Science Day

BIO2003: Reporter's Notebook

Washington, DC.—Policy is easy: science is hard. Policy is ugly: science is elegant. The final day of the BIO 2003 convention in Washington, D.C., I decided to listen to presentations on some of the most elegant medical biotech being done today.

The first panel was on the fascinating and rapidly moving area of ribonucleic acid interference (RNAi). The second panel looked at Genomics and Mental Illness—for example, how profiling the expression of hundreds of genes at once can give researchers fresh insights into the causes of mental illness, and point them in the direction of effective new medicines.

Shooting the Messenger

Less than a decade ago, researchers discovered the fascinating phenomenon of RNA interference. First, a brief lesson in molecular biology: The information for making proteins is in genes that are encoded on double strands of DNA in the nucleus of cells. In order to produce protein, the encoded information must get out of the nucleus and into protein-making machines called ribosomes, which exist in the cytoplasm of cells. To make a long story short, DNA is transcribed into single stranded molecules called messenger RNA (mRNA) that carry the recipe for proteins from the nucleus to the ribosomes, which then translate that recipe into proteins.

In many disease processes, say, cancer, genes can become mutated either by making a bad protein recipe, or by producing too much mRNA and thus too much protein. The original idea of gene therapy was that such mutated genes could be replaced with good copies, but it turns out that this is a lot harder to do than it was initially hoped to be. However, if you can't replace the gene-gone-bad, why not shoot the messenger? This is where RNAi comes in.

It turns out that short sequences of double stranded RNA (dsRNA) can silence genes by interfering with the messenger RNA being produced by specific genes. Here is how one of the presenters on the RNAi panel, the Australian company Benitec, describes the process: "RNA interference (RNAi) is a process of selective gene silencing by destruction of messenger RNA (mRNA). It is triggered by double-stranded RNA (dsRNA), where one strand is identical to the target mRNA sequence. It is a natural process, intrinsic to every cell of every multicellular organism."

Panelist Ken Reed from Benitec gave an example of how RNAi might be used to treat cancer. According to Reed, in nearly 52 percent of all cancers, a gene called p53 is being repressed by the YB1 DNA-binding protein. This is critical, because p53's role in cells is to tell them to die if they become cancerous. RNAis can be used to repress YB1, allowing p53 to become effective again in instructing cancer cells to commit suicide.

Panelist Catherine Pachuk described how her company Nucleonics is using RNAi technology to develop ways to treat chronic Hepatitis B infections by silencing the genes the pathogen uses to produce its outer protein coat. Another panelist, Martin Woodle from Intradigm Corp., reported on how his company is using RNAi technology to inhibit the VEGF gene, which tumors use to induce the body to grow blood vessels to supply them with nutrients. And John Rossi, a researcher at the City of Hope Hospital in Los Angeles, hopes to start using RNAi technology in patients next year to target HIV/AIDS.

Your Brain on Genes

The second session I attended looked at how the genomics revolution can be applied to mental illness. Michael Palfreyman, from Psychiatric Genomics, began by pointing out that over the courses of their lives, one in five people in the industrialized countries will experience some form of mental illness. Until now most of the effective psychiatric drugs were discovered essentially by accident. For example, MOAI inhibitors for treating depression were discovered when a clinician noted that patients taking them for tuberculosis became more cheerful.

Genomics—the ability to read the actions of multiple genes in specific tissues—provides researchers with novel ways to identify disease pathways in cells and tissues. This will help them identify specific genetic and environmental risk factors for various diseases.

Palfreyman's colleague Richard Chipkin illustrated ways that genomics can be used to identify new drug targets for diseases. He showed how researchers can use biochip arrays that identify when various genes are turned off and on in brain tissue when treated by various psychiatric medicines. For example, Chipkin looked at gene changes in neurons exposed to three mood-stabilizing medicines now in use: valproate, carbamazepine, and lithium.

Valproate affected 275 genes, carbamazepine 237, and lithium 150. However, only 10 genes were affected by all three compounds, suggesting that they play a big role in the biochemical processes that cause depression and bipolar disorder. Chipkin thinks that developing drugs aimed at affecting those 10 genes have the potential to be more effective than existing anti-depressants, and with fewer side effects.

Chipkin also explained that biochips, after reading the actions of multiple genes, have shown how electro-convulsive shock (ECS) therapy works to correct severe depression in 80 percent of patients. Among other things ECS fuels the production of the crucial molecule called brain derived neurotrophic factor, which in turn stimulates neuronal growth.

Karoly Nikolich, from AGY Therapeutics, noted that mental illnesses are very complex diseases. After all, the brain has 100 million nerve cells, and more than a quadrillion synapses that connect those cells. Nikolich estimated that between 100,00 and 200,000 different proteins are relevant to the function of the central nervous system (CNS). Three hundred and seventy different diseases have been identified as affecting the CNS. He estimated that there are several thousand possible drug targets among those proteins. To date, however, current CNS drugs target only some 60 brain proteins.

Nikolich uses genomics to build pathway models of how brain diseases begin and progress over time. One pathway he's investigating is the NMDA receptor in brain cells, the optimal functioning of which is necessary for learning, memory, and plasticity of synaptic function. AGY Therpeutics has identified possible drugs that could enhance the plasticity of hippocampal neurons, thus improving the memories and learning abilities of patients.

The final speaker was Mark Brann of Acadia Pharmaceuticals, a company that is using what it calls a chemical-genomics approach to new drug discovery. Essentially, Brann claims that Acadia can use genomics, combined with a drug library, to simultaneously identify possible targets and drugs for those targets.

Using this technique Acadia found a new compound that affects a specific brain receptor, which is now in phase I clinical trials as a treatment to overcome the jerky movements (dyskinesia) that often accompany long-term use of today's drugs for Parkinson's disease. The same receptor also seems to be involved with anxiety and psychosis, so perhaps the new drug will be useful as treatment for those conditions.

Well, that was the end of BIO 2003 for another year. I came away from it with a renewed sense of just how fast biomedical science is progressing. Sure, biology is a lot more complicated than many people thought it might be a generation ago, but both the number and efficacy of our scientific tools and our scientific knowledge base are growing exponentially. There will probably be no silver bullet for curing the many ills that beset us, but who needs a silver bullet when science is providing researchers with the moral equivalent of a battery of 50-caliber machine guns?