Craig Venter Part II: Critical Tools and Technologies in Synthetic Genomics

Dr. Venter Invokes Technologies That Will Cause Biology to Undergo a Sea Change into Something Rich and Strange

J. Craig Venter, Ph.D., is founder, chairman, and CEO of the J. Craig Venter Institute (JCVI); co-founder, executive chairman, and co-chief scientist of Synthetic Genomics (SGI); and co-founder, executive chairman, and CEO of Human Longevity (HLI).

In Part I of GEN’s interview with Dr. Venter, which appeared in our March 1, 2016 issue, he spoke about future research pathways for synthetic genomics.

Now, in Part II, Dr. Venter will discuss the types of tools, technologies, and instrumentation systems needed to accelerate synthetic genomics research.

J. Craig Venter

GEN: Is it fair to say that even some of the basic tools needed to accelerate and advance the technology are still being developed and discovered?

Dr. Venter: I would say that is a great description of where the field is. We have the ability now to design new cells and modify cells to create new functions, and, hopefully, to modify major genomes (as with the organ transplantation program). Now it’s up to people’s imaginations as to what will be the ultimate applications of this technology.

With the availability of CRISPRs, because they are so easy to use, I think the field will take off a lot faster than doing it totally with synthetic DNA. JCVI and SGI have basically had no competition in the area of trying to create new cells, because that takes a lot of resources and tool sets that are not generally available. One of SGI’s goals is to make those more broadly available to be used in new types of applications.

The crossover with humans becomes the organ transplantation work, and also eventually doing editing of human stem cells and, potentially in the more distant future, of embryonic cells to get rid of lethal diseases or traits.

At HLI, which is also a spin-out of JCVI, we are now scaling up genome analysis to a new level. We are currently sequencing about 3,000 whole genomes a month, with the goal of increasing to more than 10,000 a month. The company has only been in existence 19 months, but we now have more than 20,000 full genomes in our database, all with phenotype or clinical data linked to them. This gives us a very different view of the human genome and a whole new ability to interpret that information.

We are working with the insurance industry, the pharmaceutical industry, children’s hospitals, and cancer centers to apply these tools broadly.

The biggest advance has been the new sequencing tools. It cost $100 million to sequence the first genome, my genome, about 15 years ago, and now the total cost is about $1,500 to sequence a human genome. Each of the Illumina HiSeq X10 machines we are using is equivalent to 1,350 of the machines we used to sequence the first genome at Celera Genomics. At Celera, we had 350 machines, and it took 9 months to complete one genome. It makes you appreciate the change in scale we have today.

J.Craig Venter Institute

GEN: Looking ahead, what would you identify as one or a few of the most significant hurdles that still represent major roadblocks to being able to apply efficiently and effectively the large amounts of genomic information being gathered?

Dr. Venter: I think there are a few. The biggest single one is that our medical education system doesn’t really teach much about genomics, or the fact that it might be the biggest basic tool set people will be using to aid their patients in the future.

We currently have a couple of different approaches to this. HLI has a cancer program in which we sequence the whole genome of the patient, the whole genome of the tumor to 90× coverage, the RNA of the tumor, and the entire T-cell repertoire, both from the blood and from the tumor, to understand the extent to which there’s been an immune response against the tumor. We also sequence circulating DNA in the bloodstream, and we’re working with another group to isolate and sequence circulating tumor cells in the bloodstream.

This gives an incredibly comprehensive view of cancer in that individual. We know precisely how many mutations have occurred and how many have occurred in protein-coding regions, and we’re using these protein changes to develop patient-specific RNA-based vaccines.

The goal is to be able to go in three weeks time from receiving a tumor and blood sample to having all of this information and being able to understand whether the patient would be a good candidate for immunotherapy, whether certain drugs would be better options. For patients in need of immune enhancement, the information could indicate the possibilities for developing a patient-specific, tumor-specific vaccine. We are working directly with oncologists, and they are seeing the value of this information and technology.

Within HLI’s Health Nucleus, which is our in-house health center, we’re sequencing people’s genomes and doing extensive phenotyping, analyzing their microbiomes and metabolomes, and doing hundreds of other laboratory tests. The comprehensive evaluation involves imaging studies, including brain scans for quantitative brain measurements that can track changes over time and detect changes associated with dementia even before symptoms develop.

Evaluations can also incorporate quantitative whole-body MRI scans, 4D echocardiograms, neurological examinations that include gate analysis, DEXA scans to assess bone density, measurements of muscle density, and other types of tests. All of these data are compiled into a comprehensive phenotype that is linked to a patient’s genotype in our database.

The third component of what is needed to be able to apply all of this information, together with computational activity and sequencing, is what we’re doing with machine learning. I recruited Franz Och, Ph.D., from Google; it was his team that developed Google Translate. I convinced him that translating the human genome would be the ultimate translation challenge, and we are already making amazing discoveries from the genome.

For example, we did a clinical trial with 1,000 volunteers in which we took 3D photographs of their faces and measured about 30,000 data points. We also sequenced their genomes and took phenotypic measurements and then tested the ability to predict their faces on the basis of their genetic code. We have made phenomenal progress with this and will be publishing some of our results soon. Just from a voice recording, for example, we can tell a person’s sex, age, and how tall they are.

In January, we started a program in South Africa and England working with the insurance company Discovery Health, which plans to offer whole exome and cancer sequencing to its 4.4 million clients. We’re also having discussions broadly in the United State along these same lines. This whole field is building up very rapidly, all built on the early discoveries made 10–15 years ago.

GEN: It’s as though the accumulation of information drives and supports the growth of the field, while continued growth and advances enable more efficient and effective use of the information. Would you agree?

Dr. Venter: Exactly, and we consider the database we’re building with all of this to be our most valuable asset for human longevity. We plan to make that broadly accessible in different forms.

GEN: As we’re commemorating 35 years of GEN, we’re looking back on all of the incredible genetic advances that we’ve been privileged to see from our front-row seat. Certainly, you’ve had a hand in many of these advances. Could you highlight a few for us?

Dr. Venter: GEN was there in a big way going all the way back to the development of the shotgun sequencing technique. Thinking about the two-year global ocean sampling expedition, which began in 2003 aboard the deck of the Sorcerer II sailboat, I would say that 90% of the novel genes that are available to the scientific community came from the microbes we collected.

That program is still ongoing at the Institute, which is doing microbial ocean and environmental analysis. That work led to a novel experiment doing shotgun sequencing of the human gut microbe. Karen Nelson, Ph.D., who is now president of JCVI, led the team that did that microbiome sequencing study.

We also have fundamental human research going on at the Institute, such as the “N of 1” genome survey program. We are monitoring a 16-year-old girl whose younger brother died at age 12 from neuroblastoma. She has multiple mutated oncogenes that give her a high risk of developing cancer. She is active and healthy with no sign of disease, but she is monitored on a relatively constant basis. This puts into action our thoughts behind human longevity—early detection, early prevention, or early action. If or when she develops cancer, it would be detected at the phase 0 or phase 1 stage and could be treated immediately.

Knowing you are at increased risk for disease but not doing anything about it doesn’t change anything. I use myself as an example. Because my genome was the first one sequenced, I learned early on that I had an increased risk for melanoma, so I learned to recognize melanoma at its earliest stage. When I developed a lesion on my back I recognized it immediately as a melanoma and had it surgically removed. It had not penetrated the dermis, so having it surgically excised was all that was needed.

Had I not recognized what it was and waited 6 months or a year to have it looked at, the outcome might have been quite different. It could have been much more difficult and costly to treat, and surgery might not necessarily have been 100% effective. Early detection allows for early action, better treatment options, and the potential for better outcomes.

“Critical Tools and Technologies in Synthetic Genomics” is part 2 of a 2 part interview with Craig Venter. Part 1 appeared in the March 1 issue of GEN.