Tom Maniatis, PhD, the Isidore S. Edelman Professor of Biochemistry and chair of biochemistry & molecular biophysics at P&S, was one of the original members of a universitywide task force named by Columbia President Lee Bollinger in February 2014 to plan ways to realize the promise of precision medicine, especially in genomics, data science, and the core science and engineering disciplines.
Dr. Maniatis, one of the pioneers of modern molecular biology and a cofounder of the New York Genome Center, now directs Columbia’s precision medicine initiative. Here, Dr. Maniatis discusses the field and progress made by the initiative.
What is precision medicine?
In the context of the universitywide initiative, precision medicine is the process by which we establish the ability to deliver personalized medicine. At Columbia, that’s a multidisciplinary effort to achieve the ultimate goal of diagnosing and treating disease on the basis of genetic information. It includes every aspect of health care delivery, from basic science, to human genetics and diagnostics, to genetic counseling, patient consent, law, and the economics and politics of health care.
Does it represent a major shift in terms of treating the patient as an individual?
Absolutely. Personalized medicine will make it possible to design medical treatments based on the DNA sequence of an individual. Nothing is more personal than that. Now, MDs often say, “We’ve been doing personalized medicine since Aristotle.” I understand that. But this is different in the sense that we have a much more direct and deeper understanding of the connections among genetics, disease, and medical care, and we are developing the means of translating this information into personal health care.
Some have expressed frustration that the great promise of genetic medicine hasn’t yielded many results. Is that a fair assessment?
Twenty years ago, the thought that we could actually determine the sequence of 3 billion base pairs of DNA was science fiction. I mean, how could we possibly decipher the code of the entire genome? The proposal to sequence the human genome was very controversial. But it happened—because of profound technical advances and a concerted international effort.
The fact that we’re now on the verge of interpreting the relationship between mutations in the genome and disease mechanisms is spectacular.We were then left with a seemingly random list of 3 billion letters (A, G, C, and T) that had to be decoded into interpretable genetic information. It was a mistake at the time for scientists to project expectations for personalized medicine that were clearly not going to happen in the timeframe they implied, and in 2010, Nicholas Wade of the New York Times came down hard on the field, writing that little had happened in the decade since the first human genome was sequenced.
But what happened in that 10 years was profoundly important, because it provided the punctuation and text necessary to transform the seemingly random list of letters into meaningful biological and medical information. It is equivalent to “breaking the code” necessary to identify specific genes and understand how they contribute to normal physiology and how mutations can alter the function of genes and cause human diseases. That’s an amazing advance. It actually surprised me that it was accomplished in only 10 years.
With all the pieces in place, we can explore the universe of gene functions. That’s what cell and molecular biology is: trying to understand the mechanisms by which information is transferred from DNA code into physiological events. We have developed the computer algorithms and hardware to be able to interrogate this genetic information extremely rapidly.
The fact that we’re now on the verge of interpreting the relationship between mutations in the genome and disease mechanisms is spectacular. This information will build on itself in a geometric fashion, because every time we find something new, that finding will lead to an insight into another pathway or disease mechanism. And once your DNA sequence is determined, it will serve as a lifetime permanent medical record and source of information for treatment of your diseases. When a new drug comes along, when a new treatment comes along, when a new insight comes along, the doctor will go back to your sequence and prescribe the appropriate treatment. The more we learn, the more feedback there will be for treatment. That’s something really profound.
Because precision medicine produces smaller subsets of patients—there’s no longer one type of breast cancer but many—some have argued that it is harder to build the large cohorts of patients needed for clinical trials.
The flipside of that argument is that instead of wasting drugs on the 90 percent of individuals who—we can now tell from genetics—will not respond, we’ll dramatically decrease the cost of clinical trials, which is the main argument drug companies make for high drug prices. And once you define who will most likely respond, you prescribe drugs only to those who will benefit. There’s savings at both the clinical trial and delivery end of the drug development process.
What work is Columbia’s precision medicine initiative doing?
We’re in an information-collecting mode. We’re identifying all of the intellectual disciplines on both the Morningside Heights and medical campuses that could contribute to advancing precision medicine. We’ll identify the strengths and weaknesses of those disciplines and formulate a strategy, which will lead to a strategic plan for raising and allocating resources to build physical and intellectual infrastructure. The most visible accomplishment of the initiative is the recruitment of Dr. David Goldstein, an internationally recognized leader in human genetics who is in the process of establishing the Institute of Genetic Medicine (IGM) at Columbia. The IGM will be a center of activities directed toward the application of state-of-the-art genetics and genomics technology to the identification of disease-causing mutations, the understanding of disease mechanisms, and the establishment of a clinical genetics infrastructure. We believe that the IGM will place Columbia among the premier programs in clinical genetics, internationally.
We are currently focusing on programs of similar scale in the area of cancer precision medicine.
We also have held a series of workshops on topics central to precision medicine, ranging from basic science, to technology, to clinical genetics, to big data and bioengineering, with the goal of establishing the information necessary to generate a long-term strategic plan. Success will require a deep and long-term commitment to build and enhance all disciplines and activities that impact on precision medicine.
What’s on the horizon for precision medicine?
One of the most powerful tools that emerged only recently is the ability to edit DNA in living cells. These tools emerged from a very unlikely area of research—how simple bacteria fight off virus infections. These studies led to the discovery of molecules called CRISPRS, which can distinguish between the host bacterial DNA and the DNA of invading viruses. In 2012 bacterial CRISPRS were re-engineered and redeployed to “edit” DNA sequences in human cells. It’s now possible to specifically change a single letter in the 3 billion letter human genome with the objective of introducing disease-causing mutations into cells or model organisms as a means of studying disease mechanisms and ultimately to screen for drugs that can reverse the effects of the mutations. This exciting new technology will revolutionize the way we study human disease mechanisms, and it will lay the groundwork for new possibilities in both gene and stem cell therapy.
Read more about Columbia’s precision medicine initiative.