One of the founders of modern molecular cloning and a recipient of the Lasker prize (America’s Nobel prize), Maniatis is now spearheading a new revolution that will potentially change medicine forever. It’s called Precision Medicine and if you haven’t heard of it, chances are you will have soon.

Imagine sitting down with your GP in the future, having them comb through your genetic DNA, taking into account your individual variability not only in your genes but also environment and lifestyle, and subsequently receiving a personalized prescription for your specific ailment. From some of the most complex diseases to common complaints, the possibilities behind this new science are endless.  Ethical questions have been raised about its efficacy, but while the discussion rages on, there is no doubt, this is the bold future of medicine.

You’re considered something of a legend in the world of genetics. What you accomplished back in the 70’s has been described as “the most transformative event in biological sciences over the past century.” This was the advent of gene cloning. Can you tell us a bit more about your history with that?

Well, I have not heard that quote, but the late 70’s was indeed a time at which a major transition occurred in molecular biology. The focus at that time dramatically changed from studies of the genetics and molecular biology of “simple” organisms (bacteria and the viruses that infect them) to studies of higher organisms, including humans. The study of simple organisms provided fundamental insights into the nature of the genetic code, the “central dogma” of gene expression, and details of genetic mechanisms that universally apply to all organisms.

To be clear, my lab did not invent gene cloning – the concept and early demonstration is credited to Stanley Cohen, Herbert Boyer and Paul Berg.  However my lab developed powerful cloning tools that made it possible to isolate and study individual human genes. In fact we were the first to produce a human genomic DNA “library” and to clone the first human gene – the human b-globin gene.

In order for people to understand this I need to briefly describe how genes work. Human cells have approximately 25,000 genes that “encode” the blueprints for proteins that make up all of the cells in our body. These proteins are not only building blocks (muscle, bone, blood etc.) they form the basis of all human functions from movement to sensory perception, in fact to all brain activities. The primary challenge in the late 70’s was to isolate and study the function of individual genes. This was a remarkable time, and the privilege of being a part of this genetic revolution is deeply gratifying.

You set up a successful privately funded company in 1980 called the Genetics Institute. One of the most significant accomplishments of the company enabled people with hemophilia A or B to live normal lives. How did this occur?

When I was an undergraduate student in zoology at the University of Colorado in Boulder in the mid-60’s the thought of combining science and business was the last thing I could imagine. However fifteen years later my postdoctoral mentor Mark Ptashne and I cofounded Genetics Institute, with the goal of producing therapeutic proteins using recombinant DNA methods (a hybrid between the human DNA and the viral DNA) . The hemophilia A and B programs provide an excellent example of the vision of the company. The strategy was to identify genetic diseases in which critical proteins are not produced because of a mutation. The “normal” gene was then cloned from a healthy individual and stably inserted into a mammalian cell engineered to produce large amounts of the protein in cell culture. No blood is involved in this process, so large amounts of highly purified disease-free protein could be produced and used to treat individuals with the genetic disease hemophilia.

Unfortunately, many blood donors were infected by the AIDS virus, so their disease was unknowingly transmitted not only to hemophilia patients but others who received blood transfusions. The most famous example was Arthur Ashe the great American tennis champion of Wimbledon and the US Open, who was infected by the AIDS through a blood transfusion and later died of AIDS. The production of factor VII and factor IX made it possible for individuals with hemophilia to live normal lives without the fear of being infected by blood-borne diseases including hepatitis.

Precision Medicine is beyond exciting. It has been called the future of medicine and has the capacity essentially to deliver the right treatment to the right person at the right time, every time. Can you articulate for us what exactly precision medicine is?

The concept of Precision or ‘personalized’ medicine is that human diseases can be diagnosed and treated based on an individual’s genetic makeup. This is a complex process that requires progress on many scientific and medical fronts, not all of which have advanced to the point at which they can impact on day to day medical practice. The first step in the process was the determination of the DNA sequence of the human genome, which was accomplished over fifteen years ago by a world-wide multi-billion dollar effort. However in order to identify individual genes and the DNA sequences, required to determine when and where in the body they act over a decade was required to “annotate” the genome. This means determining where these individual genes are located, so they can be read, as a means of understanding what genes do and identifying mutations that cause disease.

Since then, sequencing and computer technology has dramatically advanced, and the cost has precipitously dropped. The determination of an individual genomic sequence is approaching $1000 – well within the range of typical diagnostic assays. However, there is much to be learned about the relationship between mutations in DNA and basic disease mechanisms and in turn the development of new drugs for treating specific diseases. However, there are now clear examples in which this approach has worked, but we have a long way to go before the full impact of precision medicine will be felt. The good news is that both genetic diagnosis and drug development are cumulative – that is, the more we advance, the more diseases that will be treatable or even cured by this approach. The full impact will also require major changes in how medicine is practiced and funded.

When we traded emails initially you were suspicious of doing this feature as you said the press have misinterpreted a lot about precision medicine. Can articulate for us what exactly you meant?

Basically some members of the scientific community over-promised and under-estimated the complexity. Thus, precision medicine become a buzz word that has been somewhat misunderstood. The fact that precision medicine is not widely practiced a decade later has led to much skepticism.  However, as I mentioned, there is real progress and most scientists and doctors would generally agree that

Vertex Pharmaceuticals released a drug called Kalydeco that helped address the genetic cause of cystic fibrosis, even curing some patients of this horrible disease. The Food and Drug Administration approved Kalydeco in 2012 in a review that took just three months rather than the standard ten or accelerated six. Do you think these kinds of decisions are preemptive and indicative of a frenzy of sorts or part of a new way of delivering drugs faster?

There is a constant tension between patients wanting to have access to new drugs and the FDA ensuring that drugs are safe and effective. This is a very complex conflict but I believe that the FDA has made great progress in finding the sweet spot between safety and demand. In fact, the opposite concern has been argued, that it takes too long for the FDA to approve drugs that could save lives and suffering. There will almost certainly continue to be tension between faster approval and safety concerns but I believe that the FDA will adjust the approval process to optimize benefits and reduce risks of new drugs.

We are coming up on one year since President Obama, in his State of the Union address, committed the nation to a $215 million investment in Precision Medicine. What has happened since that announcement?

The process has been moving forward. Planning the roll out of large scale initiatives requires time and discussion. Ultimately the whole genome sequences of millions of individuals will be determined, along with clinical data. The process is not only technically complex, matters such as consent, privacy and other ethical issues must be carefully considered. Perhaps the most serious problem is funding the program. The NIH budget has decreased over the past decade and there are many competing and important alternatives, most importantly basic funding. The promise of precision medicine will never be realized if fundamental knowledge is not advanced through robust basic research, the two go hand in hand. The future of precision medicine will depend on achieving the right balance between basic and translational research, and both require funding as a national priority. Considering the current dysfunction of the political system and differences in spending priorities this will be a challenge.

I’ve seen articles arguing that we should be focusing on preventive medicine instead of precision medicine. What is your take on this?

Both are important but certainly not mutually exclusive. It would be a mistake to slow down on either front. A perfect example of this is a recent study clearly showing that different individuals can consume identical diets and display radically different metabolisms as a consequence of differences in their genetics and the nature of their gut microbiomes. This is a perfect coalescence of preventive and precision medicine, whereby behavior (in this case diet) is adjusted on the basis of genetics and biology.

We just ran a story about CRISPR (Clustered regularly-interspaced short palindromic repeats.) What implications does this new technology have on precision medicine?

This extraordinary new DNA editing technology has already had a profound impact on basic science and studies of disease mechanisms. The time required to rigorously determine fundamental biological processes has been dramatically reduced. The use of this technology to actually treat diseases is further off but interesting possibilities are already emerging, as indicated by the founding of several well funded DNA editing biotech companies. Of course, genetic manipulation of the human genome raises ethical issues which are currently being widely discussed. These issues range from safety to religion. Should mankind edit their own genomes to engineer future generations?

There are a lot of universities across the world that are in this precision medicine race. Notre Dame, Columbia, Stanford, the list goes on. Are they all in it for people’s best interests or just the next windfall financially?

I cannot speak for other initiatives but I can assure you that at Columbia the prospect of a financial windfall is far overshadowed by the cost for building the scientific and medical infrastructure, which will have to come from philanthropy, government and private foundation grants and partnerships with industry. Of course there could be big payoffs for major breakthroughs, but that is not a driving force.

So just how much private investment excitement is there in this as opposed to government spending?

The majority of biotech startups are in one way or another connected to precision medicine, all using a combination of genetics and genomics to address the identification of therapeutic targets and to develop both the data and the computer algorithms to cure diseases. I’m not familiar with the numbers but I would not be surprised if the investment in commercial activities exceeds that of the government.

It was said by Obama, “Gone might be the days when wasteful medicine and wasteful prescriptions and wasteful consultations cause a mismanaged health economy.” Can you elaborate on what he was specifically talking about?

The point here is that if you carry out clinical trials with patients that will likely benefit from the drug based on their genetics, the cost of clinical trials will be far less, since those who will clearly not benefit will not be tested. Similarly, once the drug is approved only those with the right genetics will be given the drug, thus saving the cost of administering the drug to those who will be unlikely to benefit. Of course, in both cases rigorous research is required to definitively show the specificity of the drug treatment so that individuals who might benefit will not be deprived.

How far away are we from a realistic working model of precision medicine?

I believe that we are already seeing examples of this, and they will continue at an accelerating rate over the next decade. The basic outline is clear and I believe the proof of principle will be strongly demonstrated during the next decade.

Let’s talk about the insidious side for a moment. It’s easy to imagine that with all these good intentions will also come the ethically questionable. What about a time when people can deliver ‘precision harm’? For instance, the creation of a disease that only affects a certain proportion of the population with that gene code.

There’s an insidious side to all technology and I believe that it would be a mistake to prohibit advances that could provide overwhelming benefits out of a fear that the technology would be abused. Politicians and political movements must work to prevent abuse, just as it has for other technologies. For example, similar arguments were made about the abuses of recombinant DNA technologies in the 1970’s and over forty years later, virtually none of the doomsday scenarios actually occurred. Instead enormous progress was made in advancing the fundamental understanding of biology and many life-saving drugs were developed using the technology.

One of the more interesting critiques of precision medicine has been that doctors and GPs will be unable to interpret genetic tests or communicate results accurately to their patients. What do you make of that? Not to mention that if precision drugs were available they would be out of the reach of most ordinary citizens in terms of cost.

I agree with those concerns and that is why those two problems are central to Columbia’s precision medicine initiative. Education is key to the answer of the first problem. We believe that we have to start now to educate doctors, nurses and genetic councillors. If precision medicine succeeds, health care will be practiced in an entirely different way and it will require doctors to be knowledgeable in genetics, genomics and precision medicine, as well as a supportive infrastructure of professionals trained in the generation and interpretation of genetic data.

The second problem is very real, as we have seen from recent price increases in drugs used in targeted therapies. In addition, healthcare inequities are clearly an important issue but no more important than they currently are. The Columbia precision medicine initiative is devoting significant effort to this problem through joint efforts between the medical school and the arts and science campus. I’m optimistic that these problems will be addressed. They have to be.

Another critique of precision medicine has been that very few ailments are due to a single gene or even a small group of genes. What’s your response to this implication?

This is absolutely correct. Most genetic diseases are in fact complex. However the more genetic sequencing data we obtain for specific diseases and controls, the more the complexity is revealed. My laboratory is deeply involved in research of the disease Amyotrophic Lateral Sclerosis (ALS or better known as Lou Gherig’s disease). The motor neuron disease which leads to complete paralysis was first described over 100 years ago and there is yet an effective treatment, due in large measure to the genetic complexity.

However as the genetic technology has advanced, nearly 25 genes have been shown to be specifically associated with patients with ALS. Many of these genes encode proteins that have been shown to play fundamental roles in specific physiological pathways for which drugs are available. A better understanding of these pathways in the emerging field of ‘systems biology’ will make it possible to target key regulators of these pathways with drugs and thereby treat complex genetic diseases. The application of the most sophisticated mathematics to complex genetic data is leading to exciting new insights and this will continue to advance in the near future. Thus, I would make the opposite argument made by your critic.  Precision medicine through genetic and genomic studies in conjunction with advance in basic biology is the only way we will be able to understand and treat complex genetic diseases such as ALS, Alzheimers and Parkinson’s disease.

You’ve won America’s version of the Noble prize, the Lasker Award. Do those type of awards encourage you to do greater work in your profession? What do they mean to you?

I am, of course, deeply honored by the recognition, but most scientists feel that such recognition has both positive and negative impacts on the scientific enterprise. On the positive side, these honors bring major scientific advances to the attention of the public and this leads to a better understanding of science and sometimes more funding of research. It also celebrates exciting breakthroughs by the many individuals in the field.

The negative impact of these honors is that it conveys an inaccurate impression of how scientific discoveries are made. In most cases breakthroughs in science are made possible on the basis of years of research by large numbers of scientists. Those honored are singled out because of a particularly significant advance, but that advance would not have been possible without the important contributions of many. This is especially true of genetics and genomics which has become a consortium-based activity involving literally hundreds of scientists. I believe that we need to find a way of honoring and celebrating breakthrough science by a different mechanism that acknowledges how science is actually practiced.

Last year you launched a new gut-brain biotech ‘Kallyope’ with the aim of “understanding how the gut communicates with other organs and our brains about our physiological, metabolic and internal state.” We interviewed Stanford scientists Justin and Erica Sonnenburg who work in a similar area. This field looks very exciting and also quite hyped. Would you agree? And if so can you elaborate on what you will try and do over the next few years at Kallyope?

I haven’t seen your interview but I presume it concerned the microbiome, which I agree is quite hyped but nevertheless of enormous potential. We believe that Kallyope is currently unique. It is the only company we know of that is taking a multidisciplinary approach to understanding how the brain monitors and controls fundamental physiology, ranging from metabolism to complex behaviors such as sleep, satiety, addiction etc.

This will require the application of technologies ranging from single cell genomics, to brain imaging, to behavioral studies, and we have assembled an outstanding team of young scientists to identify new ways of treating diseases. The technology has moved so rapidly that executing the scientific strategy of the company would not have been possible only a few years ago. I have been fortunate to co-found successful companies that have led to several FDA approved drugs and I believe that Kallyope has the potential of having an even greater impact.

Photos:

1. – Tom Maniatis
2. – Photo of Tom and his colleagues circa. 1976-1978
3. – Tom in his lab at The Maniatis Laboratory at Columbia University
4. – Barack Obama unveiling his support in 2015 for Precision Medicine.