Working for David Galas

 

David Galas hired me to direct a genomics group at Darwin Molecular. It was my first job in industry and had a huge influence on my professional path. Darwin Molecular was a wildly ambitious biotech that combined immunology, bioinformatics, combinatorial chemistry, and genomics. We believed that we would upend the way drugs are discovered with a great team, stellar advisors and this combination of (then) emerging technologies. David was the CSO of Darwin and helped found the company. I was recruited from one of the Stanford Genome Centers to serve as Director of Genomics.  

 

Although Darwin was started before the human genome project was finished, part of David’s vision was to use the flood of information human sequencing to discover new drugs in new ways. With David’s support I built a department that combined high-throughput DNA sequencing and mapping with human and model organism genetics. At first we did what everybody else was doing- we studied disease mechanisms by looking for genes that affect the severity, the timing or probability of exhibiting a particular disease. We helped isolate Alzheimer’s genes and a progeria gene, mapped psoriasis susceptibility and studied the inheritance of severe arthritis. David and our Director of Development Diane Isonaka had worldwide connections in the human genomics and genetics fields. Through them we were able to meet multiple potential academic partners and to review hundreds of human genetic mapping projects. Our discussions with Professor Peter Beighton at University of Cape Town in South Africa led to one our most fruitful collaborations.

 

Professor Beighton and his collaborators had collected pedigrees for dozens of human genetic diseases. It was while reviewing the genetic and phenotypic characterization of these pedigrees that Jeff Van Ness and I came across the genetic disease that would ultimately yield a new drug and a new strategy for finding drug targets. David immediately recognized the value of this project and was instrumental in its ultimate success.

 

The genetic disease is called Sclerosteosis. Dr. Beighton and his colleagues had collected pedigrees for this rare disease that affects bone growth. In affected individuals, bone deposition continues as an adult and eventually leads to death by compression of the brain stem by the skull as it continues to grow. These individuals have very strong bones, and Beighton’s genetic analysis showed that the disease is inherited as a recessive trait. David, Jeff and I realized that this meant the loss of function of this gene product leads to bone deposition in adults. Most drugs block the activity of a particular protein or function, so this disease gave us a human genetic model of a drug that would increase bone density in adults. In the past we, like everyone else, had used genetics to study disease mechanisms. We realized that we had discovered a new way to find drugs- if we could find a drug that blocked the protein whose gene is mutated in sclerosteosis, it could be a treatment for osteoporosis. Sclerosteosis may have little or nothing to do with osteoporosis, but this rare disease could teach us how to make a drug that could help millions of people with low bone density.

 

David’s leadership was critical in bringing this project to fruition. Cloning the gene consumed a large fraction of my group’s effort over the next few years - it would have been easy to move the resources to other projects and miss what turned out to be a great opportunity. In the end we showed that the sclerosteosis mutation was in a cysteine-knot protein that we named sclerostin (paper linked at top of page). It is a soluble protein that is produced by one type of bone cell (osteocytes) and down-regulates the bone deposition activity of another type of bone cell (osteoblasts). An antibody to this protein was developed by Amgen and approved by the FDA as a treatment for osteoporosis in 2017.

 

I left Darwin Molecular in 1999 to start a new company called Blue Heron Biotechnology. David was a seed investor and served on the Blue Heron Board of Directors. Our goal was to automate gene synthesis and make this a service that would replace most molecular biology and cloning.  David and I were both involved in the early stages of the Human Genome Project and had watched first-hand as a concerted technology development effort by the NIH and the Department of Energy increased the productivity of DNA sequencing by at least 5,000-fold. Reading DNA sequence is at the heart of modern biology- it is very rare to see a key technology increase in productivity so much in such a short period of time. DNA sequencing is a process for reading information from DNA into computer data, while gene synthesis is the process of writing data back into DNA.  The goal for Blue Heron was to replicate the productivity increases seen in reading DNA for the process of writing DNA. We tried to build a “lights-out” factory that would fully automate the process for any DNA sequence. We only completed part of the integrated automation but we did build a sophisticated, database-driven manufacturing process that is only now being matched in the leading synthetic biology companies.

 

After 10 years I realized that it is challenging to make money selling something that is hard to make, has to be perfect and whose price goes down by half every 18 months. We sold Blue Heron in 2010 to another biotechnology company and I moved on to try something new. I worked with David again while he was at the ISB and we were trying to start a new company based on the drug surrogate model that we used to find the sclerostin gene. This company never got off the ground but we stayed in touch and David played a critical role in helping with my next company.

 

After the debacle at ISB caused by “he who shall remain unnamed”, David moved his group to the Pacific Northwest Diabetes Research Institute (PNDRI). Around the same time I came up with an idea for a glucose-responsive insulin and decided to start a company to develop the idea. Without data the assertion that this mechanism “…should be physically possible…” was unconvincing to venture investors. I talked with David and he suggested that I try the idea out in his lab at PNDRI. It was very speculative but right in line with PNDRI’s mission, so with David’s endorsement they invested in the concept by providing me with bench space and a modest supply budget in return for equity in my new company, now called Glycostasis. It took me two years working in David’s lab to build and test the first working version of the molecule. It sensed the wrong level of glucose and delivered the wrong level insulin but it worked beautifully in vitro and showed that the concept was sound.

 

With this data I raised a small seed round from Karl Handelsman at Codon Capital and went looking for a pharma partner. My goal was a partnership based around an option, where the company would pay Glycostasis to take the drug into the clinic in return for the right to buy it at a predetermined price. I spent a year on the business development part of the project and in the end sold it out-right to Lilly, with a modest upfront and typical “biobucks” milestones. They were interested in the option deal but were convinced that they could take it forward a lot better than I could. This did not turn out to be true, but since Glycostasis was a one-person company the modest upfront was a significant win for my family.

 

The Glycostasis project convinced me that it was feasible to design protein therapeutics that could sense and respond to their environment. Karl Handelsman and I did a seed investment in a new company called Good Therapeutics with the aim of building allosteric regulation into protein therapeutics. I launched the company at a bench in David’s lab, once again relying on David’s help and advice and once again giving PNDRI equity for lab space. We moved out of David’s lab six years ago and have grown to a company of 25 people with cool projects and strong interest from pharma partners, but it all started on that bench with David’s help.  

 

I met David when he hired me to take my first industry job at Darwin Molecular. I learned a lot at Darwin by making a lot of my own mistakes and by watching David’s triumphs and failures managing the company and the science. My goal at every company I have started has been to recreate the scientific atmosphere of Darwin- it was full of smart people working together to do cool things, even if we never figured out how to make it a business. David has played a role, big or small, in everything I have done since then and none of the really cool stuff would have happened without his help.  

 

 

John Mulligan