is a clear proponent of what he calls “the scientist at the bench” – the lone researcher or graduate student working late into the night – and not a fan of large-scale genomics.  Dr. Brenner joked that many people say sequencing the genome was like sending a man to the moon, and he agrees, because “it’s easy.  The hard part is bringing him back.”

The Cell as the Correct Level of Abstraction

He went on to address the complexity of understanding biology at its various levels of abstraction – gene, protein, cell, tissue, organism, etc. – and argued that the cell is the “correct level of abstraction” to talk about the genome.  The genome itself presents a problem of complexity – 20,000 genes, each encoding one or more proteins.  If the genes are the templates, then what they encode might be called “instantiations” of genes, and can vary widely.  In fact, Dr. Brenner posited that the human genome may encode as many as 150,000 “instantiations” from 20,000 genes.

Reducing Genome Complexity

So how does one reduce the complexity?  This is a problem, Dr. Brenner said, that has already been solved by nature: by assembling small groups of proteins into sub-machinery complexes (e.g. spliceosome), the complexity is reduced by modularization.  He likened it to two watch-makers, one of whom assembles watches one piece at a time, while the other assembles pieces into subcomponents before putting them all together.  The second watchmaker is the one who will ever finish a watch.

Dr. Brenner filled the hour with little metaphors like these; there were no slides.  He was like a storyteller, and the audience listened with rapt attention.

Systems Biology: What They Should Be Doing

The speaker remarked that many questions asked by scientists are “inverse problems” – using observations (data) to infer mechanisms and function underlying them.  He gave as an example fellow Nobel laureates Watson and Crick, who had sought to use X-ray diffraction data to infer the structure of DNA.  They were all three at Cambridge at the same time, it turns out.  Unfortunately, the output of diffraction experiments provide a value that is the square of what’s being measured – the phasing information is lost, so there was no way to know if it was 1 or -1.  There is not enough computing power in the world to test all of the possible combinations, not even if they started calculating 2,000 years ago.  So instead, Watson and Crick took a more direct approach – they built models, predicted what the diffraction output of each model would be, and then compared it to the actual output.

Artificial Intelligence Combined with Human Stupidity

Omics sciences, Dr. Brenner argued, instead try to measure everything (e.g. sequence the entire genome) and hope that a magical computer program will provide the answers, something he called “Artificial intelligence combined with human stupidity.”  He said that such an approach to science was low input, high throughput, no output – where you put garbage in and get garbage out.  Instead, Dr. Brenner encouraged us to start with high input, which, he said, is what’s in your head.

Yesterday Harold Varmus, Nobel laureate and president of the Memorial Sloan-Kettering Cancer Center, visited WashU and gave a talk on the “New Age of Cancer Research.” The auditorium was packed with just about every key researcher I know on campus. Tim Ley, longtime collaborator and co-director of the Genome Center, made the introduction. Together with Michael J. Bishop, Harold Varmus demonstrated the cellular origins of oncogenes – genes that control cell growth and proliferation that, when mutated, often lead to cancer – for which they won the Nobel Prize in 1989.

Dr. Varmus began with an overview of the three classes of genes involved in oncogenesis:

1. Proto-oncogenes
2. Tumor suppressor genes
3. Genes coverning DNA integrity

The protein products of these genes have diverse biochemical and physiological functions, including enzymes (e.g. tyrosine kinases). The discovery of oncogenes led to some new paradigms of cancer research, like the design of antibodies against oncogenic proteins (e.g. Herceptin), risk assessment by inherited mutation analysis, and occasional gene expression/ mutational profiling for diagnosis/prognosis/Rx.

Improved Mouse Models of Human Cancers

Recent improvements in mouse models of human disease, specifically models in which oncogenes can be switched on or off, were the central experimental focus of the talk. Basically, his group creates transgenic mice that express, or do not express, certain genes based on whether they are fed, or not fed, doxycycline. It offers a powerful model to study short and long-term effects of both oncogenes and cancer drugs.

Tumor Maintenance Genes and “Oncogene Addiction”

One important point Dr. Varmus made is that oncogenes not only initiate the oncogenic state, they maintain it as well. Without continued oncogene expression, cancerous cells die. Mouse models of this oncogene dependence phenomenon have led to the implication of several tumor maintenance genes, including:

• C-MYC in T-cell myeloid leukemia
• H-RAS in melanomas
• BCR-ABL in B cell tumors
• MET in hepatomas
• C-MYC, NEV, and WNT-1 in mammary tumors
• K-RAS in lung adenocarcinomas

It turns out that many cancer drugs work by targeting these genes. The poster child of such designer drugs is Gleevec, which treats chronic myeloid leukemia (CML). CML is the most common form of adult leukemia, and almost always arises from the “Philadelphia Chromosome”, a somatic translocation of chromosomes 9 and 22 that creates a fusion protein, BCR-ABL. Gleevec is remarkably effective at treating human cancers; some patients are disease-free for up to 7 years.

Tyrosine Kinase Inhibitors and Lung Adenocarcinoma

Other tyrosine kinase inhibitors have proven to be potent anti-cancer agents. Dr. Varmus told the well-known story of Iressa and Tarceva (gefitinib and erlotinib), which target mutant epidermal growth factor receptor (EGFR) proteins in lung adenocarinoma. The before-after slides of the lungs of a patient treated with these drugs are quite dramatic – about 4 days into treatment, the tumors are just gone. Before treatment, she was in a wheelchair and on oxygen because of the tumor load. Two weeks later she walks into the doctor’s office on her own feet, no oxygen.

Drug Resistance

Unfortunately, there’s a sad part to the story, as is often the case with cancer. Gleevec might buy you a few years. Gefitinib/Erlotinib work are effective for about one year. After that, the tumors become drug resistant, almost always because of secondary mutations in the tyrosine kinase domain. Sometimes, other drugs can treat the resistant tumors, but not always.

Katerina Politi, a talented postdoc in the Varmus lab, developed a mouse model of drug resistance to gefitinib/erlotinib by constitutively expressing mutant EGFR but intermittently treating mice with the drugs (4 week intervals). In the drugs-on phase, most tumor cells are eliminated, but the few that survive grow in the drugs-off phase. It’s a rapid model of selection for drug-resistant tumors. This mouse model led to several revelations about the secondary mutations underlying drug resistance [see Politi et al 2006]. Almost all are in the tyrosine kinase domain of the targeted protein, but other pathways (such as MET amplification) can lead to drug resistance as well. One particular mutation, T790M, is really bad news – tumors bearing it are refractory to virtually all drug alternatives.

The Future of Oncogenic Research

Dr. Varmus left us with a few points about where cancer research should go from here.

• Genomics (and Epigenomics) – moving beyond the candidate gene approach to get the full repertoire of somatic changes in cancer. Obviously, the WashU GC is working on this.
• Progression and metastasis - there’s more to learn about how tumor cells interact with their micro-environment.
• New targets, new drugs, and better understanding of resistance – always more to learn.
• Relate cancer to development – studying the vulnerability of certain cells to certain cancer types, and working with “cancer stem cells.”
• Extend the mouse models – this guy loves a good mouse model
• Form multidisciplinary teams – bringing together people with different expertise who can all tackle the cancer problem, like the TCGA project. Also, train scientists who work both in the lab and in the clinic to gain a more complete understanding of the disease.

As Tim Ley said, it’s good to see a Nobel laureate not “resting on his laurels.”